|
1
|
Zhu S, Chen X, Sun L, Li X, Chen Y, Li L, Suo X, Xu C, Ji M, Wang J, Wang H, Zhang L, Meng X, Huang C, Li J. N6-Methyladenosine modification of circDcbld2 in Kupffer cells promotes hepatic fibrosis via targeting miR-144-3p/Et-1 axis. Acta Pharm Sin B 2024. [DOI: 10.1016/j.apsb.2024.11.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2025] Open
|
|
2
|
Tan X, Xiang Y, Shi J, Chen L, Yu D. Targeting NTCP for liver disease treatment: A promising strategy. J Pharm Anal 2024; 14:100979. [PMID: 39310850 PMCID: PMC11415714 DOI: 10.1016/j.jpha.2024.100979] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2023] [Revised: 04/10/2024] [Accepted: 04/15/2024] [Indexed: 09/25/2024] Open
Abstract
The sodium taurocholate co-transporting polypeptide (NTCP), a bile acids transporter, has been identified as a new therapeutic target for the treatment of liver disease. This paper thoroughly investigates the function of NTCP for regulating bile acid regulation, its correlation with hepatitis B and D infections, and its association with various liver diseases. Additionally, in this review we examine recent breakthroughs in creating NTCP inhibitors and their prospective applications in liver disease treatment. While this review emphasizes the promising potential of targeting NTCP, it concurrently underscores the need for broader and more detailed research to fully understand the long-term implications and potential side effects associated with NTCP inhibition.
Collapse
Affiliation(s)
- Xin Tan
- Department of Pharmacy, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610072, China
- Personalized Drug Therapy Key Laboratory of Sichuan Province, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610072, China
| | - Yu Xiang
- College of Medicine, University of Electronic Science and Technology, Chengdu, 610072, China
| | - Jianyou Shi
- Department of Pharmacy, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610072, China
- Personalized Drug Therapy Key Laboratory of Sichuan Province, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610072, China
| | - Lu Chen
- Department of Pharmacy, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610072, China
- Personalized Drug Therapy Key Laboratory of Sichuan Province, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610072, China
- Guanghan People's Hospital, Guanghan, Sichuan, 618300, China
| | - Dongke Yu
- Department of Pharmacy, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610072, China
- Personalized Drug Therapy Key Laboratory of Sichuan Province, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610072, China
| |
Collapse
|
|
3
|
Brea R, Casanova N, Alvarez-Lucena C, Fuertes-Agudo M, Luque-Tevar M, Cucarella C, Capitani MC, Marinochi MV, Fusini ME, Lahoz A, Nogueroles ML, Fraile J, Ronco MT, Boscá L, González-Rodríguez Á, García-Monzón C, Martín-Sanz P, Casado M, Francés DE. Beneficial effects of hepatic cyclooxygenase-2 expression against cholestatic injury after common bile duct ligation in mice. Liver Int 2024; 44:2409-2423. [PMID: 38847511 DOI: 10.1111/liv.16004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2023] [Revised: 05/01/2024] [Accepted: 05/23/2024] [Indexed: 08/30/2024]
Abstract
BACKGROUND AND AIMS Cyclooxygenase-2 (COX-2) is involved in different liver diseases, but little is known about the significance of COX-2 in cholestatic injury. This study was designed to elucidate the role of COX-2 expression in hepatocytes during the pathogenesis of obstructive cholestasis. METHODS We used genetically modified mice constitutively expressing human COX-2 in hepatocytes. Transgenic mice (hCOX-2-Tg) and their wild-type (Wt) littermates were either subjected to a mid-abdominal laparotomy or common bile duct ligation (BDL) for 2 or 5 days. Then, we explored the mechanisms underlying the role of COX-2 and its derived prostaglandins in liver function, and the synthesis and excretion of bile acids (BA) in response to cholestatic liver injury. RESULTS After BDL, hCOX-2-Tg mice showed lower grades of hepatic necrosis and inflammation than Wt mice, in part by a reduced hepatic neutrophil recruitment associated with lower mRNA levels of pro-inflammatory cytokines. Furthermore, hCOX-2-Tg mice displayed a differential metabolic pattern of BA synthesis that led to an improved clearance after BDL-induced accumulation. In addition, an enhanced response to the BDL-induced oxidative stress and hepatic apoptosis was observed. In vitro experiments using hepatic cells that stably express hCOX-2 confirmed the cytoprotective role of prostaglandin E2 against BA toxicity. CONCLUSIONS Taken together, our data indicate that constitutive expression of COX-2 in hepatocytes ameliorates cholestatic liver injury in mice by reducing inflammation and cell damage and by modulating BA metabolism, pointing to a role for COX-2 as a defensive response against cholestasis-derived BA accumulation and injury.
Collapse
Affiliation(s)
- Rocío Brea
- Instituto de Investigaciones Biomédicas Sols-Morreale (IIBM), CSIC-UAM, Madrid, Spain
| | - Natalia Casanova
- Instituto de Investigaciones Biomédicas Sols-Morreale (IIBM), CSIC-UAM, Madrid, Spain
| | | | - Marina Fuertes-Agudo
- Instituto de Biomedicina de Valencia (IBV), CSIC, Valencia, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain
| | - María Luque-Tevar
- Instituto de Biomedicina de Valencia (IBV), CSIC, Valencia, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain
| | - Carme Cucarella
- Instituto de Biomedicina de Valencia (IBV), CSIC, Valencia, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain
| | - María C Capitani
- Instituto de Fisiología Experimental (IFISE-CONICET), Rosario, Argentina
| | - María V Marinochi
- Instituto de Fisiología Experimental (IFISE-CONICET), Rosario, Argentina
| | - Matías E Fusini
- Cátedra de Histología y Embriología Humana-Fac. Cs. Médicas-UNR, Rosario, Argentina
| | | | | | - Juan Fraile
- Instituto de Investigaciones Biomédicas Sols-Morreale (IIBM), CSIC-UAM, Madrid, Spain
| | - María T Ronco
- Instituto de Fisiología Experimental (IFISE-CONICET), Rosario, Argentina
| | - Lisardo Boscá
- Instituto de Investigaciones Biomédicas Sols-Morreale (IIBM), CSIC-UAM, Madrid, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain
| | - Águeda González-Rodríguez
- Instituto de Investigaciones Biomédicas Sols-Morreale (IIBM), CSIC-UAM, Madrid, Spain
- Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, Spain
| | - Carmelo García-Monzón
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain
- Liver Research Unit, Hospital Universitario Santa Cristina, Instituto de Investigación Sanitaria Princesa, Madrid, Spain
| | - Paloma Martín-Sanz
- Instituto de Investigaciones Biomédicas Sols-Morreale (IIBM), CSIC-UAM, Madrid, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain
| | - Marta Casado
- Instituto de Biomedicina de Valencia (IBV), CSIC, Valencia, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain
| | - Daniel E Francés
- Instituto de Fisiología Experimental (IFISE-CONICET), Rosario, Argentina
| |
Collapse
|
|
4
|
Zhuang L, Jia N, Zhang L, Zhang Q, Antwi SO, Sartorius K, Wu K, Sun D, Xi D, Lu Y. Gpbar-1/cAMP/PKA signaling mitigates macrophage-mediated acute cholestatic liver injury via antagonizing NLRP3-ASC inflammasome. Biochim Biophys Acta Mol Basis Dis 2024; 1870:167266. [PMID: 38806072 DOI: 10.1016/j.bbadis.2024.167266] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2023] [Revised: 05/17/2024] [Accepted: 05/20/2024] [Indexed: 05/30/2024]
Abstract
Acute cholestatic liver injury (ACLI) is a disease associated with bile duct obstruction that causes liver inflammation and apoptosis. Although G protein-coupled bile acid receptor1 (Gpbar-1) has diverse metabolic roles, its involvement in ACLI-associated immune activation remains unclear. Liver tissues and blood samples from 20 patients with ACLI and 20 healthy individuals were analyzed using biochemical tests, H&E staining, western blotting, and immunohistochemistry to verify liver damage and expression of Gpbar-1. The expression of Gpbar-1, cAMP/PKA signaling, and the NLRP3 inflammasome was tested in wild-type (WT) and Gpbar-1 knockdown (si-Gpbar-1) mice with ACLI induced by bile duct ligation (BDL) and in primary Kupffer cells (KCs) with or without Gpbar-1-siRNA. The results showed that total bile acids and Gpbar-1 expressions were elevated in patients with ACLI. Gpbar-1 knockdown significantly worsened BDL-induced acute hepatic damage, inflammation, and liver apoptosis in vivo. Knockdown of Gpbar-1 heightened KC sensitivity to lipopolysaccharide (LPS) stimulation. Gpbar-1 activation inhibited LPS-induced pro-inflammatory responses in normal KCs but not in Gpbar-1-knockdown KCs. Notably, NLRP3-ASC inflammasome expression was effectively enhanced by Gpbar-1 deficiency. Additionally, Gpbar-1 directly increased intracellular cAMP levels and PKA phosphorylation, thus disrupting the NLRP3-ASC inflammasome. The pro-inflammatory characteristic of Gpbar-1 deficiency was almost neutralized by the NLRP3 inhibitor CY-09. In vitro, M1 polarization was accelerated in LPS-stimulated Gpbar-1-knockdown KCs. Therapeutically, Gpbar-1 deficiency exacerbated BDL-induced ACLI, which could be rescued by inhibition of the NLRP3-ASC inflammasome. Our study reveal that Gpbar-1 may act as a novel immune-mediated regulator of ACLI by inhibiting the NLRP3-ASC inflammasome.
Collapse
Affiliation(s)
- Lin Zhuang
- The First People's Hospital of Changzhou, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu 213000, China; Department of General Surgery, Wujin Affiliated Hospital of Jiangsu University and The Wujin clinical college of Xuzhou medical university, Changzhou Key Laboratory of Molecular Diagnostics and Precision Cancer Medicine, Wujin Institute of Molecular Diagnostics and Precision Cancer Medicine of Jiangsu University, Changzhou, Jiangsu 213000, China
| | - Naixin Jia
- Department of Hepatobiliary Surgery, Kunshan First People's Hospital affiliated to Jiangsu University, Kunshan, Jiangsu 215300, China
| | - Li Zhang
- The First People's Hospital of Changzhou, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu 213000, China
| | - Qi Zhang
- Department of Oncology, Wujin Affiliated Hospital of Jiangsu University and The Wujin clinical college of Xuzhou Medical University, Changzhou Key Laboratory of Molecular Diagnostics and Precision Cancer Medicine, Wujin Institute of Molecular Diagnostics and Precision Cancer Medicine of Jiangsu University, Changzhou, Jiangsu 213000, China
| | - Samuel O Antwi
- Department of Quantitative Health Sciences, Mayo Clinic, Jacksonville, FL 32224, USA; The Africa Hepatopancreatobiliary Cancer Consortium (AHPBCC), Mayo Clinic, Jacksonville, FL 32224, USA
| | - Kurt Sartorius
- The Africa Hepatopancreatobiliary Cancer Consortium (AHPBCC), Mayo Clinic, Jacksonville, FL 32224, USA; School of Laboratory Medicine and Molecular Sciences, College of Health Sciences, University of Kwazulu-Natal, Durban 4041, South Africa; UKZN Gastrointestinal Cancer Research Unit, University of Kwazulu-Natal, Durban 4041, South Africa
| | - Kejia Wu
- The First People's Hospital of Changzhou, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu 213000, China
| | - Donglin Sun
- The First People's Hospital of Changzhou, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu 213000, China.
| | - Dong Xi
- Department of Oncology, Wujin Affiliated Hospital of Jiangsu University and The Wujin clinical college of Xuzhou Medical University, Changzhou Key Laboratory of Molecular Diagnostics and Precision Cancer Medicine, Wujin Institute of Molecular Diagnostics and Precision Cancer Medicine of Jiangsu University, Changzhou, Jiangsu 213000, China.
| | - Yunjie Lu
- Department of General Surgery, Wujin Affiliated Hospital of Jiangsu University and The Wujin clinical college of Xuzhou medical university, Changzhou Key Laboratory of Molecular Diagnostics and Precision Cancer Medicine, Wujin Institute of Molecular Diagnostics and Precision Cancer Medicine of Jiangsu University, Changzhou, Jiangsu 213000, China; The Africa Hepatopancreatobiliary Cancer Consortium (AHPBCC), Mayo Clinic, Jacksonville, FL 32224, USA; Department of Hepatopancreatobiliary surgery, The First Affiliated Hospital of Soochow University, Suzhou 215100, China.
| |
Collapse
|
|
5
|
Sui B, Wang R, Chen C, Kou X, Wu D, Fu Y, Lei F, Wang Y, Liu Y, Chen X, Xu H, Liu Y, Kang J, Liu H, Kwok RTK, Tang BZ, Yan H, Wang M, Xiang L, Yan X, Zhang X, Ma L, Shi S, Jin Y. Apoptotic Vesicular Metabolism Contributes to Organelle Assembly and Safeguards Liver Homeostasis and Regeneration. Gastroenterology 2024; 167:343-356. [PMID: 38342194 DOI: 10.1053/j.gastro.2024.02.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2023] [Revised: 02/01/2024] [Accepted: 02/04/2024] [Indexed: 02/13/2024]
Abstract
BACKGROUND & AIMS Apoptosis generates plenty of membrane-bound nanovesicles, the apoptotic vesicles (apoVs), which show promise for biomedical applications. The liver serves as a significant organ for apoptotic material removal. Whether and how the liver metabolizes apoptotic vesicular products and contributes to liver health and disease is unrecognized. METHODS apoVs were labeled and traced after intravenous infusion. Apoptosis-deficient mice by Fas mutant (Fasmut) and Caspase-3 knockout (Casp3-/-) were used with apoV replenishment to evaluate the physiological apoV function. Combinations of morphologic, biochemical, cellular, and molecular assays were applied to assess the liver while hepatocyte analysis was performed. Partial hepatectomy and acetaminophen liver failure models were established to investigate liver regeneration and disease recovery. RESULTS We discovered that the liver is a major metabolic organ of circulatory apoVs, in which apoVs undergo endocytosis by hepatocytes via a sugar recognition system. Moreover, apoVs play an indispensable role to counteract hepatocellular injury and liver impairment in apoptosis-deficient mice upon replenishment. Surprisingly, apoVs form a chimeric organelle complex with the hepatocyte Golgi apparatus through the soluble N-ethylmaleimide-sensitive factor attachment protein receptor machinery, which preserves Golgi integrity, promotes microtubule acetylation by regulating α-tubulin N-acetyltransferase 1, and consequently facilitates hepatocyte cytokinesis for liver recovery. The assembly of the apoV-Golgi complex is further revealed to contribute to liver homeostasis, regeneration, and protection against acute liver failure. CONCLUSIONS These findings establish a previously unrecognized functional and mechanistic framework that apoptosis through vesicular metabolism safeguards liver homeostasis and regeneration, which holds promise for hepatic disease therapeutics.
Collapse
Affiliation(s)
- Bingdong Sui
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi Clinical Research Center for Oral Diseases, Shaanxi International Joint Research Center for Oral Diseases, Research and Development Center for Tissue Engineering, The Fourth Military Medical University, Xi'an, Shaanxi, China; Department of Anatomy and Cell Biology, University of Pennsylvania, School of Dental Medicine, Philadelphia, Pennsylvania
| | - Runci Wang
- Department of Anatomy and Cell Biology, University of Pennsylvania, School of Dental Medicine, Philadelphia, Pennsylvania
| | - Chider Chen
- Department of Anatomy and Cell Biology, University of Pennsylvania, School of Dental Medicine, Philadelphia, Pennsylvania
| | - Xiaoxing Kou
- Department of Anatomy and Cell Biology, University of Pennsylvania, School of Dental Medicine, Philadelphia, Pennsylvania; Hospital of Stomatology, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Stomatology, South China Center of Craniofacial Stem Cell Research, Guangzhou, China
| | - Di Wu
- Hospital of Stomatology, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Stomatology, South China Center of Craniofacial Stem Cell Research, Guangzhou, China
| | - Yu Fu
- Hospital of Stomatology, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Stomatology, South China Center of Craniofacial Stem Cell Research, Guangzhou, China
| | - Fangcao Lei
- Hospital of Stomatology, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Stomatology, South China Center of Craniofacial Stem Cell Research, Guangzhou, China
| | - Yanzhuang Wang
- Department of Molecular, Cellular and Developmental Biology, University of Michigan, Ann Arbor, Michigan
| | - Yijing Liu
- Hubei Key Laboratory of Bioinorganic Chemistry and Materia Medica, School of Chemistry and Chemical Engineering, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Xiaoyuan Chen
- Departments of Diagnostic Radiology, Surgery, Chemical and Biomolecular Engineering, and Biomedical Engineering, Yong Loo Lin School of Medicine and College of Design and Engineering, National University of Singapore, Singapore, Singapore; Clinical Imaging Research Centre, Centre for Translational Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore; Nanomedicine Translational Research Program, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore; Institute of Molecular and Cell Biology, Agency for Science, Technology, and Research (A∗STAR), Singapore, Singapore
| | - Hui Xu
- Department of Neurobiology and Collaborative Innovation Center for Brain Science, School of Basic Medicine, The Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Yingying Liu
- Department of Neurobiology and Collaborative Innovation Center for Brain Science, School of Basic Medicine, The Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Junjun Kang
- Department of Neurobiology and Collaborative Innovation Center for Brain Science, School of Basic Medicine, The Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Haixiang Liu
- Department of Chemical and Biological Engineering, Department of Chemistry, The Hong Kong Branch of Chinese National Engineering Research Center for Tissue Restoration and Reconstruction and Institute for Advanced Study, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China
| | - Ryan Tsz Kin Kwok
- Department of Chemical and Biological Engineering, Department of Chemistry, The Hong Kong Branch of Chinese National Engineering Research Center for Tissue Restoration and Reconstruction and Institute for Advanced Study, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China
| | - Ben Zhong Tang
- Shenzhen Institute of Aggregate Science and Technology, School of Science and Engineering, The Chinese University of Hong Kong, Shenzhen, Guangdong, China
| | - Hexin Yan
- Department of Anesthesiology and Critical Care Medicine, Renji Hospital, Jiaotong University School of Medicine, Shanghai, China
| | - Minjun Wang
- Department of Cell Biology, Center for Stem Cell and Medicine, The Second Military Medical University, Shanghai, China
| | - Lei Xiang
- Hospital of Stomatology, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Stomatology, South China Center of Craniofacial Stem Cell Research, Guangzhou, China
| | - Xutong Yan
- Hospital of Stomatology, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Stomatology, South China Center of Craniofacial Stem Cell Research, Guangzhou, China
| | - Xiao Zhang
- Department of Anatomy and Cell Biology, University of Pennsylvania, School of Dental Medicine, Philadelphia, Pennsylvania
| | - Lan Ma
- Department of Anatomy and Cell Biology, University of Pennsylvania, School of Dental Medicine, Philadelphia, Pennsylvania; Hospital of Stomatology, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Stomatology, South China Center of Craniofacial Stem Cell Research, Guangzhou, China
| | - Songtao Shi
- Department of Anatomy and Cell Biology, University of Pennsylvania, School of Dental Medicine, Philadelphia, Pennsylvania; Hospital of Stomatology, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Stomatology, South China Center of Craniofacial Stem Cell Research, Guangzhou, China.
| | - Yan Jin
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi Clinical Research Center for Oral Diseases, Shaanxi International Joint Research Center for Oral Diseases, Research and Development Center for Tissue Engineering, The Fourth Military Medical University, Xi'an, Shaanxi, China.
| |
Collapse
|
|
6
|
Cheng WY, Zeng XX, Cheng P, Zhang JX. Loureirin B ameliorates cholestatic liver fibrosis via AKT/mTOR/ATG7-mediated autophagy of hepatic stellate cells. Eur J Pharmacol 2024; 971:176552. [PMID: 38580181 DOI: 10.1016/j.ejphar.2024.176552] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2024] [Revised: 03/21/2024] [Accepted: 03/28/2024] [Indexed: 04/07/2024]
Abstract
AIM OF THE STUDY Chronic cholestasis leads to liver fibrosis, which lacks effective treatment. In this study, we investigated the role and mechanisms of action of loureirin B (LB) in cholestatic liver fibrosis. MATERIALS AND METHODS Bile duct ligation (BDL)-induced hepatic fibrosis mice were used as in vivo models. Transforming growth factor-β1 (TGF-β1)-pretreated HSC-T6 cells were used to explore the mechanism by which LB attenuates liver fibrosis in vitro. RNA sequencing, quantitative PCR (qPCR), western blotting, immunohistochemistry and immunofluorescence were performed to detect the fibrosis markers and measure autophagy levels. Flow cytometry, cell counting kit-8 (CCK-8) assay, and 5'-ethynyl-2'-deoxyuridine (EdU) assay were conducted to detect cell proliferation and viability. GFP-RFP-LC3 adenovirus, autophagy-related protein 7 (ATG7) siRNA, and bafilomycin A1 (BafA1) were used to verify autophagic flux. RESULTS Our results showed that LB ameliorates liver injury, inhibits collagen deposition, and decreases the expressions of fibrosis-related markers in BDL-induced mouse livers. In vitro, we found that LB inhibited proliferation and migration, promoted apoptosis, and inhibited the activation of HSC-T6 cells pretreated with TGF-β1. RNA sequencing analysis of HSC-T6 cells showed that LB treatment predominantly targeted autophagy-related pathways. Further protein analysis indicated that LB downregulated the expression of phosphorylated AKT (p-AKT) and phosphorylated mTOR (p-mTOR), and upregulated LC3-II, p62, and ATG7 both in vivo and in vitro. Intriguingly, ATG7 inactivation reversed the antifibrotic effects of LB on HSC-T6 cells. CONCLUSIONS LB can improve BDL-induced liver fibrosis by inhibiting the activation and proliferation of HSCs and is expected to be a promising antifibrotic drug.
Collapse
Affiliation(s)
- Wei-Yi Cheng
- Department of Emergency General Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Xi-Xi Zeng
- Department of Anatomy, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China
| | - Ping Cheng
- Department of Emergency General Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Jin-Xiang Zhang
- Department of Emergency General Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
| |
Collapse
|
|
7
|
Li Z, Yang H, Li X, She T, Tao Z, Zhong Y, Su T, Feng Y, Shi Q, Li L, Tian R, Wang S, Cheng J, Cai H, Lu X. Platelet-derived growth factor receptor β-targeted positron emission tomography imaging for the noninvasive monitoring of liver fibrosis. Eur J Nucl Med Mol Imaging 2024; 51:1530-1543. [PMID: 38189910 DOI: 10.1007/s00259-023-06577-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2023] [Accepted: 12/15/2023] [Indexed: 01/09/2024]
Abstract
PURPOSE Noninvasive quantifying activated hepatic stellate cells (aHSCs) by molecular imaging is helpful for assessing disease progression and therapeutic responses of liver fibrosis. Our purpose is to develop platelet-derived growth factor receptor β (PDGFRβ)-targeted radioactive tracer for assessing liver fibrosis by positron emission tomography (PET) imaging of aHSCs. METHODS Comparative transcriptomics, immunofluorescence staining and flow cytometry were used to evaluate PDGFRβ as biomarker for human aHSCs and determine the correlation of PDGFRβ with the severity of liver fibrosis. The high affinity affibody for PDGFRβ (ZPDGFRβ) was labeled with gallium-68 (68Ga) for PET imaging of mice with carbon tetrachloride (CCl4)-induced liver fibrosis. Binding of the [68Ga]Ga-labeled ZPDGFRβ ([68Ga]Ga-DOTA-ZPDGFRβ) for aHSCs in human liver tissues was measured by autoradiography. RESULTS PDGFRβ overexpressed in aHSCs was highly correlated with the severity of liver fibrosis in patients and CCl4-treated mice. The 68Ga-labeled ZPDGFRβ affibody ([68Ga]Ga-DOTA-ZPDGFRβ) showed PDGFRβ-dependent binding to aHSCs. According to the PET imaging, hepatic uptake of [68Ga]Ga-DOTA-ZPDGFRβ increased with the accumulation of aHSCs and collagens in the fibrotic livers of mice. In contrast, hepatic uptake of [68Ga]Ga-DOTA-ZPDGFRβ decreased with spontaneous recovery or treatment of liver fibrosis, indicating that the progression and therapeutic responses of liver fibrosis in mice could be visualized by PDGFRβ-targeted PET imaging. [68Ga]Ga-DOTA-ZPDGFRβ also bound human aHSCs and visualized fibrosis in patient-derived liver tissues. CONCLUSIONS PDGFRβ is a reliable biomarker for both human and mouse aHSCs. PDGFRβ-targeted PET imaging could be used for noninvasive monitoring of liver fibrosis in mice and has great potential for clinical translation.
Collapse
Affiliation(s)
- Zhao Li
- Department of Nuclear Medicine, NHC Key Lab of Transplant Engineering and Immunology, West China Hospital, Sichuan University, Chengdu, 610041, China
- Department of Nuclear Medicine , West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Hao Yang
- Department of Nuclear Medicine, NHC Key Lab of Transplant Engineering and Immunology, West China Hospital, Sichuan University, Chengdu, 610041, China
- Sichuan Provincial Engineering Laboratory of Pathology in Clinical Application, West China Hospital, Sichuan University, Chengdu, 610041, China
- Institutes for Systems Genetics, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Xin Li
- Department of Nuclear Medicine , West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Tianshan She
- Department of Nuclear Medicine, NHC Key Lab of Transplant Engineering and Immunology, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Ze Tao
- Department of Nuclear Medicine, NHC Key Lab of Transplant Engineering and Immunology, West China Hospital, Sichuan University, Chengdu, 610041, China
- Sichuan Provincial Engineering Laboratory of Pathology in Clinical Application, West China Hospital, Sichuan University, Chengdu, 610041, China
- Institutes for Systems Genetics, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Yi Zhong
- Laboratory of Clinical Proteomics and Metabolomics, Institutes for Systems Genetics , West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Tao Su
- Laboratory of Clinical Proteomics and Metabolomics, Institutes for Systems Genetics , West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Yanru Feng
- Department of Nuclear Medicine, NHC Key Lab of Transplant Engineering and Immunology, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Qiuxiao Shi
- Department of Nuclear Medicine, NHC Key Lab of Transplant Engineering and Immunology, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Lin Li
- Department of Nuclear Medicine , West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Rong Tian
- Department of Nuclear Medicine , West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Shisheng Wang
- Laboratory of Clinical Proteomics and Metabolomics, Institutes for Systems Genetics , West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Jingqiu Cheng
- Department of Nuclear Medicine, NHC Key Lab of Transplant Engineering and Immunology, West China Hospital, Sichuan University, Chengdu, 610041, China
- Sichuan Provincial Engineering Laboratory of Pathology in Clinical Application, West China Hospital, Sichuan University, Chengdu, 610041, China
- Institutes for Systems Genetics, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Huawei Cai
- Department of Nuclear Medicine , West China Hospital, Sichuan University, Chengdu, 610041, China.
| | - Xiaofeng Lu
- Department of Nuclear Medicine, NHC Key Lab of Transplant Engineering and Immunology, West China Hospital, Sichuan University, Chengdu, 610041, China.
- Sichuan Provincial Engineering Laboratory of Pathology in Clinical Application, West China Hospital, Sichuan University, Chengdu, 610041, China.
- Institutes for Systems Genetics, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, 610041, China.
| |
Collapse
|
|
8
|
Wu Q, Leng X, Zhang Q, Zhu YZ, Zhou R, Liu Y, Mei C, Zhang D, Liu S, Chen S, Wang X, Lin A, Lin X, Liang T, Shen L, Feng XH, Xia B, Xu P. IRF3 activates RB to authorize cGAS-STING-induced senescence and mitigate liver fibrosis. SCIENCE ADVANCES 2024; 10:eadj2102. [PMID: 38416816 PMCID: PMC10901380 DOI: 10.1126/sciadv.adj2102] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/14/2023] [Accepted: 01/23/2024] [Indexed: 03/01/2024]
Abstract
Cytosolic double-stranded DNA surveillance by cyclic GMP-AMP synthase (cGAS)-Stimulator of Interferon Genes (STING) signaling triggers cellular senescence, autophagy, biased mRNA translation, and interferon-mediated immune responses. However, detailed mechanisms and physiological relevance of STING-induced senescence are not fully understood. Here, we unexpectedly found that interferon regulatory factor 3 (IRF3), activated during innate DNA sensing, forms substantial endogenous complexes in the nucleus with retinoblastoma (RB), a key cell cycle regulator. The IRF3-RB interaction attenuates cyclin-dependent kinase 4/6 (CDK4/6)-mediated RB hyperphosphorylation that mobilizes RB to deactivate E2 family (E2F) transcription factors, thereby driving cells into senescence. STING-IRF3-RB signaling plays a notable role in hepatic stellate cells (HSCs) within various murine models, pushing activated HSCs toward senescence. Accordingly, IRF3 global knockout or conditional deletion in HSCs aggravated liver fibrosis, a process mitigated by the CDK4/6 inhibitor. These findings underscore a straightforward yet vital mechanism of cGAS-STING signaling in inducing cellular senescence and unveil its unexpected biology in limiting liver fibrosis.
Collapse
Affiliation(s)
- Qirou Wu
- MOE Laboratory of Biosystems Homeostasis and Protection, Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou 310058, China
| | - Xiaohong Leng
- MOE Laboratory of Biosystems Homeostasis and Protection, Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou 310058, China
| | - Qian Zhang
- MOE Laboratory of Biosystems Homeostasis and Protection, Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou 310058, China
- Department of Hepatobiliary and Pancreatic Surgery and Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, University School of Medicine, Zhejiang University, Hangzhou 310058, China
| | - Ye-Zhang Zhu
- MOE Laboratory of Biosystems Homeostasis and Protection, Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou 310058, China
| | - Ruyuan Zhou
- MOE Laboratory of Biosystems Homeostasis and Protection, Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou 310058, China
- Department of Hepatobiliary and Pancreatic Surgery and Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, University School of Medicine, Zhejiang University, Hangzhou 310058, China
| | - Yutong Liu
- MOE Laboratory of Biosystems Homeostasis and Protection, Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou 310058, China
| | - Chen Mei
- MOE Laboratory of Biosystems Homeostasis and Protection, Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou 310058, China
| | - Dan Zhang
- MOE Laboratory of Biosystems Homeostasis and Protection, Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou 310058, China
| | - Shengduo Liu
- MOE Laboratory of Biosystems Homeostasis and Protection, Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou 310058, China
- Department of Hepatobiliary and Pancreatic Surgery and Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, University School of Medicine, Zhejiang University, Hangzhou 310058, China
- ZJU-Hangzhou Global Scientific and Technological Innovation Center, Hangzhou 310058, China
| | - Shasha Chen
- MOE Laboratory of Biosystems Homeostasis and Protection, Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou 310058, China
| | - Xiaojian Wang
- Institute of Immunology, Zhejiang University School of Medicine, Hangzhou 310058, China
| | - Aifu Lin
- MOE Laboratory of Biosystem Homeostasis and Protection, College of Life Sciences, Zhejiang University, Hangzhou 310058, China
| | - Xia Lin
- MOE Laboratory of Biosystems Homeostasis and Protection, Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou 310058, China
| | - Tingbo Liang
- Department of Hepatobiliary and Pancreatic Surgery and Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, University School of Medicine, Zhejiang University, Hangzhou 310058, China
- Cancer Center, Zhejiang University, Hangzhou 310058, China
| | - Li Shen
- MOE Laboratory of Biosystems Homeostasis and Protection, Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou 310058, China
| | - Xin-Hua Feng
- MOE Laboratory of Biosystems Homeostasis and Protection, Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou 310058, China
- Department of Thoracic Cancer, Affiliated Hangzhou Cancer Hospital, School of Medicine, Zhejiang University, Hangzhou 310058, China
| | - Bing Xia
- Cancer Center, Zhejiang University, Hangzhou 310058, China
| | - Pinglong Xu
- MOE Laboratory of Biosystems Homeostasis and Protection, Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou 310058, China
- Department of Hepatobiliary and Pancreatic Surgery and Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, University School of Medicine, Zhejiang University, Hangzhou 310058, China
- ZJU-Hangzhou Global Scientific and Technological Innovation Center, Hangzhou 310058, China
- Department of Thoracic Cancer, Affiliated Hangzhou Cancer Hospital, School of Medicine, Zhejiang University, Hangzhou 310058, China
| |
Collapse
|
|
9
|
Dixon ME, Williams M, Pappas SG. Cholangiocarcinoma. Cancer Treat Res 2024; 192:165-184. [PMID: 39212921 DOI: 10.1007/978-3-031-61238-1_9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/04/2024]
Abstract
Cholangiocarcinoma (CC) is a heterogeneous group of malignancies that originates at any point along the biliary tree. CC is an uncommon malignancy as it represents approximately 3% of all gastrointestinal malignancies, though its global incidence is rising. CC can often be asymptomatic in its early stages and as a result, it is frequently diagnosed in later stages, leading to challenges in clinical management.
Collapse
Affiliation(s)
- Matthew E Dixon
- Division of Surgical Oncology, Department of Surgery, Rush University Medical Center, Chicago, IL, USA
| | - Michael Williams
- Division of Surgical Oncology, Department of Surgery, Rush University Medical Center, Chicago, IL, USA
| | - Sam G Pappas
- Division of Surgical Oncology, Department of Surgery, Rush University Medical Center, Chicago, IL, USA.
| |
Collapse
|
|
10
|
Kolaric TO, Kuna L, Covic M, Roguljic H, Matic A, Sikora R, Hefer M, Petrovic A, Mihaljevic V, Smolic R, Bilic-Curcic I, Vcev A, Smolic M. Preclinical Models and Promising Pharmacotherapeutic Strategies in Liver Fibrosis: An Update. Curr Issues Mol Biol 2023; 45:4246-4260. [PMID: 37232739 DOI: 10.3390/cimb45050270] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2023] [Revised: 04/28/2023] [Accepted: 05/10/2023] [Indexed: 05/27/2023] Open
Abstract
Liver fibrosis represents one of the greatest challenges in medicine. The fact that it develops with the progression of numerous diseases with high prevalence (NAFLD, viral hepatitis, etc.) makes liver fibrosis an even greater global health problem. Accordingly, it has received much attention from numerous researchers who have developed various in vitro and in vivo models to better understand the mechanisms underlying fibrosis development. All these efforts led to the discovery of numerous agents with antifibrotic properties, with hepatic stellate cells and the extracellular matrix at the center of these pharmacotherapeutic strategies. This review focuses on the current data on numerous in vivo and in vitro models of liver fibrosis and on various pharmacotherapeutic targets in the treatment of liver fibrosis.
Collapse
Affiliation(s)
- Tea Omanovic Kolaric
- Department of Pharmacology and Biochemistry, Faculty of Dental Medicine and Health, 31000 Osijek, Croatia
- Department of Pharmacology, Faculty of Medicine, 31000 Osijek, Croatia
| | - Lucija Kuna
- Department of Pharmacology and Biochemistry, Faculty of Dental Medicine and Health, 31000 Osijek, Croatia
| | - Marina Covic
- Department of Pharmacology and Biochemistry, Faculty of Dental Medicine and Health, 31000 Osijek, Croatia
| | - Hrvoje Roguljic
- Department of Pharmacology and Biochemistry, Faculty of Dental Medicine and Health, 31000 Osijek, Croatia
- Department of Pharmacology, Faculty of Medicine, 31000 Osijek, Croatia
- Department of Internal Medicine, University Hospital Osijek, 31000 Osijek, Croatia
| | - Anita Matic
- Department of Pharmacology, Faculty of Medicine, 31000 Osijek, Croatia
- Department of Pathophysiology and Physiology with Immunology, Faculty of Dental Medicine and Health, 31000 Osijek, Croatia
| | - Renata Sikora
- Department of Dental Medicine, Faculty of Dental Medicine and Health, 31000 Osijek, Croatia
| | - Marija Hefer
- Department of Physics, Biophysics, and Chemistry, Faculty of Dental Medicine and Health, 31000 Osijek, Croatia
| | - Ana Petrovic
- Department of Pharmacology and Biochemistry, Faculty of Dental Medicine and Health, 31000 Osijek, Croatia
| | - Vjera Mihaljevic
- Department of Pharmacology and Biochemistry, Faculty of Dental Medicine and Health, 31000 Osijek, Croatia
| | - Robert Smolic
- Department of Pharmacology and Biochemistry, Faculty of Dental Medicine and Health, 31000 Osijek, Croatia
| | - Ines Bilic-Curcic
- Department of Pharmacology, Faculty of Medicine, 31000 Osijek, Croatia
- Department of Endocrinology, University Hospital Osijek, 31000 Osijek, Croatia
| | - Aleksandar Vcev
- Department of Pathophysiology and Physiology with Immunology, Faculty of Dental Medicine and Health, 31000 Osijek, Croatia
| | - Martina Smolic
- Department of Pharmacology and Biochemistry, Faculty of Dental Medicine and Health, 31000 Osijek, Croatia
- Department of Pharmacology, Faculty of Medicine, 31000 Osijek, Croatia
| |
Collapse
|
|
11
|
Vitale I, Pietrocola F, Guilbaud E, Aaronson SA, Abrams JM, Adam D, Agostini M, Agostinis P, Alnemri ES, Altucci L, Amelio I, Andrews DW, Aqeilan RI, Arama E, Baehrecke EH, Balachandran S, Bano D, Barlev NA, Bartek J, Bazan NG, Becker C, Bernassola F, Bertrand MJM, Bianchi ME, Blagosklonny MV, Blander JM, Blandino G, Blomgren K, Borner C, Bortner CD, Bove P, Boya P, Brenner C, Broz P, Brunner T, Damgaard RB, Calin GA, Campanella M, Candi E, Carbone M, Carmona-Gutierrez D, Cecconi F, Chan FKM, Chen GQ, Chen Q, Chen YH, Cheng EH, Chipuk JE, Cidlowski JA, Ciechanover A, Ciliberto G, Conrad M, Cubillos-Ruiz JR, Czabotar PE, D'Angiolella V, Daugaard M, Dawson TM, Dawson VL, De Maria R, De Strooper B, Debatin KM, Deberardinis RJ, Degterev A, Del Sal G, Deshmukh M, Di Virgilio F, Diederich M, Dixon SJ, Dynlacht BD, El-Deiry WS, Elrod JW, Engeland K, Fimia GM, Galassi C, Ganini C, Garcia-Saez AJ, Garg AD, Garrido C, Gavathiotis E, Gerlic M, Ghosh S, Green DR, Greene LA, Gronemeyer H, Häcker G, Hajnóczky G, Hardwick JM, Haupt Y, He S, Heery DM, Hengartner MO, Hetz C, Hildeman DA, Ichijo H, Inoue S, Jäättelä M, Janic A, Joseph B, Jost PJ, Kanneganti TD, Karin M, Kashkar H, Kaufmann T, Kelly GL, Kepp O, Kimchi A, Kitsis RN, Klionsky DJ, Kluck R, Krysko DV, Kulms D, Kumar S, Lavandero S, Lavrik IN, Lemasters JJ, Liccardi G, Linkermann A, Lipton SA, Lockshin RA, López-Otín C, Luedde T, MacFarlane M, Madeo F, Malorni W, Manic G, Mantovani R, Marchi S, Marine JC, Martin SJ, Martinou JC, Mastroberardino PG, Medema JP, Mehlen P, Meier P, Melino G, Melino S, Miao EA, Moll UM, Muñoz-Pinedo C, Murphy DJ, Niklison-Chirou MV, Novelli F, Núñez G, Oberst A, Ofengeim D, Opferman JT, Oren M, Pagano M, Panaretakis T, Pasparakis M, Penninger JM, Pentimalli F, Pereira DM, Pervaiz S, Peter ME, Pinton P, Porta G, Prehn JHM, Puthalakath H, Rabinovich GA, Rajalingam K, Ravichandran KS, Rehm M, Ricci JE, Rizzuto R, Robinson N, Rodrigues CMP, Rotblat B, Rothlin CV, Rubinsztein DC, Rudel T, Rufini A, Ryan KM, Sarosiek KA, Sawa A, Sayan E, Schroder K, Scorrano L, Sesti F, Shao F, Shi Y, Sica GS, Silke J, Simon HU, Sistigu A, Stephanou A, Stockwell BR, Strapazzon F, Strasser A, Sun L, Sun E, Sun Q, Szabadkai G, Tait SWG, Tang D, Tavernarakis N, Troy CM, Turk B, Urbano N, Vandenabeele P, Vanden Berghe T, Vander Heiden MG, Vanderluit JL, Verkhratsky A, Villunger A, von Karstedt S, Voss AK, Vousden KH, Vucic D, Vuri D, Wagner EF, Walczak H, Wallach D, Wang R, Wang Y, Weber A, Wood W, Yamazaki T, Yang HT, Zakeri Z, Zawacka-Pankau JE, Zhang L, Zhang H, Zhivotovsky B, Zhou W, Piacentini M, Kroemer G, Galluzzi L. Apoptotic cell death in disease-Current understanding of the NCCD 2023. Cell Death Differ 2023; 30:1097-1154. [PMID: 37100955 PMCID: PMC10130819 DOI: 10.1038/s41418-023-01153-w] [Citation(s) in RCA: 150] [Impact Index Per Article: 75.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2023] [Revised: 03/10/2023] [Accepted: 03/17/2023] [Indexed: 04/28/2023] Open
Abstract
Apoptosis is a form of regulated cell death (RCD) that involves proteases of the caspase family. Pharmacological and genetic strategies that experimentally inhibit or delay apoptosis in mammalian systems have elucidated the key contribution of this process not only to (post-)embryonic development and adult tissue homeostasis, but also to the etiology of multiple human disorders. Consistent with this notion, while defects in the molecular machinery for apoptotic cell death impair organismal development and promote oncogenesis, the unwarranted activation of apoptosis promotes cell loss and tissue damage in the context of various neurological, cardiovascular, renal, hepatic, infectious, neoplastic and inflammatory conditions. Here, the Nomenclature Committee on Cell Death (NCCD) gathered to critically summarize an abundant pre-clinical literature mechanistically linking the core apoptotic apparatus to organismal homeostasis in the context of disease.
Collapse
Affiliation(s)
- Ilio Vitale
- IIGM - Italian Institute for Genomic Medicine, c/o IRCSS Candiolo, Torino, Italy.
- Candiolo Cancer Institute, FPO -IRCCS, Candiolo, Italy.
| | - Federico Pietrocola
- Department of Biosciences and Nutrition, Karolinska Institute, Huddinge, Sweden
| | - Emma Guilbaud
- Department of Radiation Oncology, Weill Cornell Medical College, New York, NY, USA
| | - Stuart A Aaronson
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York City, NY, USA
| | - John M Abrams
- Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Dieter Adam
- Institut für Immunologie, Kiel University, Kiel, Germany
| | - Massimiliano Agostini
- Department of Experimental Medicine, University of Rome Tor Vergata, TOR, Rome, Italy
| | - Patrizia Agostinis
- Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium
- VIB Center for Cancer Biology, Leuven, Belgium
| | - Emad S Alnemri
- Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, PA, USA
| | - Lucia Altucci
- Department of Precision Medicine, University of Campania Luigi Vanvitelli, Naples, Italy
- BIOGEM, Avellino, Italy
| | - Ivano Amelio
- Division of Systems Toxicology, Department of Biology, University of Konstanz, Konstanz, Germany
| | - David W Andrews
- Sunnybrook Research Institute, Toronto, ON, Canada
- Departments of Biochemistry and Medical Biophysics, University of Toronto, Toronto, ON, Canada
| | - Rami I Aqeilan
- Hebrew University of Jerusalem, Lautenberg Center for Immunology & Cancer Research, Institute for Medical Research Israel-Canada (IMRIC), Faculty of Medicine, Jerusalem, Israel
| | - Eli Arama
- Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel
| | - Eric H Baehrecke
- Department of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA, USA
| | - Siddharth Balachandran
- Blood Cell Development and Function Program, Fox Chase Cancer Center, Philadelphia, PA, USA
| | - Daniele Bano
- Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Bonn, Germany
| | - Nickolai A Barlev
- Department of Biomedicine, Nazarbayev University School of Medicine, Astana, Kazakhstan
| | - Jiri Bartek
- Department of Medical Biochemistry and Biophysics, Science for Life Laboratory, Karolinska Institute, Stockholm, Sweden
- Danish Cancer Society Research Center, Copenhagen, Denmark
| | - Nicolas G Bazan
- Neuroscience Center of Excellence, School of Medicine, Louisiana State University Health New Orleans, New Orleans, LA, USA
| | - Christoph Becker
- Department of Medicine 1, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany
| | - Francesca Bernassola
- Department of Experimental Medicine, University of Rome Tor Vergata, TOR, Rome, Italy
| | - Mathieu J M Bertrand
- VIB-UGent Center for Inflammation Research, Ghent, Belgium
- Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium
| | - Marco E Bianchi
- Università Vita-Salute San Raffaele, School of Medicine, Milan, Italy and Ospedale San Raffaele IRCSS, Milan, Italy
| | | | - J Magarian Blander
- Department of Medicine, Jill Roberts Institute for Research in Inflammatory Bowel Disease, Weill Cornell Medicine, New York, NY, USA
- Department of Microbiology and Immunology, Weill Cornell Medicine, New York, NY, USA
- Sandra and Edward Meyer Cancer Center, New York, NY, USA
| | | | - Klas Blomgren
- Department of Women's and Children's Health, Karolinska Institute, Stockholm, Sweden
- Pediatric Hematology and Oncology, Karolinska University Hospital, Stockholm, Sweden
| | - Christoph Borner
- Institute of Molecular Medicine and Cell Research, Medical Faculty, Albert Ludwigs University of Freiburg, Freiburg, Germany
| | - Carl D Bortner
- Signal Transduction Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, Durham, NC, USA
| | - Pierluigi Bove
- Department of Experimental Medicine, University of Rome Tor Vergata, TOR, Rome, Italy
| | - Patricia Boya
- Centro de Investigaciones Biologicas Margarita Salas, CSIC, Madrid, Spain
| | - Catherine Brenner
- Université Paris-Saclay, CNRS, Institut Gustave Roussy, Aspects métaboliques et systémiques de l'oncogénèse pour de nouvelles approches thérapeutiques, Villejuif, France
| | - Petr Broz
- Department of Immunobiology, University of Lausanne, Epalinges, Vaud, Switzerland
| | - Thomas Brunner
- Department of Biology, University of Konstanz, Konstanz, Germany
| | - Rune Busk Damgaard
- Department of Biotechnology and Biomedicine, Technical University of Denmark, Kongens Lyngby, Denmark
| | - George A Calin
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Center for RNA Interference and Non-Coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Michelangelo Campanella
- Department of Comparative Biomedical Sciences, The Royal Veterinary College, University of London, London, UK
- UCL Consortium for Mitochondrial Research, London, UK
- Department of Biology, University of Rome Tor Vergata, Rome, Italy
| | - Eleonora Candi
- Department of Experimental Medicine, University of Rome Tor Vergata, TOR, Rome, Italy
| | - Michele Carbone
- Thoracic Oncology, University of Hawaii Cancer Center, Honolulu, HI, USA
| | | | - Francesco Cecconi
- Cell Stress and Survival Unit, Center for Autophagy, Recycling and Disease (CARD), Danish Cancer Society Research Center, Copenhagen, Denmark
- Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
- Università Cattolica del Sacro Cuore, Rome, Italy
| | - Francis K-M Chan
- Department of Immunology, Duke University School of Medicine, Durham, NC, USA
| | - Guo-Qiang Chen
- State Key Lab of Oncogene and its related gene, Ren-Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Quan Chen
- College of Life Sciences, Nankai University, Tianjin, China
| | - Youhai H Chen
- Shenzhen Institute of Advanced Technology (SIAT), Shenzhen, Guangdong, China
| | - Emily H Cheng
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Jerry E Chipuk
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - John A Cidlowski
- Signal Transduction Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, Durham, NC, USA
| | - Aaron Ciechanover
- The Technion-Integrated Cancer Center, The Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel
| | | | - Marcus Conrad
- Helmholtz Munich, Institute of Metabolism and Cell Death, Neuherberg, Germany
| | - Juan R Cubillos-Ruiz
- Department of Obstetrics and Gynecology, Weill Cornell Medical College, New York, NY, USA
| | - Peter E Czabotar
- The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia
- Department of Medical Biology, The University of Melbourne, Melbourne, Victoria, Australia
| | | | - Mads Daugaard
- Department of Urologic Sciences, Vancouver Prostate Centre, Vancouver, BC, Canada
| | - Ted M Dawson
- Institute for Cell Engineering and the Departments of Neurology, Neuroscience and Pharmacology & Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Valina L Dawson
- Institute for Cell Engineering and the Departments of Neurology, Neuroscience and Pharmacology & Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Ruggero De Maria
- Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
- Università Cattolica del Sacro Cuore, Rome, Italy
| | - Bart De Strooper
- VIB Centre for Brain & Disease Research, Leuven, Belgium
- Department of Neurosciences, Leuven Brain Institute, KU Leuven, Leuven, Belgium
- The Francis Crick Institute, London, UK
- UK Dementia Research Institute at UCL, University College London, London, UK
| | - Klaus-Michael Debatin
- Department of Pediatrics and Adolescent Medicine, Ulm University Medical Center, Ulm, Germany
| | - Ralph J Deberardinis
- Howard Hughes Medical Institute and Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Alexei Degterev
- Department of Developmental, Molecular and Chemical Biology, Tufts University School of Medicine, Boston, MA, USA
| | - Giannino Del Sal
- Department of Life Sciences, University of Trieste, Trieste, Italy
- International Centre for Genetic Engineering and Biotechnology (ICGEB), Area Science Park-Padriciano, Trieste, Italy
- IFOM ETS, the AIRC Institute of Molecular Oncology, Milan, Italy
| | - Mohanish Deshmukh
- Department of Cell Biology and Physiology, University of North Carolina, Chapel Hill, NC, USA
| | | | - Marc Diederich
- College of Pharmacy, Seoul National University, Seoul, South Korea
| | - Scott J Dixon
- Department of Biology, Stanford University, Stanford, CA, USA
| | - Brian D Dynlacht
- Department of Pathology, New York University Cancer Institute, New York University School of Medicine, New York, NY, USA
| | - Wafik S El-Deiry
- Division of Hematology/Oncology, Brown University and the Lifespan Cancer Institute, Providence, RI, USA
- Legorreta Cancer Center at Brown University, The Warren Alpert Medical School, Brown University, Providence, RI, USA
- Department of Pathology and Laboratory Medicine, The Warren Alpert Medical School, Brown University, Providence, RI, USA
| | - John W Elrod
- Cardiovascular Research Center, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, USA
| | - Kurt Engeland
- Molecular Oncology, University of Leipzig, Leipzig, Germany
| | - Gian Maria Fimia
- Department of Epidemiology, Preclinical Research and Advanced Diagnostics, National Institute for Infectious Diseases 'L. Spallanzani' IRCCS, Rome, Italy
- Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy
| | - Claudia Galassi
- Department of Radiation Oncology, Weill Cornell Medical College, New York, NY, USA
| | - Carlo Ganini
- Department of Experimental Medicine, University of Rome Tor Vergata, TOR, Rome, Italy
- Biochemistry Laboratory, Dermopatic Institute of Immaculate (IDI) IRCCS, Rome, Italy
| | - Ana J Garcia-Saez
- CECAD, Institute of Genetics, University of Cologne, Cologne, Germany
| | - Abhishek D Garg
- Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium
| | - Carmen Garrido
- INSERM, UMR, 1231, Dijon, France
- Faculty of Medicine, Université de Bourgogne Franche-Comté, Dijon, France
- Anti-cancer Center Georges-François Leclerc, Dijon, France
| | - Evripidis Gavathiotis
- Department of Biochemistry, Albert Einstein College of Medicine, New York, NY, USA
- Department of Medicine, Albert Einstein College of Medicine, New York, NY, USA
- Albert Einstein Cancer Center, Albert Einstein College of Medicine, New York, NY, USA
- Institute for Aging Research, Albert Einstein College of Medicine, New York, NY, USA
- Wilf Family Cardiovascular Research Institute, Albert Einstein College of Medicine, New York, NY, USA
| | - Motti Gerlic
- Department of Clinical Microbiology and Immunology, Sackler school of Medicine, Tel Aviv university, Tel Aviv, Israel
| | - Sourav Ghosh
- Department of Neurology and Department of Pharmacology, Yale School of Medicine, New Haven, CT, USA
| | - Douglas R Green
- Department of Immunology, St Jude Children's Research Hospital, Memphis, TN, USA
| | - Lloyd A Greene
- Department of Pathology and Cell Biology, Columbia University, New York, NY, USA
| | - Hinrich Gronemeyer
- Department of Functional Genomics and Cancer, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Illkirch, France
- Centre National de la Recherche Scientifique, UMR7104, Illkirch, France
- Institut National de la Santé et de la Recherche Médicale, U1258, Illkirch, France
- Université de Strasbourg, Illkirch, France
| | - Georg Häcker
- Faculty of Medicine, Institute of Medical Microbiology and Hygiene, Medical Center, University of Freiburg, Freiburg, Germany
- BIOSS Centre for Biological Signalling Studies, University of Freiburg, Freiburg, Germany
| | - György Hajnóczky
- MitoCare Center, Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA, USA
| | - J Marie Hardwick
- Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
- Departments of Molecular Microbiology and Immunology, Pharmacology, Oncology and Neurology, Johns Hopkins Bloomberg School of Public Health and School of Medicine, Baltimore, MD, USA
| | - Ygal Haupt
- VITTAIL Ltd, Melbourne, VIC, Australia
- Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
| | - Sudan He
- Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
- Suzhou Institute of Systems Medicine, Suzhou, Jiangsu, China
| | - David M Heery
- School of Pharmacy, University of Nottingham, Nottingham, UK
| | | | - Claudio Hetz
- Biomedical Neuroscience Institute, Faculty of Medicine, University of Chile, Santiago, Chile
- Center for Geroscience, Brain Health and Metabolism, Santiago, Chile
- Center for Molecular Studies of the Cell, Program of Cellular and Molecular Biology, Institute of Biomedical Sciences, University of Chile, Santiago, Chile
- Buck Institute for Research on Aging, Novato, CA, USA
| | - David A Hildeman
- Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
| | - Hidenori Ichijo
- Laboratory of Cell Signaling, The University of Tokyo, Tokyo, Japan
| | - Satoshi Inoue
- National Cancer Center Research Institute, Tokyo, Japan
| | - Marja Jäättelä
- Cell Death and Metabolism, Center for Autophagy, Recycling and Disease, Danish Cancer Society Research Center, Copenhagen, Denmark
- Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Denmark
| | - Ana Janic
- Department of Medicine and Life Sciences, Pompeu Fabra University, Barcelona, Spain
| | - Bertrand Joseph
- Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Philipp J Jost
- Clinical Division of Oncology, Department of Internal Medicine, Medical University of Graz, Graz, Austria
| | | | - Michael Karin
- Departments of Pharmacology and Pathology, School of Medicine, University of California San Diego, San Diego, CA, USA
| | - Hamid Kashkar
- CECAD Research Center, Institute for Molecular Immunology, University of Cologne, Cologne, Germany
| | - Thomas Kaufmann
- Institute of Pharmacology, University of Bern, Bern, Switzerland
| | - Gemma L Kelly
- The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia
- Department of Medical Biology, The University of Melbourne, Melbourne, Victoria, Australia
| | - Oliver Kepp
- Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Center, Université Paris Saclay, Villejuif, France
- Centre de Recherche des Cordeliers, Equipe labellisée par la Ligue contre le cancer, Université de Paris, Sorbonne Université, Inserm U1138, Institut Universitaire de France, Paris, France
| | - Adi Kimchi
- Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel
| | - Richard N Kitsis
- Department of Biochemistry, Albert Einstein College of Medicine, New York, NY, USA
- Department of Medicine, Albert Einstein College of Medicine, New York, NY, USA
- Albert Einstein Cancer Center, Albert Einstein College of Medicine, New York, NY, USA
- Institute for Aging Research, Albert Einstein College of Medicine, New York, NY, USA
- Department of Cell Biology, Albert Einstein College of Medicine, New York, NY, USA
- Einstein-Mount Sinai Diabetes Research Center, Albert Einstein College of Medicine, New York, NY, USA
| | | | - Ruth Kluck
- The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia
- Department of Medical Biology, The University of Melbourne, Melbourne, Victoria, Australia
| | - Dmitri V Krysko
- Cell Death Investigation and Therapy Lab, Department of Human Structure and Repair, Ghent University, Ghent, Belgium
- Cancer Research Institute Ghent (CRIG), Ghent, Belgium
| | - Dagmar Kulms
- Department of Dermatology, Experimental Dermatology, TU-Dresden, Dresden, Germany
- National Center for Tumor Diseases Dresden, TU-Dresden, Dresden, Germany
| | - Sharad Kumar
- Centre for Cancer Biology, University of South Australia, Adelaide, SA, Australia
- Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide, SA, Australia
| | - Sergio Lavandero
- Universidad de Chile, Facultad Ciencias Quimicas y Farmaceuticas & Facultad Medicina, Advanced Center for Chronic Diseases (ACCDiS), Santiago, Chile
- Department of Internal Medicine, Cardiology Division, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Inna N Lavrik
- Translational Inflammation Research, Medical Faculty, Otto von Guericke University, Magdeburg, Germany
| | - John J Lemasters
- Departments of Drug Discovery & Biomedical Sciences and Biochemistry & Molecular Biology, Medical University of South Carolina, Charleston, SC, USA
| | - Gianmaria Liccardi
- Center for Biochemistry, Medical Faculty, University of Cologne, Cologne, Germany
| | - Andreas Linkermann
- Division of Nephrology, Department of Internal Medicine 3, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
- Biotechnology Center, Technische Universität Dresden, Dresden, Germany
| | - Stuart A Lipton
- Neurodegeneration New Medicines Center and Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, USA
- Department of Neurosciences, University of California, San Diego, School of Medicine, La Jolla, CA, USA
- Department of Neurology, Yale School of Medicine, New Haven, CT, USA
| | - Richard A Lockshin
- Department of Biology, Queens College of the City University of New York, Flushing, NY, USA
- St. John's University, Jamaica, NY, USA
| | - Carlos López-Otín
- Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Instituto Universitario de Oncología (IUOPA), Universidad de Oviedo, Oviedo, Spain
| | - Tom Luedde
- Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Duesseldorf, Heinrich Heine University, Duesseldorf, Germany
| | - Marion MacFarlane
- Medical Research Council Toxicology Unit, University of Cambridge, Cambridge, UK
| | - Frank Madeo
- Institute of Molecular Biosciences, NAWI Graz, University of Graz, Graz, Austria
- BioTechMed Graz, Graz, Austria
- Field of Excellence BioHealth - University of Graz, Graz, Austria
| | - Walter Malorni
- Center for Global Health, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Gwenola Manic
- IIGM - Italian Institute for Genomic Medicine, c/o IRCSS Candiolo, Torino, Italy
- Candiolo Cancer Institute, FPO -IRCCS, Candiolo, Italy
| | - Roberto Mantovani
- Dipartimento di Bioscienze, Università degli Studi di Milano, Milano, Italy
| | - Saverio Marchi
- Department of Clinical and Molecular Sciences, Marche Polytechnic University, Ancona, Italy
| | - Jean-Christophe Marine
- VIB Center for Cancer Biology, Leuven, Belgium
- Department of Oncology, KU Leuven, Leuven, Belgium
| | | | - Jean-Claude Martinou
- Department of Cell Biology, Faculty of Sciences, University of Geneva, Geneva, Switzerland
| | - Pier G Mastroberardino
- Department of Molecular Genetics, Rotterdam, the Netherlands
- IFOM-ETS The AIRC Institute for Molecular Oncology, Milan, Italy
- Department of Life, Health, and Environmental Sciences, University of L'Aquila, L'Aquila, Italy
| | - Jan Paul Medema
- Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
- Oncode Institute, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Patrick Mehlen
- Apoptosis, Cancer, and Development Laboratory, Equipe labellisée 'La Ligue', LabEx DEVweCAN, Centre de Recherche en Cancérologie de Lyon, INSERM U1052-CNRS UMR5286, Centre Léon Bérard, Université de Lyon, Université Claude Bernard Lyon1, Lyon, France
| | - Pascal Meier
- The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, UK
| | - Gerry Melino
- Department of Experimental Medicine, University of Rome Tor Vergata, TOR, Rome, Italy
| | - Sonia Melino
- Department of Chemical Science and Technologies, University of Rome Tor Vergata, Rome, Italy
| | - Edward A Miao
- Department of Immunology, Duke University School of Medicine, Durham, NC, USA
| | - Ute M Moll
- Department of Pathology and Stony Brook Cancer Center, Renaissance School of Medicine, Stony Brook University, Stony Brook, NY, USA
| | - Cristina Muñoz-Pinedo
- Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), L'Hospitalet de Llobregat, Spain
| | - Daniel J Murphy
- School of Cancer Sciences, University of Glasgow, Glasgow, UK
- Cancer Research UK Beatson Institute, Glasgow, UK
| | | | - Flavia Novelli
- Thoracic Oncology, University of Hawaii Cancer Center, Honolulu, HI, USA
| | - Gabriel Núñez
- Department of Pathology and Rogel Cancer Center, The University of Michigan, Ann Arbor, MI, USA
| | - Andrew Oberst
- Department of Immunology, University of Washington, Seattle, WA, USA
| | - Dimitry Ofengeim
- Rare and Neuroscience Therapeutic Area, Sanofi, Cambridge, MA, USA
| | - Joseph T Opferman
- Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN, USA
| | - Moshe Oren
- Department of Molecular Cell Biology, The Weizmann Institute, Rehovot, Israel
| | - Michele Pagano
- Department of Biochemistry and Molecular Pharmacology, New York University Grossman School of Medicine and Howard Hughes Medical Institute, New York, NY, USA
| | - Theocharis Panaretakis
- Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
- Department of GU Medical Oncology, MD Anderson Cancer Center, Houston, TX, USA
| | | | - Josef M Penninger
- IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Vienna, Austria
- Department of Medical Genetics, Life Sciences Institute, University of British Columbia, Vancouver, Canada
| | | | - David M Pereira
- REQUIMTE/LAQV, Laboratório de Farmacognosia, Departamento de Química, Faculdade de Farmácia, Universidade do Porto, Porto, Portugal
| | - Shazib Pervaiz
- Department of Physiology, YLL School of Medicine, National University of Singapore, Singapore, Singapore
- NUS Centre for Cancer Research (N2CR), National University of Singapore, Singapore, Singapore
- National University Cancer Institute, NUHS, Singapore, Singapore
- ISEP, NUS Graduate School, National University of Singapore, Singapore, Singapore
| | - Marcus E Peter
- Department of Medicine, Division Hematology/Oncology, Northwestern University, Chicago, IL, USA
| | - Paolo Pinton
- Department of Medical Sciences, University of Ferrara, Ferrara, Italy
| | - Giovanni Porta
- Center of Genomic Medicine, Department of Medicine and Surgery, University of Insubria, Varese, Italy
| | - Jochen H M Prehn
- Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland (RCSI) University of Medicine and Health Sciences, Dublin 2, Ireland
| | - Hamsa Puthalakath
- Department of Biochemistry and Chemistry, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, VIC, Australia
| | - Gabriel A Rabinovich
- Laboratorio de Glicomedicina. Instituto de Biología y Medicina Experimental (IBYME), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
| | | | - Kodi S Ravichandran
- VIB-UGent Center for Inflammation Research, Ghent, Belgium
- Division of Immunobiology, Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA
- Center for Cell Clearance, Department of Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, VA, USA
| | - Markus Rehm
- Institute of Cell Biology and Immunology, University of Stuttgart, Stuttgart, Germany
| | - Jean-Ehrland Ricci
- Université Côte d'Azur, INSERM, C3M, Equipe labellisée Ligue Contre le Cancer, Nice, France
| | - Rosario Rizzuto
- Department of Biomedical Sciences, University of Padua, Padua, Italy
| | - Nirmal Robinson
- Centre for Cancer Biology, University of South Australia, Adelaide, SA, Australia
| | - Cecilia M P Rodrigues
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
| | - Barak Rotblat
- Department of Life sciences, Ben Gurion University of the Negev, Beer Sheva, Israel
- The NIBN, Beer Sheva, Israel
| | - Carla V Rothlin
- Department of Immunobiology and Department of Pharmacology, Yale School of Medicine, New Haven, CT, USA
| | - David C Rubinsztein
- Department of Medical Genetics, Cambridge Institute for Medical Research, Cambridge, UK
- UK Dementia Research Institute, University of Cambridge, Cambridge Institute for Medical Research, Cambridge, UK
| | - Thomas Rudel
- Microbiology Biocentre, University of Würzburg, Würzburg, Germany
| | - Alessandro Rufini
- Dipartimento di Bioscienze, Università degli Studi di Milano, Milano, Italy
- University of Leicester, Leicester Cancer Research Centre, Leicester, UK
| | - Kevin M Ryan
- School of Cancer Sciences, University of Glasgow, Glasgow, UK
- Cancer Research UK Beatson Institute, Glasgow, UK
| | - Kristopher A Sarosiek
- John B. Little Center for Radiation Sciences, Harvard School of Public Health, Boston, MA, USA
- Department of Systems Biology, Lab of Systems Pharmacology, Harvard Program in Therapeutics Science, Harvard Medical School, Boston, MA, USA
- Department of Environmental Health, Molecular and Integrative Physiological Sciences Program, Harvard School of Public Health, Boston, MA, USA
| | - Akira Sawa
- Johns Hopkins Schizophrenia Center, Johns Hopkins University, Baltimore, MD, USA
| | - Emre Sayan
- Faculty of Medicine, Cancer Sciences Unit, University of Southampton, Southampton, UK
| | - Kate Schroder
- Institute for Molecular Bioscience, The University of Queensland, St Lucia, QLD, Australia
| | - Luca Scorrano
- Department of Biology, University of Padua, Padua, Italy
- Veneto Institute of Molecular Medicine, Padua, Italy
| | - Federico Sesti
- Department of Neuroscience and Cell Biology, Robert Wood Johnson Medical School, Rutgers University, NJ, USA
| | - Feng Shao
- National Institute of Biological Sciences, Beijing, PR China
| | - Yufang Shi
- Department of Experimental Medicine, University of Rome Tor Vergata, TOR, Rome, Italy
- The Third Affiliated Hospital of Soochow University and State Key Laboratory of Radiation Medicine and Protection, Institutes for Translational Medicine, Soochow University, Suzhou, Jiangsu, China
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai, China
| | - Giuseppe S Sica
- Department of Surgical Science, University Tor Vergata, Rome, Italy
| | - John Silke
- The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia
- Department of Medical Biology, The University of Melbourne, Melbourne, Victoria, Australia
| | - Hans-Uwe Simon
- Institute of Pharmacology, University of Bern, Bern, Switzerland
- Institute of Biochemistry, Brandenburg Medical School, Neuruppin, Germany
| | - Antonella Sistigu
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy
| | | | - Brent R Stockwell
- Department of Biological Sciences and Department of Chemistry, Columbia University, New York, NY, USA
| | - Flavie Strapazzon
- IRCCS Fondazione Santa Lucia, Rome, Italy
- Univ Lyon, Univ Lyon 1, Physiopathologie et Génétique du Neurone et du Muscle, UMR5261, U1315, Institut NeuroMyogène CNRS, INSERM, Lyon, France
| | - Andreas Strasser
- The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia
- Department of Medical Biology, The University of Melbourne, Melbourne, Victoria, Australia
| | - Liming Sun
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China
| | - Erwei Sun
- Department of Rheumatology and Immunology, The Third Affiliated Hospital, Southern Medical University, Guangzhou, China
| | - Qiang Sun
- Laboratory of Cell Engineering, Institute of Biotechnology, Beijing, China
- Research Unit of Cell Death Mechanism, 2021RU008, Chinese Academy of Medical Science, Beijing, China
| | - Gyorgy Szabadkai
- Department of Biomedical Sciences, University of Padua, Padua, Italy
- Department of Cell and Developmental Biology, Consortium for Mitochondrial Research, University College London, London, UK
| | - Stephen W G Tait
- School of Cancer Sciences, University of Glasgow, Glasgow, UK
- Cancer Research UK Beatson Institute, Glasgow, UK
| | - Daolin Tang
- Department of Surgery, The University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA
| | - Nektarios Tavernarakis
- Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology-Hellas, Heraklion, Crete, Greece
- Department of Basic Sciences, School of Medicine, University of Crete, Heraklion, Crete, Greece
| | - Carol M Troy
- Departments of Pathology & Cell Biology and Neurology, Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Irving Medical Center, New York, NY, USA
| | - Boris Turk
- Department of Biochemistry and Molecular and Structural Biology, J. Stefan Institute, Ljubljana, Slovenia
- Faculty of Chemistry and Chemical Technology, University of Ljubljana, Ljubljana, Slovenia
| | - Nicoletta Urbano
- Department of Oncohaematology, University of Rome Tor Vergata, TOR, Rome, Italy
| | - Peter Vandenabeele
- VIB-UGent Center for Inflammation Research, Ghent, Belgium
- Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium
- Methusalem Program, Ghent University, Ghent, Belgium
| | - Tom Vanden Berghe
- VIB-UGent Center for Inflammation Research, Ghent, Belgium
- Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium
- Infla-Med Centre of Excellence, Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium
| | - Matthew G Vander Heiden
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA
- Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA
- Dana-Farber Cancer Institute, Boston, MA, USA
| | | | - Alexei Verkhratsky
- Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK
- Achucarro Center for Neuroscience, IKERBASQUE, Bilbao, Spain
- School of Forensic Medicine, China Medical University, Shenyang, China
- State Research Institute Centre for Innovative Medicine, Vilnius, Lithuania
| | - Andreas Villunger
- Institute for Developmental Immunology, Biocenter, Medical University of Innsbruck, Innsbruck, Austria
- The Research Center for Molecular Medicine (CeMM) of the Austrian Academy of Sciences (OeAW), Vienna, Austria
- The Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases (LBI-RUD), Vienna, Austria
| | - Silvia von Karstedt
- Department of Translational Genomics, Faculty of Medicine and University Hospital Cologne, Cologne, Germany
- CECAD Cluster of Excellence, University of Cologne, Cologne, Germany
- Center for Molecular Medicine Cologne (CMMC), Faculty of Medicine and University Hospital Cologne, Cologne, Germany
| | - Anne K Voss
- The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia
- Department of Medical Biology, The University of Melbourne, Melbourne, Victoria, Australia
| | | | - Domagoj Vucic
- Department of Early Discovery Biochemistry, Genentech, South San Francisco, CA, USA
| | - Daniela Vuri
- Department of Experimental Medicine, University of Rome Tor Vergata, TOR, Rome, Italy
| | - Erwin F Wagner
- Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria
- Department of Dermatology, Medical University of Vienna, Vienna, Austria
| | - Henning Walczak
- Center for Biochemistry, Medical Faculty, University of Cologne, Cologne, Germany
- CECAD Cluster of Excellence, University of Cologne, Cologne, Germany
- Centre for Cell Death, Cancer and Inflammation, UCL Cancer Institute, University College London, London, UK
| | - David Wallach
- Department of Biomolecular Sciences, The Weizmann Institute of Science, Rehovot, Israel
| | - Ruoning Wang
- Center for Childhood Cancer and Blood Diseases, Abigail Wexner Research Institute at Nationwide Children's Hospital, The Ohio State University, Columbus, OH, USA
| | - Ying Wang
- Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai, China
| | - Achim Weber
- University of Zurich and University Hospital Zurich, Department of Pathology and Molecular Pathology, Zurich, Switzerland
- University of Zurich, Institute of Molecular Cancer Research, Zurich, Switzerland
| | - Will Wood
- Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK
| | - Takahiro Yamazaki
- Department of Radiation Oncology, Weill Cornell Medical College, New York, NY, USA
| | - Huang-Tian Yang
- Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai, China
| | - Zahra Zakeri
- Queens College and Graduate Center, City University of New York, Flushing, NY, USA
| | - Joanna E Zawacka-Pankau
- Department of Medicine Huddinge, Karolinska Institute, Stockholm, Sweden
- Department of Biochemistry, Laboratory of Biophysics and p53 protein biology, Medical University of Warsaw, Warsaw, Poland
| | - Lin Zhang
- Department of Pharmacology & Chemical Biology, UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Haibing Zhang
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai, China
| | - Boris Zhivotovsky
- Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
- Faculty of Medicine, Lomonosov Moscow State University, Moscow, Russia
| | - Wenzhao Zhou
- Laboratory of Cell Engineering, Institute of Biotechnology, Beijing, China
- Research Unit of Cell Death Mechanism, 2021RU008, Chinese Academy of Medical Science, Beijing, China
| | - Mauro Piacentini
- Department of Biology, University of Rome Tor Vergata, Rome, Italy
- National Institute for Infectious Diseases IRCCS "Lazzaro Spallanzani", Rome, Italy
| | - Guido Kroemer
- Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Center, Université Paris Saclay, Villejuif, France
- Centre de Recherche des Cordeliers, Equipe labellisée par la Ligue contre le cancer, Université de Paris, Sorbonne Université, Inserm U1138, Institut Universitaire de France, Paris, France
- Institut du Cancer Paris CARPEM, Department of Biology, Hôpital Européen Georges Pompidou, AP-HP, Paris, France
| | - Lorenzo Galluzzi
- Department of Radiation Oncology, Weill Cornell Medical College, New York, NY, USA.
- Sandra and Edward Meyer Cancer Center, New York, NY, USA.
- Caryl and Israel Englander Institute for Precision Medicine, New York, NY, USA.
| |
Collapse
|
|
12
|
Carbonic anhydrase 14 protects the liver against the cytotoxicity of bile acids in a biliary bicarbonate umbrella-related manner. Life Sci 2022; 310:121117. [DOI: 10.1016/j.lfs.2022.121117] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2022] [Revised: 10/18/2022] [Accepted: 10/19/2022] [Indexed: 11/09/2022]
|
|
13
|
Di Ciaula A, Bonfrate L, Baj J, Khalil M, Garruti G, Stellaard F, Wang HH, Wang DQH, Portincasa P. Recent Advances in the Digestive, Metabolic and Therapeutic Effects of Farnesoid X Receptor and Fibroblast Growth Factor 19: From Cholesterol to Bile Acid Signaling. Nutrients 2022; 14:nu14234950. [PMID: 36500979 PMCID: PMC9738051 DOI: 10.3390/nu14234950] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2022] [Revised: 11/18/2022] [Accepted: 11/20/2022] [Indexed: 11/23/2022] Open
Abstract
Bile acids (BA) are amphiphilic molecules synthesized in the liver (primary BA) starting from cholesterol. In the small intestine, BA act as strong detergents for emulsification, solubilization and absorption of dietary fat, cholesterol, and lipid-soluble vitamins. Primary BA escaping the active ileal re-absorption undergo the microbiota-dependent biotransformation to secondary BA in the colon, and passive diffusion into the portal vein towards the liver. BA also act as signaling molecules able to play a systemic role in a variety of metabolic functions, mainly through the activation of nuclear and membrane-associated receptors in the intestine, gallbladder, and liver. BA homeostasis is tightly controlled by a complex interplay with the nuclear receptor farnesoid X receptor (FXR), the enterokine hormone fibroblast growth factor 15 (FGF15) or the human ortholog FGF19 (FGF19). Circulating FGF19 to the FGFR4/β-Klotho receptor causes smooth muscle relaxation and refilling of the gallbladder. In the liver the binding activates the FXR-small heterodimer partner (SHP) pathway. This step suppresses the unnecessary BA synthesis and promotes the continuous enterohepatic circulation of BAs. Besides BA homeostasis, the BA-FXR-FGF19 axis governs several metabolic processes, hepatic protein, and glycogen synthesis, without inducing lipogenesis. These pathways can be disrupted in cholestasis, nonalcoholic fatty liver disease, and hepatocellular carcinoma. Thus, targeting FXR activity can represent a novel therapeutic approach for the prevention and the treatment of liver and metabolic diseases.
Collapse
Affiliation(s)
- Agostino Di Ciaula
- Clinica Medica “A. Murri”, Department of Biomedical Sciences & Human Oncology, University of Bari “Aldo Moro” Medical School, 70124 Bari, Italy
| | - Leonilde Bonfrate
- Clinica Medica “A. Murri”, Department of Biomedical Sciences & Human Oncology, University of Bari “Aldo Moro” Medical School, 70124 Bari, Italy
| | - Jacek Baj
- Department of Anatomy, Medical University of Lublin, 20-059 Lublin, Poland
| | - Mohamad Khalil
- Clinica Medica “A. Murri”, Department of Biomedical Sciences & Human Oncology, University of Bari “Aldo Moro” Medical School, 70124 Bari, Italy
| | - Gabriella Garruti
- Section of Endocrinology, Department of Emergency and Organ Transplantations, University of Bari “Aldo Moro” Medical School, 70124 Bari, Italy
| | - Frans Stellaard
- Institute of Clinical Chemistry and Clinical Pharmacology, Venusberg-Campus 1, University Hospital Bonn, 53127 Bonn, Germany
| | - Helen H. Wang
- Department of Medicine and Genetics, Division of Gastroenterology and Liver Diseases, Marion Bessin Liver Research Center, Einstein-Mount Sinai Diabetes Research Center, Albert Einstein College of Medicine, Bronx, NY 10461, USA
| | - David Q.-H. Wang
- Department of Medicine and Genetics, Division of Gastroenterology and Liver Diseases, Marion Bessin Liver Research Center, Einstein-Mount Sinai Diabetes Research Center, Albert Einstein College of Medicine, Bronx, NY 10461, USA
| | - Piero Portincasa
- Clinica Medica “A. Murri”, Department of Biomedical Sciences & Human Oncology, University of Bari “Aldo Moro” Medical School, 70124 Bari, Italy
- Correspondence: ; Tel.: +39-328-4687215
| |
Collapse
|
|
14
|
Conde de la Rosa L, Goicoechea L, Torres S, Garcia-Ruiz C, Fernandez-Checa JC. Role of Oxidative Stress in Liver Disorders. LIVERS 2022; 2:283-314. [DOI: 10.3390/livers2040023] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/03/2025] Open
Abstract
Oxygen is vital for life as it is required for many different enzymatic reactions involved in intermediate metabolism and xenobiotic biotransformation. Moreover, oxygen consumption in the electron transport chain of mitochondria is used to drive the synthesis of ATP to meet the energetic demands of cells. However, toxic free radicals are generated as byproducts of molecular oxygen consumption. Oxidative stress ensues not only when the production of reactive oxygen species (ROS) exceeds the endogenous antioxidant defense mechanism of cells, but it can also occur as a consequence of an unbalance between antioxidant strategies. Given the important role of hepatocytes in the biotransformation and metabolism of xenobiotics, ROS production represents a critical event in liver physiology, and increasing evidence suggests that oxidative stress contributes to the development of many liver diseases. The present review, which is part of the special issue “Oxidant stress in Liver Diseases”, aims to provide an overview of the sources and targets of ROS in different liver diseases and highlights the pivotal role of oxidative stress in cell death. In addition, current antioxidant therapies as treatment options for such disorders and their limitations for future trial design are discussed.
Collapse
Affiliation(s)
- Laura Conde de la Rosa
- Department of Cell Death and Proliferation, Institute of Biomedical Research of Barcelona (IIBB), CSIC, 08036 Barcelona, Spain
- Liver Unit, Hospital Clinic i Provincial de Barcelona, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain
- Centro de Investigación Biomédica en Red (CIBEREHD), 08036 Barcelona, Spain
| | - Leire Goicoechea
- Department of Cell Death and Proliferation, Institute of Biomedical Research of Barcelona (IIBB), CSIC, 08036 Barcelona, Spain
- Liver Unit, Hospital Clinic i Provincial de Barcelona, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain
- Centro de Investigación Biomédica en Red (CIBEREHD), 08036 Barcelona, Spain
| | - Sandra Torres
- Department of Cell Death and Proliferation, Institute of Biomedical Research of Barcelona (IIBB), CSIC, 08036 Barcelona, Spain
- Liver Unit, Hospital Clinic i Provincial de Barcelona, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain
- Centro de Investigación Biomédica en Red (CIBEREHD), 08036 Barcelona, Spain
| | - Carmen Garcia-Ruiz
- Department of Cell Death and Proliferation, Institute of Biomedical Research of Barcelona (IIBB), CSIC, 08036 Barcelona, Spain
- Liver Unit, Hospital Clinic i Provincial de Barcelona, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain
- Centro de Investigación Biomédica en Red (CIBEREHD), 08036 Barcelona, Spain
- Research Center for ALPD, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
| | - José C. Fernandez-Checa
- Department of Cell Death and Proliferation, Institute of Biomedical Research of Barcelona (IIBB), CSIC, 08036 Barcelona, Spain
- Liver Unit, Hospital Clinic i Provincial de Barcelona, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain
- Centro de Investigación Biomédica en Red (CIBEREHD), 08036 Barcelona, Spain
- Research Center for ALPD, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
| |
Collapse
|
|
15
|
Didamoony MA, Atwa AM, Abd El-Haleim EA, Ahmed LA. Bromelain ameliorates D-galactosamine-induced acute liver injury: role of SIRT1/LKB1/AMPK, GSK3β/Nrf2 and NF-κB p65/TNF-α/caspase-8, -9 signalling pathways. J Pharm Pharmacol 2022; 74:1765-1775. [PMID: 36227279 DOI: 10.1093/jpp/rgac071] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/18/2022] [Indexed: 11/14/2022]
Abstract
OBJECTIVES The present research focused on estimating, for the first time, the potential protective effects of bromelain against D-galactosamine-induced acute liver injury in rats as well as identifying the possible underlying mechanisms. METHODS Silymarin (100 mg/kg/day, p.o.) as a reference drug or bromelain (20 and 40 mg/kg/day, p.o.) were administered for 10 days, and on the 8th day of the experiment, a single dose of galactosamine (400 mg/kg/i.p.) induced acute liver injury. KEY FINDINGS Pretreatment with bromelain improved liver functions and histopathological alterations induced by galactosamine. Bromelain ameliorated oxidative stress by inducing SIRT1 protein expression and increasing LKB1 content. This resulted in phosphorylating the AMPK/GSK3β axis, which stimulated Nrf2 activation in hepatic cells and thus increased the activity of its downstream antioxidant enzymes [HO-1 and NQO1]. Besides, bromelain exerted significant anti-apoptotic and anti-inflammatory effects by suppressing hepatic contents of TNF-α, NF-κB p65, as well as caspase-8 and caspase-9. The protective effects of bromelain40 were proved to be better than silymarin and bromelain20 in most of the assessed parameters. CONCLUSIONS Our results highlight the significant hepatoprotective effects of bromelain against acute liver injury through modulation of SIRT1/LKB1/AMPK, GSK3β/Nrf2 signalling in addition to NF-κB p65/TNF-α/ caspase-8 and -9 pathway.
Collapse
Affiliation(s)
- Manar A Didamoony
- Pharmacology and Toxicology Department, Faculty of Pharmacy, Egyptian Russian University, Egypt
| | - Ahmed M Atwa
- Pharmacology and Toxicology Department, Faculty of Pharmacy, Egyptian Russian University, Egypt
| | - Enas A Abd El-Haleim
- Pharmacology and Toxicology Department, Faculty of Pharmacy, Cairo University, Egypt
| | - Lamiaa A Ahmed
- Pharmacology and Toxicology Department, Faculty of Pharmacy, Cairo University, Egypt
| |
Collapse
|
|
16
|
Wei M, Zhang Y, Zhang H, Huang Z, Miao H, Zhang T, Lu B, Ji L. HMGB1 induced endothelial to mesenchymal transition in liver fibrosis: The key regulation of early growth response factor 1. Biochim Biophys Acta Gen Subj 2022; 1866:130202. [PMID: 35820641 DOI: 10.1016/j.bbagen.2022.130202] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2022] [Revised: 06/29/2022] [Accepted: 07/06/2022] [Indexed: 11/25/2022]
Abstract
BACKGROUND Liver fibrosis has been the focus and difficulty of medical research in the world and its concrete pathogenesis remains unclear. This study aims to observe the high-mobility group box 1 (HMGB1)-induced hepatic endothelial to mesenchymal transition (EndoMT) during the development of hepatic fibrosis, and further to explore the crucial involvement of Egr1 in this process. METHODS Carbon tetrachloride (CCl4), diosbulbin B (DB), N-acetyl-p-aminophenol (APAP) and bile duct ligation (BDL) were used to induce liver fibrosis in mice. Serum HMGB1 content, the occurrence of EndoMT and the production of extracellular matrix (ECM) in vitro and in vivo were detected by Western-blot. RESULTS The elevated serum HMGB1 content, the occurrence of EndoMT, the production of ECM and the activation of Egr1 were observed in mice with liver fibrosis induced by CCl4, DB, APAP or BDL. HMGB1 induced EndoMT and ECM production in human hepatic sinusoidal endothelial cells (HHSECs), and then HHSECs lost the ability to inhibit the activation of hepatic stellate cells (HSCs). The hepatic deposition of collagen, the increased serum HMGB1 content and hepatic EndoMT were further aggravated in Egr1 knockout mice. Natural compound silymarin attenuated liver fibrosis in mice induced by CCl4 via increasing Egr1 nuclear accumulation, decreasing serum HMGB1 content and inhibiting hepatic EndoMT. CONCLUSION Egr1 regulated the expression of HMGB1 that induced hepatic EndoMT, which plays an important role in the development of liver fibrosis. GENERAL SIGNIFICANCE This study provides a novel therapeutic strategy for the treatment of liver fibrosis in clinic.
Collapse
Affiliation(s)
- Mengjuan Wei
- The MOE Key Laboratory for Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines and The SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Yi Zhang
- The MOE Key Laboratory for Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines and The SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Hong Zhang
- The MOE Key Laboratory for Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines and The SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Zhenlin Huang
- The MOE Key Laboratory for Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines and The SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Hui Miao
- The MOE Key Laboratory for Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines and The SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Tianyu Zhang
- The MOE Key Laboratory for Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines and The SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Bin Lu
- The MOE Key Laboratory for Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines and The SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Lili Ji
- The MOE Key Laboratory for Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines and The SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
| |
Collapse
|
|
17
|
Ding Z, Cheng R, Liu J, Zhao Y, Ge W, Yang Y, Xu X, Wang S, Zhang J. The suppression of pancreatic lipase-related protein 2 ameliorates experimental hepatic fibrosis in mice. Biochim Biophys Acta Mol Cell Biol Lipids 2022; 1867:159102. [PMID: 34995790 DOI: 10.1016/j.bbalip.2021.159102] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2021] [Revised: 11/20/2021] [Accepted: 12/15/2021] [Indexed: 11/24/2022]
Abstract
Quiescent hepatic stellate cells (HSCs) store vitamin A as lipid droplets in the cytoplasm. When activated, these cells lose vitamin A and exhibit an increased capacity for proliferation, mobility, contractility, and the synthesis of collagen and other components of the extracellular matrix. Our previous work demonstrated that the lipid hydrolytic gene pancreatic lipase-related protein 2 (mPlrp2) is involved in the hydrolysis of retinyl esters (REs) in the liver. Here, we showed that bile duct ligation (BDL)-induced liver injury triggered the conditional expression of mPlrp2 in livers and describe evidence of a strong relationship between the expression of mPlrp2 and Acta-2, a marker for activated HSCs. RNA interference targeting mPlrp2 inhibited HSC activation and ameliorated hepatic fibrosis induced by BDL in mice. Liver BDL markedly reduced the adenosine level and increased the ratio between S-adenosyl-L-methionine (SAM) and S-adenosyl-L-homocysteine (SAH). Chromatin immunoprecipitation (ChIP) analysis demonstrated an increase in trimethylated histone H3K4 at the mPlrp2 promoter in BDL mice, which was associated with the conditional expression of mPlrp2 in the liver. SAM, a well-known hepatoprotective substance, inhibited mPlrp2 expression and reduced RE hydrolysis in mice with hepatic fibrosis induced by chronic CCl4 treatment. Liver fibrosis induced by CCl4 or BDL was improved in Plrp2-/- mice. Our results reveal that mPlrp2 suppression is a potential approach for treating hepatic fibrosis.
Collapse
Affiliation(s)
- Zhao Ding
- Center for Molecular Metabolism, Nanjing University of Science & Technology, Nanjing, China
| | - Rui Cheng
- Center for Molecular Metabolism, Nanjing University of Science & Technology, Nanjing, China
| | - Junhao Liu
- Center for Molecular Metabolism, Nanjing University of Science & Technology, Nanjing, China
| | - Yang Zhao
- Center for Molecular Metabolism, Nanjing University of Science & Technology, Nanjing, China
| | - Wenhao Ge
- Center for Molecular Metabolism, Nanjing University of Science & Technology, Nanjing, China
| | - Yunxia Yang
- Center for Molecular Metabolism, Nanjing University of Science & Technology, Nanjing, China
| | - Xi Xu
- Center for Molecular Metabolism, Nanjing University of Science & Technology, Nanjing, China
| | - Shiming Wang
- Center for Molecular Metabolism, Nanjing University of Science & Technology, Nanjing, China
| | - Jianfa Zhang
- Center for Molecular Metabolism, Nanjing University of Science & Technology, Nanjing, China.
| |
Collapse
|
|
18
|
Guedes PLR, Carvalho CPF, Carbonel AAF, Simões MJ, Icimoto MY, Aguiar JAK, Kouyoumdjian M, Gazarini ML, Nagaoka MR. Chondroitin Sulfate Protects the Liver in an Experimental Model of Extra-Hepatic Cholestasis Induced by Common Bile Duct Ligation. MOLECULES (BASEL, SWITZERLAND) 2022; 27:molecules27030654. [PMID: 35163920 PMCID: PMC8839946 DOI: 10.3390/molecules27030654] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/13/2021] [Revised: 01/06/2022] [Accepted: 01/12/2022] [Indexed: 12/15/2022]
Abstract
During liver fibrogenesis, there is an imbalance between regeneration and wound healing. The current treatment is the withdrawal of the causing agent; thus, investigation of new and effective treatments is important. Studies have highlighted the action of chondroitin sulfate (CS) in different cells; thus, our aim was to analyze its effect on an experimental model of bile duct ligation (BDL). Adult Wistar rats were subjected to BDL and treated with CS for 7, 14, 21, or 28 days intraperitoneally. We performed histomorphometric analyses on Picrosirius-stained liver sections. Cell death was analyzed according to caspase-3 and cathepsin B activity and using a TUNEL assay. Regeneration was evaluated using PCNA immunohistochemistry. BDL led to increased collagen content with corresponding decreased liver parenchyma. CS treatment reduced total collagen and increased parenchyma content after 21 and 28 days. The treatment also promoted changes in the hepatic collagen type III/I ratio. Furthermore, it was observed that CS treatment reduced caspase-3 activity and the percentage of TUNEL-positive cells after 14 days and cathepsin B activity only after 28 days. The regeneration increased after 14, 21, and 28 days of CS treatment. In conclusion, our study showed a promising hepatoprotective action of CS in fibrogenesis induced by BDL.
Collapse
Affiliation(s)
- Pedro L. R. Guedes
- Department of Medicine, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo 04023-062, Brazil;
| | - Carolina P. F. Carvalho
- Department of Biosciences, Instituto Saúde Sociedade, Universidade Federal de São Paulo, Santos 11015-020, Brazil; (C.P.F.C.); (M.L.G.)
| | - Adriana A. F. Carbonel
- Department of Gynecology, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo 04039-001, Brazil;
| | - Manuel J. Simões
- Department of Morphology and Genetic, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo 04023-900, Brazil;
| | - Marcelo Y. Icimoto
- Department of Biophysics, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo 04039-032, Brazil;
| | - Jair A. K. Aguiar
- Department of Biochemistry, Universidade Federal de Juiz de Fora, Juiz de Fora 36036-900, Brazil;
| | - Maria Kouyoumdjian
- Department of Biochemistry, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo 04023-062, Brazil;
| | - Marcos L. Gazarini
- Department of Biosciences, Instituto Saúde Sociedade, Universidade Federal de São Paulo, Santos 11015-020, Brazil; (C.P.F.C.); (M.L.G.)
| | - Marcia R. Nagaoka
- Department of Biosciences, Instituto Saúde Sociedade, Universidade Federal de São Paulo, Santos 11015-020, Brazil; (C.P.F.C.); (M.L.G.)
- Correspondence:
| |
Collapse
|
|
19
|
Reaction of the Liver upon Long-Term Treatment of Fluoxetine and Atorvastatin Compared with Alcohol in a Mouse Model. J Toxicol 2022; 2021:9974969. [PMID: 35003254 PMCID: PMC8740222 DOI: 10.1155/2021/9974969] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Revised: 08/19/2021] [Accepted: 11/30/2021] [Indexed: 12/19/2022] Open
Abstract
Background Alcoholism is known to cause liver toxicity and is extensively researched. On the other hand, stress, depression, and obesity are interrelated conditions with alcoholism, and their medications would affect the liver itself. In this study, we investigated the effects of the drugs fluoxetine and atorvastatin on the liver and compared with those of alcohol in a mouse model. Methods Comparisons of animals treated with the three drugs were carried out: serum aspartate transaminase (AST), alanine transaminase (ALT), and albumin were measured; liver tumor necrosis factor alpha (TNF alpha) and transforming growth factor beta (TGF beta-1) levels were evaluated; proliferative cells were detected via immunohistochemistry (IHC) targeting on proliferating cell nuclear antigen (PCNA) and minichromosome maintenance complex component 2 (MCM2); for apoptosis, IHC targeting on activated caspase-3 and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) were employed; and histopathology was also documented in all groups. Results For ALT, AST, albumin, and liver TNF alpha, only the ethanol group surged to significantly higher levels. For TGF beta-1, both ethanol and atorvastatin groups reached a significantly higher level. PCNA and MCM2 showed increased proliferation in the livers of all three groups, with the ethanol group having the highest number of positive cells followed by atorvastatin and then the fluoxetine group. As for cell death, both ethanol and fluoxetine groups showed significantly more apoptosis than control in TUNEL and activated caspase-3, while in the atorvastatin group, activated caspase-3 positive cells increased significantly, but the increase in TUNEL-positive cells did not reach statistical significance.
Collapse
|
|
20
|
Meng F, Zong W, Wei X, Tao Y, Wang G, Liao Z, Chen M. Dolomiaea souliei ethyl acetate extract protected against α-naphthylisothiocyanate-induced acute intrahepatic cholestasis through regulation of farnesoid x receptor-mediated bile acid metabolism. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2021; 87:153588. [PMID: 34091148 DOI: 10.1016/j.phymed.2021.153588] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Revised: 04/25/2021] [Accepted: 04/29/2021] [Indexed: 06/12/2023]
Abstract
BACKGROUND Cholestasis is characterized by accumulation of bile components in liver and systemic circulation. Restoration of bile acid homeostasis via activating farnesoid x receptor (FXR) is a promising strategy for the treatment of cholestasis. FXR-SHP (small heterodimer partner) axis plays an important role in maintaining bile acid homeostasis. PURPOSE To investigate the anti-cholestasis effect of Dolomiaea souliei (Franch.) C.Shih (D. souliei) and clarify its underlying mechanism against α-naphthylisothiocyanate (ANIT) induced acute intrahepatic cholestasis. METHODS ANIT-induced Sprague-Dawley rats were employed to investigate the anti-cholestasis effect of D. souliei ethyl acetate extract (DSE). Ursodeoxycholic acid (UDCA) was used as positive control. Bile flow and blood biochemical parameters were measured. Liver histopathological examination was conducted via hematoxylin-eosin staining. Western blot analysis was carried out to evaluate the protein levels related to bile acids metabolism and inflammation. The interactions between FXR and costunolide or dehydrocostus lactone, were conducted by molecular docking experiments. The effect of costunolide and dehydrocostus lactone on aspartate aminotransferase (AST), alanine aminotransferase (ALT) levels and FXR expression were also evaluated using guggulsterone-induced L02 cells. RESULTS DSE could promote bile excretions and protect against ANIT-induced liver damage in cholestasis rats. Protein levels of FXR, SHP, Na+/taurocholate cotransporter (NTCP), bile salt export pump (BSEP), multidrug resistance-associated protein 2 (MRP2) were increased and the expressions of cholesterol 7α-hydroxylase (CYP7A1) and sterol 27-hydroxylase (CYP27A1) were decreased by DSE. Meanwhile, the anti-inflammatory factors, tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6) were also significantly increased, and the pro-inflammatory factor, interleukin-10 (IL-10), was significantly decreased in rats of DSE groups. Molecular docking revealed that costunolide and dehydrocostus lactone could be well docked into the FXR protein molecule, and hydrophobic interactions played the main function. Costunolide could reverse the increased AST and ALT levels and increase the FXR expression in guggulsterone-induced L02 cells. CONCLUSION DSE had an anti-cholestasis effect by activating FXR-SHP axis, inhibiting synthesis of bile acid, and increasing bile secretion, together with inflammatory response and improving liver injury. Costunolide may be the main active component. This study provided a potential therapeutic mechanism for D. souliei as an anti-cholestasis medicine in the treatment of cholestasis liver diseases.
Collapse
Affiliation(s)
- FanCheng Meng
- College of Pharmaceutical Sciences, Key Laboratory of Luminescence Analysis and Molecular Sensing (Ministry of Education), Southwest University, No. 2 Tiansheng Road, Chongqing 400715, P.R. China
| | - Wei Zong
- College of Pharmaceutical Sciences, Key Laboratory of Luminescence Analysis and Molecular Sensing (Ministry of Education), Southwest University, No. 2 Tiansheng Road, Chongqing 400715, P.R. China
| | - XiaoDong Wei
- College of Pharmaceutical Sciences, Key Laboratory of Luminescence Analysis and Molecular Sensing (Ministry of Education), Southwest University, No. 2 Tiansheng Road, Chongqing 400715, P.R. China
| | - YunYi Tao
- College of Pharmaceutical Sciences, Key Laboratory of Luminescence Analysis and Molecular Sensing (Ministry of Education), Southwest University, No. 2 Tiansheng Road, Chongqing 400715, P.R. China
| | - GuoWei Wang
- College of Pharmaceutical Sciences, Key Laboratory of Luminescence Analysis and Molecular Sensing (Ministry of Education), Southwest University, No. 2 Tiansheng Road, Chongqing 400715, P.R. China
| | - ZhiHua Liao
- School of Life Sciences, Southwest University, No. 2 Tiansheng Road, Chongqing 400715, P.R. China
| | - Min Chen
- College of Pharmaceutical Sciences, Key Laboratory of Luminescence Analysis and Molecular Sensing (Ministry of Education), Southwest University, No. 2 Tiansheng Road, Chongqing 400715, P.R. China.
| |
Collapse
|
|
21
|
Gijbels E, Pieters A, De Muynck K, Vinken M, Devisscher L. Rodent models of cholestatic liver disease: A practical guide for translational research. Liver Int 2021; 41:656-682. [PMID: 33486884 PMCID: PMC8048655 DOI: 10.1111/liv.14800] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2020] [Revised: 01/08/2021] [Accepted: 01/15/2021] [Indexed: 12/12/2022]
Abstract
Cholestatic liver disease denotes any situation associated with impaired bile flow concomitant with a noxious bile acid accumulation in the liver and/or systemic circulation. Cholestatic liver disease can be subdivided into different types according to its clinical phenotype, such as biliary atresia, drug-induced cholestasis, gallstone liver disease, intrahepatic cholestasis of pregnancy, primary biliary cholangitis and primary sclerosing cholangitis. Considerable effort has been devoted to elucidating underlying mechanisms of cholestatic liver injuries and explore novel therapeutic and diagnostic strategies using animal models. Animal models employed according to their appropriate applicability domain herein play a crucial role. This review provides an overview of currently available in vivo animal models, fit-for-purpose in modelling different types of cholestatic liver diseases. Moreover, a practical guide and workflow is provided which can be used for translational research purposes, including all advantages and disadvantages of currently available in vivo animal models.
Collapse
Affiliation(s)
- Eva Gijbels
- Department of In Vitro Toxicology and Dermato‐CosmetologyVrije Universiteit BrusselBrusselsBelgium,Gut‐Liver Immunopharmacology Unit, Basic and Applied Medical SciencesLiver Research Center GhentFaculty of Medicine and Health SciencesGhent UniversityGhentBelgium
| | - Alanah Pieters
- Department of In Vitro Toxicology and Dermato‐CosmetologyVrije Universiteit BrusselBrusselsBelgium
| | - Kevin De Muynck
- Gut‐Liver Immunopharmacology Unit, Basic and Applied Medical SciencesLiver Research Center GhentFaculty of Medicine and Health SciencesGhent UniversityGhentBelgium,Hepatology Research UnitInternal Medicine and PaediatricsLiver Research Center GhentFaculty of Medicine and Health SciencesGhent UniversityGhentBelgium
| | - Mathieu Vinken
- Department of In Vitro Toxicology and Dermato‐CosmetologyVrije Universiteit BrusselBrusselsBelgium
| | - Lindsey Devisscher
- Gut‐Liver Immunopharmacology Unit, Basic and Applied Medical SciencesLiver Research Center GhentFaculty of Medicine and Health SciencesGhent UniversityGhentBelgium
| |
Collapse
|
|
22
|
Adomati T, Cham LB, Hamdan TA, Bhat H, Duhan V, Li F, Ali M, Lang E, Huang A, Naser E, Khairnar V, Friedrich SK, Lang J, Friebus-Kardash J, Bergerhausen M, Schiller M, Machlah YM, Lang F, Häussinger D, Ferencik S, Hardt C, Lang PA, Lang KS. Dead Cells Induce Innate Anergy via Mertk after Acute Viral Infection. Cell Rep 2021; 30:3671-3681.e5. [PMID: 32187540 DOI: 10.1016/j.celrep.2020.02.101] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2019] [Revised: 11/13/2019] [Accepted: 02/26/2020] [Indexed: 12/13/2022] Open
Abstract
Infections can result in a temporarily restricted unresponsiveness of the innate immune response, thereby limiting pathogen control. Mechanisms of such unresponsiveness are well studied in lipopolysaccharide tolerance; however, whether mechanisms of tolerance limit innate immunity during virus infection remains unknown. Here, we find that infection with the highly cytopathic vesicular stomatitis virus (VSV) leads to innate anergy for several days. Innate anergy is associated with induction of apoptotic cells, which activates the Tyro3, Axl, and Mertk (TAM) receptor Mertk and induces high levels of interleukin-10 (IL-10) and transforming growth factor β (TGF-β). Lack of Mertk in Mertk-/- mice prevents induction of IL-10 and TGF-β, resulting in abrogation of innate anergy. Innate anergy is associated with enhanced VSV replication and poor survival after infection. Mechanistically, Mertk signaling upregulates suppressor of cytokine signaling 1 (SOCS1) and SOCS3. Dexamethasone treatment upregulates Mertk and enhances innate anergy in a Mertk-dependent manner. In conclusion, we identify Mertk as one major regulator of innate tolerance during infection with VSV.
Collapse
Affiliation(s)
- Tom Adomati
- Institute of Immunology, University of Duisburg-Essen, Essen, Germany.
| | - Lamin B Cham
- Institute of Immunology, University of Duisburg-Essen, Essen, Germany
| | - Thamer A Hamdan
- Institute of Immunology, University of Duisburg-Essen, Essen, Germany
| | - Hilal Bhat
- Institute of Immunology, University of Duisburg-Essen, Essen, Germany
| | - Vikas Duhan
- Institute of Immunology, University of Duisburg-Essen, Essen, Germany; Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
| | - Fanghui Li
- Institute of Immunology, University of Duisburg-Essen, Essen, Germany
| | - Murtaza Ali
- Institute of Immunology, University of Duisburg-Essen, Essen, Germany
| | - Elisabeth Lang
- University Psychiatric Clinics Basel, Basel, Switzerland
| | - Anfei Huang
- Institute of Molecular Medicine, Heinrich Heine University, Düsseldorf, Germany
| | - Eyad Naser
- Department of Molecular Biology, University of Duisburg-Essen, Essen, Germany
| | - Vishal Khairnar
- Institute of Immunology, University of Duisburg-Essen, Essen, Germany; Department of Systems Biology, City of Hope Comprehensive Cancer Center, Monrovia, CA, USA
| | | | - Judith Lang
- Institute of Immunology, University of Duisburg-Essen, Essen, Germany
| | | | | | | | | | - Florian Lang
- Department of Physiology I, Eberhard Karls University of Tübingen, Tübingen, Germany
| | - Dieter Häussinger
- Clinic of Gastroenterology, Hepatology and Infectious Diseases, Heinrich Heine University, Düsseldorf, Germany
| | | | - Cornelia Hardt
- Institute of Immunology, University of Duisburg-Essen, Essen, Germany
| | - Philipp A Lang
- Institute of Molecular Medicine, Heinrich Heine University, Düsseldorf, Germany
| | - Karl S Lang
- Institute of Immunology, University of Duisburg-Essen, Essen, Germany.
| |
Collapse
|
|
23
|
Kim S, Hong HS. Substance-P prevents the cholestatic liver injury by regulating inflammatory responses. Peptides 2021; 137:170494. [PMID: 33440226 DOI: 10.1016/j.peptides.2021.170494] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2020] [Revised: 11/11/2020] [Accepted: 12/30/2020] [Indexed: 02/03/2023]
Abstract
Substance-P (SP) is a neuropeptide that modulates immune responses and accelerates tissue repair in critical inflammatory disease. Liver fibrosis and cirrhosis are the ultimate outcomes of almost all chronic liver diseases caused by viral infection, steatohepatitis, autoimmune, and cholestatic injury. Despite the development of new drugs, liver transplantation is still the only fundamental treatment; thus, new therapeutic approaches to mitigate liver fibrosis and chronic inflammation are constantly being needed. The aim of this study was to examine the effect of SP on liver damage due to cholestatic stress. To induce cholestatic injury, common bile duct ligation (CBDL) was attempted, followed by systemic application of SP. SP treatment increased IL-10 and decreased TNF-α in serum with increasing levels of circulating regulatory T cells (Tregs) from the early stage of CBDL. Moreover, SP decreased CBDL-induced TGF-β1 expression in the circulation. This could create anti-inflammatory/anti-fibrotic environment under CBDL, which might ameliorate the progression of liver fibrosis in CBDL. Histological and molecular analysis revealed that SP treatment reduced ductular reaction, hepatic damage, and apoptotic hepatocytes, accompanied by diminishing type I collagen and upregulating MMP-9. These studies found that SP is a promising therapeutic candidate for immune-related liver disease as well as cholestatic liver disease, by providing hepatic protective effects via immune suppression.
Collapse
Affiliation(s)
- Suna Kim
- Graduate School of Biotechnology & Department of Genetic Engineering, College of Life Science, Kyung Hee University, Seochun-dong, Kiheung-ku, Yong In, 17104, Republic of Korea
| | - Hyun Sook Hong
- College of Medicine/ East-West Medical Research Institute, Kyung Hee University, 1 Hoegi-dong. Dongdaemun-gu, Seoul, 02447, Republic of Korea; Department of Biomedical Science and Technology, Graduate School, Kyung Hee University, Kyung Hee University, Seoul, 02447, Republic of Korea.
| |
Collapse
|
|
24
|
Engin A. Bile Acid Toxicity and Protein Kinases. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1275:229-258. [PMID: 33539018 DOI: 10.1007/978-3-030-49844-3_9] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
If the bile acids reach to pathological concentrations due to cholestasis, accumulation of hydrophobic bile acids within the hepatocyte may result in cell death. Thus, hydrophobic bile acids induce apoptosis in hepatocytes, while hydrophilic bile acids increase intracellular adenosine 3',5'-monophosphate (cAMP) levels and activate mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) pathways to protect hepatocytes from apoptosis.Two apoptotic pathways have been described in bile acids-induced death. Both are controlled by multiple protein kinase signaling pathways. In mitochondria-controlled pathway, caspase-8 is activated with death domain-independent manner, whereas, Fas-dependent classical pathway involves ligand-independent oligomerization of Fas.Hydrophobic bile acids dose-dependently upregulate the inflammatory response by further stimulating production of inflammatory cytokines. Death receptor-mediated apoptosis is regulated at the cell surface by the receptor expression, at the death-inducing signaling complex (DISC) by expression of procaspase-8, the death receptors Fas-associated death domain (FADD), and cellular FADD-like interleukin 1-beta (IL-1β)-converting enzyme (FLICE) inhibitory protein (cFLIP). Bile acids prevent cFLIP recruitment to the DISC and thereby enhance initiator caspase activation and lead to cholestatic apoptosis. At mitochondria, the expression of B-cell leukemia/lymphoma-2 (Bcl-2) family proteins contribute to apoptosis by regulating mitochondrial cytochrome c release via Bcl-2, Bcl-2 homology 3 (BH3) interacting domain death agonist (Bid), or Bcl-2 associated protein x (Bax). Fas receptor CD95 activation by hydrophobic bile acids is initiated by reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-dependent reactive oxygen species (ROS) signaling. However, activation of necroptosis by ligands of death receptors requires the kinase activity of receptor interacting protein1 (RIP1), which mediates the activation of RIP3 and mixed lineage kinase domain-like protein (MLKL). In this chapter, mainly the effect of protein kinases signal transduction on the mechanisms of hydrophobic bile acids-induced inflammation, apoptosis, necroptosis and necrosis are discussed.
Collapse
Affiliation(s)
- Atilla Engin
- Department of General Surgery, Faculty of Medicine, Gazi University, Ankara, Turkey.
| |
Collapse
|
|
25
|
Shojaie L, Iorga A, Dara L. Cell Death in Liver Diseases: A Review. Int J Mol Sci 2020; 21:ijms21249682. [PMID: 33353156 PMCID: PMC7766597 DOI: 10.3390/ijms21249682] [Citation(s) in RCA: 175] [Impact Index Per Article: 35.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2020] [Revised: 12/15/2020] [Accepted: 12/16/2020] [Indexed: 12/11/2022] Open
Abstract
Regulated cell death (RCD) is pivotal in directing the severity and outcome of liver injury. Hepatocyte cell death is a critical event in the progression of liver disease due to resultant inflammation leading to fibrosis. Apoptosis, necrosis, necroptosis, autophagy, and recently, pyroptosis and ferroptosis, have all been investigated in the pathogenesis of various liver diseases. These cell death subroutines display distinct features, while sharing many similar characteristics with considerable overlap and crosstalk. Multiple types of cell death modes can likely coexist, and the death of different liver cell populations may contribute to liver injury in each type of disease. This review addresses the known signaling cascades in each cell death pathway and its implications in liver disease. In this review, we describe the common findings in each disease model, as well as the controversies and the limitations of current data with a particular focus on cell death-related research in humans and in rodent models of alcoholic liver disease, non-alcoholic fatty liver disease and steatohepatitis (NASH/NAFLD), acetaminophen (APAP)-induced hepatotoxicity, autoimmune hepatitis, cholestatic liver disease, and viral hepatitis.
Collapse
Affiliation(s)
- Layla Shojaie
- Division of Gastrointestinal & Liver Diseases, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA; (L.S.); (A.I.)
- Research Center for Liver Disease, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
| | - Andrea Iorga
- Division of Gastrointestinal & Liver Diseases, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA; (L.S.); (A.I.)
- Research Center for Liver Disease, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
| | - Lily Dara
- Division of Gastrointestinal & Liver Diseases, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA; (L.S.); (A.I.)
- Research Center for Liver Disease, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
- Correspondence:
| |
Collapse
|
|
26
|
Portincasa P, Di Ciaula A, Garruti G, Vacca M, De Angelis M, Wang DQH. Bile Acids and GPBAR-1: Dynamic Interaction Involving Genes, Environment and Gut Microbiome. Nutrients 2020; 12:E3709. [PMID: 33266235 PMCID: PMC7760347 DOI: 10.3390/nu12123709] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2020] [Revised: 11/25/2020] [Accepted: 11/26/2020] [Indexed: 02/06/2023] Open
Abstract
Bile acids (BA) are amphiphilic molecules synthesized in the liver from cholesterol. BA undergo continuous enterohepatic recycling through intestinal biotransformation by gut microbiome and reabsorption into the portal tract for uptake by hepatocytes. BA are detergent molecules aiding the digestion and absorption of dietary fat and fat-soluble vitamins, but also act as important signaling molecules via the nuclear receptor, farnesoid X receptor (FXR), and the membrane-associated G protein-coupled bile acid receptor 1 (GPBAR-1) in the distal intestine, liver and extra hepatic tissues. The hydrophilic-hydrophobic balance of the BA pool is finely regulated to prevent BA overload and liver injury. By contrast, hydrophilic BA can be hepatoprotective. The ultimate effects of BA-mediated activation of GPBAR-1 is poorly understood, but this receptor may play a role in protecting the remnant liver and in maintaining biliary homeostasis. In addition, GPBAR-1 acts on pathways involved in inflammation, biliary epithelial barrier permeability, BA pool hydrophobicity, and sinusoidal blood flow. Recent evidence suggests that environmental factors influence GPBAR-1 gene expression. Thus, targeting GPBAR-1 might improve liver protection, facilitating beneficial metabolic effects through primary prevention measures. Here, we discuss the complex pathways linked to BA effects, signaling properties of the GPBAR-1, mechanisms of liver damage, gene-environment interactions, and therapeutic aspects.
Collapse
Affiliation(s)
- Piero Portincasa
- Clinica Medica “A. Murri”, Department of Biomedical Sciences & Human Oncology, University of Bari Medical School, 70124 Bari, Italy;
| | - Agostino Di Ciaula
- Clinica Medica “A. Murri”, Department of Biomedical Sciences & Human Oncology, University of Bari Medical School, 70124 Bari, Italy;
| | - Gabriella Garruti
- Section of Endocrinology, Department of Emergency and Organ Transplantations, University of Bari “Aldo Moro” Medical School, Piazza G. Cesare 11, 70124 Bari, Italy;
| | - Mirco Vacca
- Dipartimento di Scienze del Suolo, Della Pianta e Degli Alimenti, Università degli Studi di Bari Aldo Moro, 70124 Bari, Italy; (M.V.); (M.D.A.)
| | - Maria De Angelis
- Dipartimento di Scienze del Suolo, Della Pianta e Degli Alimenti, Università degli Studi di Bari Aldo Moro, 70124 Bari, Italy; (M.V.); (M.D.A.)
| | - David Q.-H. Wang
- Department of Medicine and Genetics, Division of Gastroenterology and Liver Diseases, Marion Bessin Liver Research Center, Einstein-Mount Sinai Diabetes Research Center, Albert Einstein College of Medicine, Bronx, NY 10461, USA;
| |
Collapse
|
|
27
|
Enomoto LM, Dixon MEB, Burdette A, Gusani NJ. Biliary Drainage Before and After Liver Resection for Perihilar Cholangiocarcinoma. Am Surg 2020; 86:628-634. [PMID: 32683970 DOI: 10.1177/0003134820923287] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Perihilar cholangiocarcinoma (PHC) is a rare tumor that requires surgical resection for a potential cure. The role of preoperative biliary drainage has long been debated, given its treatment of biliary sepsis and decompression of the future liver remnant (FLR), but high procedure-specific morbidity. The indications, methods, and outcomes for preoperative biliary drainage are discussed to serve as a guide for perioperative management of patients with resectable PHC. Multiple studies from the literature related to perihilar cholangiocarcinoma, biliary drainage, and management of the FLR were reviewed. Commonly employed preoperative biliary drainage includes endoscopic biliary stenting and percutaneous transhepatic biliary drainage. Drainage of the FLR remains controversial, with most experts recommending drainage of the only in patients with an FLR <50%. Biliary drainage for resectable PHC requires a patient-specific approach with careful determination of the FLR and balancing of potential morbidity with the benefits of drainage.
Collapse
Affiliation(s)
- Laura M Enomoto
- 21823 Department of Surgery, University Surgical Oncology, University of Tennessee, Knoxville, TN, USA
| | - Matthew E B Dixon
- 311285 Department of Surgery, Program for Liver, Pancreas, and Foregut Tumors, The Pennsylvania State University, College of Medicine, Hershey, PA, USA
| | - Allene Burdette
- 311285 Department of Surgery, Program for Liver, Pancreas, and Foregut Tumors, The Pennsylvania State University, College of Medicine, Hershey, PA, USA.,311285 Department of Radiology, Penn State Heart & Vascular Institute, The Pennsylvania State University, College of Medicine, Hershey, PA, USA
| | - Niraj J Gusani
- 311285 Department of Surgery, Program for Liver, Pancreas, and Foregut Tumors, The Pennsylvania State University, College of Medicine, Hershey, PA, USA
| |
Collapse
|
|
28
|
Liu Y, Chen K, Li F, Gu Z, Liu Q, He L, Shao T, Song Q, Zhu F, Zhang L, Jiang M, Zhou Y, Barve S, Zhang X, McClain CJ, Feng W. Probiotic Lactobacillus rhamnosus GG Prevents Liver Fibrosis Through Inhibiting Hepatic Bile Acid Synthesis and Enhancing Bile Acid Excretion in Mice. Hepatology 2020; 71:2050-2066. [PMID: 31571251 PMCID: PMC7317518 DOI: 10.1002/hep.30975] [Citation(s) in RCA: 211] [Impact Index Per Article: 42.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2019] [Accepted: 09/22/2019] [Indexed: 02/05/2023]
Abstract
BACKGROUND AND AIMS Cholestatic liver disease is characterized by gut dysbiosis and excessive toxic hepatic bile acids (BAs). Modification of gut microbiota and repression of BA synthesis are potential strategies for the treatment of cholestatic liver disease. The purpose of this study was to examine the effects and to understand the mechanisms of the probiotic Lactobacillus rhamnosus GG (LGG) on hepatic BA synthesis, liver injury, and fibrosis in bile duct ligation (BDL) and multidrug resistance protein 2 knockout (Mdr2-/- ) mice. APPROACH AND RESULTS Global and intestine-specific farnesoid X receptor (FXR) inhibitors were used to dissect the role of FXR. LGG treatment significantly attenuated liver inflammation, injury, and fibrosis with a significant reduction of hepatic BAs in BDL mice. Hepatic concentration of taurine-β-muricholic acid (T-βMCA), an FXR antagonist, was markedly increased in BDL mice and reduced in LGG-treated mice, while chenodeoxycholic acid, an FXR agonist, was decreased in BDL mice and normalized in LGG-treated mice. LGG treatment significantly increased the expression of serum and ileum fibroblast growth factor 15 (FGF-15) and subsequently reduced hepatic cholesterol 7α-hydroxylase and BA synthesis in BDL and Mdr2-/- mice. At the molecular level, these changes were reversed by global and intestine-specific FXR inhibitors in BDL mice. In addition, LGG treatment altered gut microbiota, which was associated with increased BA deconjugation and increased fecal and urine BA excretion in both BDL and Mdr2-/- mice. In vitro studies showed that LGG suppressed the inhibitory effect of T-βMCA on FXR and FGF-19 expression in Caco-2 cells. CONCLUSION LGG supplementation decreases hepatic BA by increasing intestinal FXR-FGF-15 signaling pathway-mediated suppression of BA de novo synthesis and enhances BA excretion, which prevents excessive BA-induced liver injury and fibrosis in mice.
Collapse
Affiliation(s)
- Yunhuan Liu
- Department of MedicineUniversity of LouisvilleLouisvilleKY
| | - Kefei Chen
- Department of MedicineUniversity of LouisvilleLouisvilleKY
- Department of Liver Surgery and Liver Transplantation CenterWest China HospitalSichuan UniversityChengduChina
| | - Fengyuan Li
- Department of MedicineUniversity of LouisvilleLouisvilleKY
- Department of Pharmacology and ToxicologyUniversity of LouisvilleLouisvilleKY
| | - Zelin Gu
- Department of MedicineUniversity of LouisvilleLouisvilleKY
| | - Qi Liu
- Department of MedicineUniversity of LouisvilleLouisvilleKY
- The Second Affiliated HospitalWenzhou Medical UniversityWenzhouChina
| | - Liqing He
- Department of ChemistryUniversity of LouisvilleLouisvilleKY
| | - Tuo Shao
- Department of MedicineUniversity of LouisvilleLouisvilleKY
| | - Qing Song
- Department of MedicineUniversity of LouisvilleLouisvilleKY
- The First Affiliated HospitalXi'an Jiaotong UniversityXi'anChina
| | - Fenxia Zhu
- Department of MedicineUniversity of LouisvilleLouisvilleKY
- Affiliated Hospital of Integrated Traditional Chinese and Western MedicineNanjing University of Chinese MedicineNanjingChina
| | - Lihua Zhang
- Department of MedicineUniversity of LouisvilleLouisvilleKY
| | - Mengwei Jiang
- Department of MedicineUniversity of LouisvilleLouisvilleKY
- Department of Pharmacology and ToxicologyUniversity of LouisvilleLouisvilleKY
| | - Yun Zhou
- Department of MedicineUniversity of LouisvilleLouisvilleKY
| | - Shirish Barve
- Department of MedicineUniversity of LouisvilleLouisvilleKY
- Department of Pharmacology and ToxicologyUniversity of LouisvilleLouisvilleKY
- Alcohol Research CenterUniversity of LouisvilleLouisvilleKY
- Hepatobiology & Toxicology CenterUniversity of LouisvilleLouisvilleKY
| | - Xiang Zhang
- Department of Pharmacology and ToxicologyUniversity of LouisvilleLouisvilleKY
- Department of ChemistryUniversity of LouisvilleLouisvilleKY
- Alcohol Research CenterUniversity of LouisvilleLouisvilleKY
- Hepatobiology & Toxicology CenterUniversity of LouisvilleLouisvilleKY
| | - Craig J. McClain
- Department of MedicineUniversity of LouisvilleLouisvilleKY
- Department of Pharmacology and ToxicologyUniversity of LouisvilleLouisvilleKY
- Alcohol Research CenterUniversity of LouisvilleLouisvilleKY
- Hepatobiology & Toxicology CenterUniversity of LouisvilleLouisvilleKY
- Robley Rex VA Medical CenterLouisvilleKY
| | - Wenke Feng
- Department of MedicineUniversity of LouisvilleLouisvilleKY
- Department of Pharmacology and ToxicologyUniversity of LouisvilleLouisvilleKY
- Alcohol Research CenterUniversity of LouisvilleLouisvilleKY
- Hepatobiology & Toxicology CenterUniversity of LouisvilleLouisvilleKY
| |
Collapse
|
|
29
|
Merlen G, Bidault-Jourdainne V, Kahale N, Glenisson M, Ursic-Bedoya J, Doignon I, Garcin I, Humbert L, Rainteau D, Tordjmann T. Hepatoprotective impact of the bile acid receptor TGR5. Liver Int 2020; 40:1005-1015. [PMID: 32145703 DOI: 10.1111/liv.14427] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/31/2019] [Revised: 02/17/2020] [Accepted: 02/24/2020] [Indexed: 02/13/2023]
Abstract
During liver repair after injury, bile secretion has to be tightly modulated in order to preserve liver parenchyma from bile acid (BA)-induced injury. The mechanisms allowing the liver to maintain biliary homeostasis during repair after injury are not completely understood. Besides their historical role in lipid digestion, bile acids (BA) and their receptors constitute a signalling network with multiple impacts on liver repair, both stimulating regeneration and protecting the liver from BA overload. BA signal through nuclear (mainly Farnesoid X Receptor, FXR) and membrane (mainly G Protein-coupled BA Receptor 1, GPBAR-1 or TGR5) receptors to elicit a wide array of biological responses. While a great number of studies have been dedicated to the hepato-protective impact of FXR signalling, TGR5 is by far less explored in this context. Because the liver has to face massive and potentially harmful BA overload after partial ablation or destruction, BA-induced protective responses crucially contribute to spare liver repair capacities. Based on the available literature, the TGR5 BA receptor protects the remnant liver and maintains biliary homeostasis, mainly through the control of inflammation, biliary epithelial barrier permeability, BA pool hydrophobicity and sinusoidal blood flow. Mouse experimental models of liver injury reveal that in the lack of TGR5, excessive inflammation, leaky biliary epithelium and hydrophobic BA overload result in parenchymal insult and compromise optimal restoration of a functional liver mass. Translational perspectives are thus opened to target TGR5 with the aim of protecting the liver in the context of injury and BA overload.
Collapse
Affiliation(s)
- Grégory Merlen
- INSERM U1193, Faculté des Sciences d'Orsay, Université Paris Saclay, Orsay, France
| | | | - Nicolas Kahale
- INSERM U1193, Faculté des Sciences d'Orsay, Université Paris Saclay, Orsay, France
| | - Mathilde Glenisson
- INSERM U1193, Faculté des Sciences d'Orsay, Université Paris Saclay, Orsay, France
| | - José Ursic-Bedoya
- INSERM U1193, Faculté des Sciences d'Orsay, Université Paris Saclay, Orsay, France
| | - Isabelle Doignon
- INSERM U1193, Faculté des Sciences d'Orsay, Université Paris Saclay, Orsay, France
| | - Isabelle Garcin
- INSERM U1193, Faculté des Sciences d'Orsay, Université Paris Saclay, Orsay, France
| | - Lydie Humbert
- Centre de Recherche Saint Antoine, CRSA, Sorbonne Université, Paris, France
| | - Dominique Rainteau
- Centre de Recherche Saint Antoine, CRSA, Sorbonne Université, Paris, France
| | - Thierry Tordjmann
- INSERM U1193, Faculté des Sciences d'Orsay, Université Paris Saclay, Orsay, France
| |
Collapse
|
|
30
|
Abstract
Cholestasis results in blockage of bile flow whether the point of obstruction occurs extrahepatically or intrahepatically. Bile acids are a primary constituent of bile, and thus one of the primary outcomes is acute retention of bile acids in hepatocytes. Bile acids are normally secreted into the biliary tracts and then released into the small bowel before recirculating back to the liver. Retention of bile acids has long been hypothesized to be a primary cause of the associated liver injury that occurs during acute or chronic cholestasis. Despite this, a surge of papers in the last decade have reported a primary role for inflammation in the pathophysiology of cholestatic liver injury. Furthermore, it has increasingly been recognized that both the constituency of individual bile acids that make up the greater pool, as well as their conjugation status, is intimately involved in their toxicity, and this varies between species. Finally, the role of bile acids in drug-induced cholestatic liver injury remains an area of increasing interest. The purpose of this review is to critically evaluate current proposed mechanisms of cholestatic liver injury, with a focus on the evolving role of bile acids in cell death and inflammation.
Collapse
Affiliation(s)
| | - Hartmut Jaeschke
- †Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA
| |
Collapse
|
|
31
|
Zhang R, Nakao T, Luo J, Xue Y, Cornuet P, Oertel M, Kosar K, Singh S, Nejak-Bowen K. Activation of WNT/Beta-Catenin Signaling and Regulation of the Farnesoid X Receptor/Beta-Catenin Complex After Murine Bile Duct Ligation. Hepatol Commun 2019; 3:1642-1655. [PMID: 31832572 PMCID: PMC6887668 DOI: 10.1002/hep4.1430] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2019] [Accepted: 08/29/2019] [Indexed: 12/14/2022] Open
Abstract
We have recently shown that loss of β‐catenin prevents the development of cholestatic liver injury and fibrosis after bile duct ligation (BDL) due to loss of the inhibitory farnesoid X receptor (FXR)/β‐catenin complex, which results in decreased hepatic bile acids (BAs) through activation of FXR. To further understand the role of Wnt/β‐catenin signaling in regulating BA metabolism and cholestasis, we performed BDL on mice in which hepatocyte Wnt signaling is deficient but β‐catenin is intact (low‐density lipoprotein receptor‐related protein [LRP]5/6 knockout [DKO]) as well as mice that have enhanced hepatocyte β‐catenin expression (serine 45 mutated to aspartic acid [S45D] transgenic [TG] mice). Despite decreased biliary injury after BDL, hepatic injury, fibrosis, and inflammation were comparable in DKO and wild‐type (WT) mice. Notably, the FXR/β‐catenin complex was maintained in DKO livers after BDL, coincident with significantly elevated hepatic BA levels. Similarly, TG mice did not display accelerated injury or increased mortality despite overexpression of β‐catenin. There was no augmentation of FXR/β‐catenin association in TG livers; this resulted in equivalent hepatic BAs in WT and TG mice after BDL. Finally, we analyzed the effect of BDL on β‐catenin activity and identified an increase in periportal cytoplasmic stabilization and association with T‐cell factor 4 that correlated with increased expression of distinct downstream target genes. Conclusion: Localization of β‐catenin and expression of Wnt‐regulated genes were altered in liver after BDL; however, neither elimination of Wnt/β‐catenin signaling nor overexpression of β‐catenin in hepatocytes significantly impacted the phenotype or progression of BA‐driven cholestatic injury.
Collapse
Affiliation(s)
- Rong Zhang
- Department of Pathology University of Pittsburgh Pittsburgh PA
| | - Toshimasa Nakao
- Department of Drug Discovery Medicine Kyoto Prefectural University of Medicine Kyoto Japan
| | - Jing Luo
- Department of Surgery University of Pittsburgh Pittsburgh PA
| | - Yuhua Xue
- Department of Pathology University of Pittsburgh Pittsburgh PA
| | - Pamela Cornuet
- Department of Pathology University of Pittsburgh Pittsburgh PA
| | - Michael Oertel
- Department of Pathology University of Pittsburgh Pittsburgh PA
| | - Karis Kosar
- Department of Pathology University of Pittsburgh Pittsburgh PA
| | - Sucha Singh
- Department of Pathology University of Pittsburgh Pittsburgh PA
| | - Kari Nejak-Bowen
- Department of Pathology University of Pittsburgh Pittsburgh PA.,Pittsburgh Liver Research Center University of Pittsburgh Pittsburgh PA
| |
Collapse
|
|
32
|
Fang J, Luo L, Ke Z, Liu C, Yin L, Yao Y, Feng Q, Huang C, Zheng P, Fan S. Polydatin protects against acute cholestatic liver injury in mice via the inhibition of oxidative stress and endoplasmic reticulum stress. J Funct Foods 2019. [DOI: 10.1016/j.jff.2019.02.029] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
|
|
33
|
Elufioye TO, Habtemariam S. Hepatoprotective effects of rosmarinic acid: Insight into its mechanisms of action. Biomed Pharmacother 2019; 112:108600. [PMID: 30780110 DOI: 10.1016/j.biopha.2019.108600] [Citation(s) in RCA: 62] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2018] [Revised: 01/11/2019] [Accepted: 01/18/2019] [Indexed: 02/06/2023] Open
Abstract
Liver diseases such as hepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma are one of the major health challenges in the world and many conditions such as inadequate nutrition, viral infection, ethanol and drug abuse, xenobiotic exposure, and metabolic diseases have been implicated in the development and progression of liver diseases. Several factors including lipid peroxidation, production of reactive oxygen species (ROS), peroxynitrite formation, complement factors and proinflammatory mediators, such as cytokines and chemokines, are involved in hepatic diseases. Rosmarinic acid (RA) is a natural phenolic compound found mainly in the family Lamiaceae consisting of several medicinal plants, herbs and spices. Several biological activities have been reported for RA and these include antioxidant properties as a ROS scavenger and lipid peroxidation inhibitor, anti-inflammatory, neuroprotective and antiangiogenic among others. This review is aimed at discussing the effects of RA on the liver, highlighting its hepatoprotective potential and the underlying mechanisms.
Collapse
Affiliation(s)
- Taiwo O Elufioye
- Department of Pharmacognosy, Faculty of Pharmacy, University of Ibadan, Nigeria.
| | - Solomon Habtemariam
- Pharmacognosy Research Laboratories & Herbal Analysis Services, University of Greenwich, Chatham, Maritime Kent, ME4 4TB, UK
| |
Collapse
|
|
34
|
Binh MT, Hoan NX, Van Tong H, Sy BT, Trung NT, Bock CT, Toan NL, Song LH, Bang MH, Meyer CG, Kremsner PG, Velavan TP. NTCP S267F variant associates with decreased susceptibility to HBV and HDV infection and decelerated progression of related liver diseases. Int J Infect Dis 2019; 80:147-152. [PMID: 30685591 DOI: 10.1016/j.ijid.2019.01.038] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2018] [Revised: 01/16/2019] [Accepted: 01/19/2019] [Indexed: 02/07/2023] Open
Abstract
OBJECTIVES To determine potential associations of the rs2296651 variant (c.800C>T, S267F) of NTCP with HBV and HBV plus concomitant HDV infection as well as with the progression of related liver diseases. METHODS The S267F variant was genotyped by DNA sequencing in 620 HBV-infected patients and 214 healthy controls (HCs). Among the patients, 450 individuals were tested for HDV by a nested PCR assay. Logistic regression was applied to examine the association. RESULTS The S267F variant was found more frequently among HCs (16%) compared to HBV-infected (6%) and HBV-HDV co-infected patients (3%) (HBV patients vs HC: OR=0.32, P=0.00002 and HDV patients vs. HC: OR=0.17, P=0.018). The frequency of S267F variant was inversely correlated with CHB, LC or HCC patients compared with HCs (OR=0.31, P=0.001; OR=0.32, P=0.013; OR=0.34, P=0.002, respectively). S267F variant was also associated with decreased risk of the development of advanced liver cirrhosis (LC) and hepatocellular carcinoma (HCC) (Child B and C vs. Child A, OR=0.26, adjusted P=0.016; BCLC B,C,D vs. BCLC A, OR=0.038, P=0.045, respectively). In addition, patients with the genotype CT had lower levels of AST, ALT, total and direct bilirubin as well as higher platelet counts, indicating an association with a more favorable clinical outcome. CONCLUSION The NTCP S267F variant of the SLC10A1 gene exhibits protective effects against HBV and HDV infection and is associated with a reduced risk of developing to advanced stages of LC and HCC.
Collapse
Affiliation(s)
- Mai Thanh Binh
- Institute of Tropical Medicine, University of Tübingen, Tübingen, Germany; Vietnamese-German Center for Medical Research, Hanoi, Vietnam; 108 Military Central Hospital, Hanoi, Vietnam
| | - Nghiem Xuan Hoan
- Institute of Tropical Medicine, University of Tübingen, Tübingen, Germany; Vietnamese-German Center for Medical Research, Hanoi, Vietnam; 108 Military Central Hospital, Hanoi, Vietnam
| | - Hoang Van Tong
- Institute of Tropical Medicine, University of Tübingen, Tübingen, Germany; Vietnamese-German Center for Medical Research, Hanoi, Vietnam; Vietnam Military Medical University, Hanoi, Vietnam
| | - Bui Tien Sy
- Vietnamese-German Center for Medical Research, Hanoi, Vietnam; 108 Military Central Hospital, Hanoi, Vietnam
| | - Ngo Tat Trung
- Vietnamese-German Center for Medical Research, Hanoi, Vietnam; 108 Military Central Hospital, Hanoi, Vietnam
| | - C-Thomas Bock
- Institute of Tropical Medicine, University of Tübingen, Tübingen, Germany; Department of Infectious Diseases, Robert Koch Institute, Berlin, Germany
| | - Nguyen Linh Toan
- Vietnamese-German Center for Medical Research, Hanoi, Vietnam; Vietnam Military Medical University, Hanoi, Vietnam
| | - Le Huu Song
- Vietnamese-German Center for Medical Research, Hanoi, Vietnam; 108 Military Central Hospital, Hanoi, Vietnam
| | | | - Christian G Meyer
- Institute of Tropical Medicine, University of Tübingen, Tübingen, Germany; Vietnamese-German Center for Medical Research, Hanoi, Vietnam; Duy Tan University, Da Nang, Vietnam
| | - Peter G Kremsner
- Institute of Tropical Medicine, University of Tübingen, Tübingen, Germany
| | - Thirumalaisamy P Velavan
- Institute of Tropical Medicine, University of Tübingen, Tübingen, Germany; Vietnamese-German Center for Medical Research, Hanoi, Vietnam; Duy Tan University, Da Nang, Vietnam.
| |
Collapse
|
|
35
|
Abstract
Cholestasis can be induced by obstruction of bile ducts or intrahepatic toxicity of drugs and chemicals. However, the mode of cell death during cholestasis, i.e., apoptosis or necrosis, has been controversial. There are fundamental reasons for the controversies, both of which are discussed here, namely the design of experiments and the use of parameters with limited specificity for a certain mode of cell death. Based on the assumption that cholestatic liver injury is caused by accumulation of bile acids, rodent (mainly rat) hepatocytes have been exposed to hydrophobic, glycine-conjugated bile acids, which resulted in apoptotic cell death. The problems with this experimental design are that in rodents bile acids are predominantly taurine conjugated and rodent hepatocytes are never exposed to these levels of glycine-conjugated bile acids. In contrast, taurine-conjugated bile acids trigger inflammatory gene activation in rodent hepatocytes and a necro-inflammatory injury in vivo. On the other hand, human hepatocytes are more resistant to glycine-conjugated bile acids and die by necrosis when exposed to high biliary levels of these bile acids. In this chapter, we describe multiple assays including the caspase activity assay, which is specific for apoptosis, and the general cell death assays alanine aminotransferase or lactate dehydrogenase activities in cell culture medium or plasma. An increase in these enzyme activities without caspase activity indicates necrotic cell death. Thus, both the experimental design and the selection of cell death parameters are critical for the relevance of the experiments for the human pathophysiology.
Collapse
Affiliation(s)
| | - Hartmut Jaeschke
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA.
| |
Collapse
|
|
36
|
Ibrahim S, Dayoub R, Krautbauer S, Liebisch G, Wege AK, Melter M, Weiss TS. Bile acid-induced apoptosis and bile acid synthesis are reduced by over-expression of Augmenter of Liver Regeneration (ALR) in a STAT3-dependent mechanism. Exp Cell Res 2019; 374:189-197. [DOI: 10.1016/j.yexcr.2018.11.023] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2018] [Revised: 10/31/2018] [Accepted: 11/25/2018] [Indexed: 11/24/2022]
|
|
37
|
Cubero FJ, Peng J, Liao L, Su H, Zhao G, Zoubek ME, Macías-Rodríguez R, Ruiz-Margain A, Reißing J, Zimmermann HW, Gassler N, Luedde T, Liedtke C, Hatting M, Trautwein C. Inactivation of caspase 8 in liver parenchymal cells confers protection against murine obstructive cholestasis. J Hepatol 2018; 69:1326-1334. [PMID: 30144553 DOI: 10.1016/j.jhep.2018.08.015] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2017] [Revised: 08/14/2018] [Accepted: 08/15/2018] [Indexed: 12/17/2022]
Abstract
BACKGROUND & AIMS Caspase 8 (CASP8) is the apical initiator caspase in death receptor-mediated apoptosis. Strong evidence for a link between death receptor signaling pathways and cholestasis has recently emerged. Herein, we investigated the role of CASP8-dependent and independent pathways during experimental cholestasis. METHODS Liver injury was characterized in a cohort of human sera (n = 28) and biopsies from patients with stage IV primary biliary cholangitis. In parallel, mice with either specific deletion of Casp8 in liver parenchymal cells (Casp8Δhepa) or hepatocytes (Casp8Δhep), and mice with constitutive Ripk3 (Ripk3-/-) deletion, were subjected to surgical ligation of the common bile duct (BDL) from 2 to 28 days. Floxed (Casp8fl/fl) and Ripk3+/+ mice were used as controls. Moreover, the pan-caspase inhibitor IDN-7314 was used, and cell death mechanisms were studied in primary isolated hepatocytes. RESULTS Overexpression of activated caspase 3, CASP8 and RIPK3 was characteristic of liver explants from patients with primary biliary cholangitis. Twenty-eight days after BDL, Casp8Δhepamice showed decreased necrotic foci, serum aminotransferase levels and apoptosis along with diminished compensatory proliferation and ductular reaction. These results correlated with a decreased inflammatory profile and ameliorated liver fibrogenesis. A similar phenotype was observed in Ripk3-/- mice. IDN-7314 treatment decreased CASP8 levels but failed to prevent BDL-induced cholestasis, independently of CASP8 in hepatocytes. CONCLUSION These findings show that intervention against CASP8 in liver parenchymal cells - specifically in cholangiocytes - might be a beneficial option for treating obstructive cholestasis, while broad pan-caspase inhibition might trigger undesirable side effects. LAY SUMMARY Loss of caspase 8 - a protein involved in programmed cell death - in liver parenchymal cells protects against experimental cholestasis. Therefore, specific pharmacological intervention against caspase 8 might be a valid alternative for the treatment of obstructive cholestasis in the clinic, whereas broad pan-caspase inhibiting drugs might trigger undesirable side effects.
Collapse
Affiliation(s)
- Francisco Javier Cubero
- Department of Internal Medicine III, University Hospital, RWTH, Aachen, Germany; Department of Immunology, Ophtalmology & ORL, Complutense University School of Medicine, Madrid, Spain; 12 de Octubre Health Research Institute (imas12), Madrid, Spain.
| | - Jin Peng
- Department of Internal Medicine III, University Hospital, RWTH, Aachen, Germany; Department of Hepatobiliary Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing Jiangsu, China
| | - Lijun Liao
- Department of Internal Medicine III, University Hospital, RWTH, Aachen, Germany; Department of Anesthesiology and Pain Management, Shanghai East Hospital, Tongji University, Shanghai, China
| | - Huan Su
- Department of Internal Medicine III, University Hospital, RWTH, Aachen, Germany
| | - Gang Zhao
- Department of Internal Medicine III, University Hospital, RWTH, Aachen, Germany
| | | | | | - Astrid Ruiz-Margain
- Department of Internal Medicine III, University Hospital, RWTH, Aachen, Germany
| | - Johanna Reißing
- Department of Internal Medicine III, University Hospital, RWTH, Aachen, Germany
| | | | - Nikolaus Gassler
- Institute of Pathology, Braunschweig Hospital, Braunschweig, Germany
| | - Tom Luedde
- Department of Internal Medicine III, University Hospital, RWTH, Aachen, Germany
| | - Christian Liedtke
- Department of Internal Medicine III, University Hospital, RWTH, Aachen, Germany
| | - Maximilian Hatting
- Department of Internal Medicine III, University Hospital, RWTH, Aachen, Germany
| | - Christian Trautwein
- Department of Internal Medicine III, University Hospital, RWTH, Aachen, Germany.
| |
Collapse
|
|
38
|
Antagonism of Interleukin-17A ameliorates experimental hepatic fibrosis by restoring the IL-10/STAT3-suppressed autophagy in hepatocytes. Oncotarget 2018; 8:9922-9934. [PMID: 28039485 PMCID: PMC5354781 DOI: 10.18632/oncotarget.14266] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2016] [Accepted: 12/01/2016] [Indexed: 12/20/2022] Open
Abstract
Interleukin-17A has been identified as a driver of hepatic stellate cell activation and plays a critical role in the pathogenesis of hepatic fibrosis. However, the underlining fibrosis-promoting mechanism of IL-17A is far from understood. Here we aimed to define whether hepatocytes directly respond to IL-17A stimulation and are associated with the development of hepatic fibrosis. The functional significance of IL-17A was evaluated in bile duct ligation (BDL) or thioacetamide (TAA) injection-induced mouse models of hepatic fibrosis. Human cirrhosis and control tissues were obtained from the patients with cirrhosis who received an open surgical repair process. Neutralizing IL-17A promoted the resolution of BDL or TAA-induced acute or chronic inflammation and fibrosis, resulted in a shift of the suppressive immune response in fibrotic liver toward a Th1-type immune response, and restored autophagy activity in both cholestatic and hepatotoxic liver injury induced fibrotic liver tissues, which was accompanied by a significant inhibition of STAT3 phosphorylation. Moreover, we found that IL-17A stimulated the concentration-and time-dependent phosphorylation of STAT3 in AML-12 liver cells. Blocking STAT3 with a specific inhibitor STATTIC or STAT3 siRNA protected from the IL-17A-induced autophagy suppression in AML-12 cells, indicating that STAT3 mediates IL-17A-suppressed autophagy. Administration of IL-10, which activated STAT3 and inhibited autophagy, reversed the therapeutic effect of IL-17A antagonism in vivo. Our study suggests that the IL-17A/STAT3 signaling pathway plays a crucial role in the pathogenesis of hepatic fibrosis through suppressing hepatocellular autophagy and that blocking this pathway may provide therapeutic benefits for the treatment of hepatic fibrosis.
Collapse
|
|
39
|
Lavoie EG, Fausther M, Goree JR, Dranoff JA. The Cholangiocyte Adenosine-IL-6 Axis Regulates Survival During Biliary Cirrhosis. Gene Expr 2017; 17:327-340. [PMID: 28893353 PMCID: PMC5885153 DOI: 10.3727/105221617x15042723767876] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Epithelial response to injury is critical to the pathogenesis of biliary cirrhosis, and IL-6 has been suggested as a mediator of this phenomenon. Several liver cell types can secrete IL-6 following activation by various signaling molecules including circulating adenosine. The aims of this study were to assess whether adenosine can induce IL-6 secretion by cholangiocytes via the A2b adenosine receptor (A2bAR) and to determine the effect of A2bAR-sensitive IL-6 release on injury response in biliary cirrhosis. Human normal cholangiocyte H69 cells were used for in vitro studies to determine the mechanism by which adenosine and the A2bAR induce release of IL-6. In vivo, control and A2bAR-deficient mice were used to determine the roles of A2bAR-sensitive IL-6 release in biliary cirrhosis induced by common bile duct ligation (BDL). Additionally, the response to exogenous IL-6 was assessed in C57BL/6 and A2bAR-deficient mice. Adenosine induced IL-6 mRNA expression and protein secretion via A2bAR activation. Although activation of A2bAR induced cAMP and intracellular Ca2+ signals, only the Ca2+ signals were linked to IL-6 upregulation. After BDL, A2bAR-deficient mice have impaired survival, which is further impaired by exogenous IL-6; however, decreased survival is not due to changes in fibrosis and no changes in inflammatory cells. Exogenous IL-6 is associated with the increased presence of bile infarcts. Extracellular adenosine induces cholangiocyte IL-6 release via the A2bAR. This signaling pathway is important in the pathogenesis of injury response in biliary cirrhosis but does not alter fibrosis. Adenosine upregulates IL-6 release by cholangiocytes via the A2bAR in a calcium-sensitive fashion. Mice deficient in A2bAR experience impaired survival after biliary cirrhosis induced by common bile duct ligation independent of changes in fibrosis.
Collapse
Affiliation(s)
- Elise G. Lavoie
- *Division of Gastroenterology and Hepatology, University of Arkansas for Medical Sciences, Little Rock, AR, USA
- †Research Service, Central Arkansas VA Healthcare System, Little Rock, AR, USA
| | - Michel Fausther
- *Division of Gastroenterology and Hepatology, University of Arkansas for Medical Sciences, Little Rock, AR, USA
- †Research Service, Central Arkansas VA Healthcare System, Little Rock, AR, USA
| | - Jessica R. Goree
- *Division of Gastroenterology and Hepatology, University of Arkansas for Medical Sciences, Little Rock, AR, USA
- †Research Service, Central Arkansas VA Healthcare System, Little Rock, AR, USA
| | - Jonathan A. Dranoff
- *Division of Gastroenterology and Hepatology, University of Arkansas for Medical Sciences, Little Rock, AR, USA
- †Research Service, Central Arkansas VA Healthcare System, Little Rock, AR, USA
| |
Collapse
|
|
40
|
Abstract
Cholestasis is a clinical disorder defined as an impairment of bile flow, and that leads to toxic bile acid (BA) accumulation in hepatocytes. Here, we investigated the hepatoprotective effect of Yinchenhaotang (YCHT), a well-known formulae for the treatment of jaundice and liver disorders, against the cholestasis using the α-naphthylisothiocyanate (ANIT)-induced cholestasis in male Wistar rats. ANIT feeding induced significant cholestasis with substantially increased intrahepatic retention of hydrophobic BAs. The dynamic changes of serum and liver BAs indicated that YCHT was able to attenuate ANIT-induced BA perturbation, which is consistent with the histopathological findings that YCHT significantly decreased the liver damage. YCHT treatment substantially reduced serum alanine aminotransferase (ALT), alkaline phosphatase (AST), total bilirubin (TBIL) and direct bilirubin (DBIL) with minimal bile duct damage in the ANIT treated rats. Elevated mRNA expression of liver IL-6, IL-17A, IL-17F, TGF-β1, α-SMA, TGR5, NTCP, OATP1a1, and ileum ASBT and decreased liver IL-10, FXR, CAR, VDR, BSEP, MRP2, MRP3, MRP4 was also observed in ANIT-induced cholestasis but were attenuated or normalized by YCHT. Our results demonstrated that the BA profiles were significantly altered with ANIT intervention and YCHT possesses the hepatoprotective potential against cholestatic liver injury induced by hepatotoxin such as ANIT.
Collapse
|
|
41
|
Said MM, Ezz MK, Matloub AA. Protective effect of sulfated polysaccharide isolated fromUlva fasciataagainst galactosamine-induced liver injury in rats. J Food Biochem 2017. [DOI: 10.1111/jfbc.12383] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Affiliation(s)
- Mahmoud M. Said
- Biochemistry Department, Faculty of Science; Ain Shams University; Cairo Egypt
| | - Magda K. Ezz
- Biochemistry Department, Faculty of Science; Ain Shams University; Cairo Egypt
| | - Azza A. Matloub
- Pharmacognosy Department, Research of Pharmaceutical and Drug Division; National Research Center; Dokki Giza Egypt
| |
Collapse
|
|
42
|
Obeticholic acid protects against carbon tetrachloride-induced acute liver injury and inflammation. Toxicol Appl Pharmacol 2017; 314:39-47. [DOI: 10.1016/j.taap.2016.11.006] [Citation(s) in RCA: 59] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2016] [Revised: 11/07/2016] [Accepted: 11/14/2016] [Indexed: 12/12/2022]
|
|
43
|
de Jonge J, Olthoff KM. Liver regeneration. BLUMGART'S SURGERY OF THE LIVER, BILIARY TRACT AND PANCREAS, 2-VOLUME SET 2017:93-109.e7. [DOI: 10.1016/b978-0-323-34062-5.00006-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
|
|
44
|
Mazzolini G, Sowa JP, Canbay A. Cell death mechanisms in human chronic liver diseases: a far cry from clinical applicability. Clin Sci (Lond) 2016; 130:2121-2138. [DOI: 10.1042/cs20160035] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/30/2023]
Abstract
The liver is constantly exposed to a host of injurious stimuli. This results in hepatocellular death mainly by apoptosis and necrosis, but also due to autophagy, necroptosis, pyroptosis and in some cases by an intricately balanced combination thereof. Overwhelming and continuous cell death in the liver leads to inflammation, fibrosis, cirrhosis, and eventually hepatocellular carcinoma. Although data from various disease models may suggest a specific (predominant) cell death mode for different aetiologies, the clinical reality is not as clear cut. Reliable and non-invasive cell death markers are not available in general practice and assessment of cell death mode to absolute certainty from liver biopsies does not seem feasible, yet. Various aetiologies probably induce different predominant cell death modes within the liver, although the death modes involved may change during disease progression. Moreover, current methods applicable in patients are limited to surrogate markers for apoptosis (M30), and possibly for pyroptosis (IL-1 family) and necro(pto)sis (HMGB1). Although markers for some death modes are not available at all (autophagy), others may not be specific for a cell death mode or might not always definitely indicate dying cells. Physicians need to take care in asserting the presence of cell death. Still the serum-derived markers are valuable tools to assess severity of chronic liver diseases. This review gives a short overview of known hepatocellular cell death modes in various aetiologies of chronic liver disease. Also the limitations of current knowledge in human settings and utilization of surrogate markers for disease assessment are summarized.
Collapse
Affiliation(s)
- Guillermo Mazzolini
- Department for Gastroenterology and Hepatology, University Hospital, University Duisburg-Essen, 45147 Essen, Germany
- Gene Therapy Laboratory, Instituto de Investigaciones Medicas Aplicadas, Universidad Austral-CONICET (Consejo Nacional de Investigaciones Científicas y Técnicas), Pilar Centro, Buenos Aires, Argentina
| | - Jan-Peter Sowa
- Department for Gastroenterology and Hepatology, University Hospital, University Duisburg-Essen, 45147 Essen, Germany
| | - Ali Canbay
- Department for Gastroenterology and Hepatology, University Hospital, University Duisburg-Essen, 45147 Essen, Germany
| |
Collapse
|
|
45
|
Aoki H, Aoki M, Yang J, Katsuta E, Mukhopadhyay P, Ramanathan R, Woelfel IA, Wang X, Spiegel S, Zhou H, Takabe K. Murine model of long-term obstructive jaundice. J Surg Res 2016; 206:118-125. [PMID: 27916350 PMCID: PMC5142243 DOI: 10.1016/j.jss.2016.07.020] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2016] [Revised: 06/16/2016] [Accepted: 07/08/2016] [Indexed: 02/06/2023]
Abstract
BACKGROUND With the recent emergence of conjugated bile acids as signaling molecules in cancer, a murine model of obstructive jaundice by cholestasis with long-term survival is in need. Here, we investigated the characteristics of three murine models of obstructive jaundice. METHODS C57BL/6J mice were used for total ligation of the common bile duct (tCL), partial common bile duct ligation (pCL), and ligation of left and median hepatic bile duct with gallbladder removal (LMHL) models. Survival was assessed by Kaplan-Meier method. Fibrotic change was determined by Masson-Trichrome staining and Collagen expression. RESULTS Overall, 70% (7 of 10) of tCL mice died by day 7, whereas majority 67% (10 of 15) of pCL mice survived with loss of jaundice. A total of 19% (3 of 16) of LMHL mice died; however, jaundice continued beyond day 14, with survival of more than a month. Compensatory enlargement of the right lobe was observed in both pCL and LMHL models. The pCL model demonstrated acute inflammation due to obstructive jaundice 3 d after ligation but jaundice rapidly decreased by day 7. The LHML group developed portal hypertension and severe fibrosis by day 14 in addition to prolonged jaundice. CONCLUSIONS The standard tCL model is too unstable with high mortality for long-term studies. pCL may be an appropriate model for acute inflammation with obstructive jaundice, but long-term survivors are no longer jaundiced. The LHML model was identified to be the most feasible model to study the effect of long-term obstructive jaundice.
Collapse
Affiliation(s)
- Hiroaki Aoki
- Division of Surgical Oncology, Department of Surgery, Virginia Commonwealth University School of Medicine, Richmond, Virginia; Department of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine, Richmond, Virginia
| | - Masayo Aoki
- Division of Surgical Oncology, Department of Surgery, Virginia Commonwealth University School of Medicine, Richmond, Virginia; Department of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine, Richmond, Virginia
| | - Jing Yang
- Department of Microbiology and Immunology, Virginia Commonwealth University School of Medicine, Richmond, Virginia
| | - Eriko Katsuta
- Division of Surgical Oncology, Department of Surgery, Virginia Commonwealth University School of Medicine, Richmond, Virginia; Department of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine, Richmond, Virginia
| | - Partha Mukhopadhyay
- Division of Surgical Oncology, Department of Surgery, Virginia Commonwealth University School of Medicine, Richmond, Virginia; Department of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine, Richmond, Virginia
| | - Rajesh Ramanathan
- Division of Surgical Oncology, Department of Surgery, Virginia Commonwealth University School of Medicine, Richmond, Virginia
| | - Ingrid A Woelfel
- Division of Surgical Oncology, Department of Surgery, Virginia Commonwealth University School of Medicine, Richmond, Virginia; Department of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine, Richmond, Virginia
| | - Xuan Wang
- Department of Microbiology and Immunology, Virginia Commonwealth University School of Medicine, Richmond, Virginia
| | - Sarah Spiegel
- Department of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine, Richmond, Virginia
| | - Huiping Zhou
- Department of Microbiology and Immunology, Virginia Commonwealth University School of Medicine, Richmond, Virginia
| | - Kazuaki Takabe
- Division of Surgical Oncology, Department of Surgery, Virginia Commonwealth University School of Medicine, Richmond, Virginia; Department of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine, Richmond, Virginia; Division of Breast Surgery, Department of Surgical Oncology, Roswell Park Cancer Institute, Buffalo, New York.
| |
Collapse
|
|
46
|
Okabe H, Yang J, Sylakowski K, Yovchev M, Miyagawa Y, Nagarajan S, Chikina M, Thompson M, Oertel M, Baba H, Monga SP, Nejak-Bowen KN. Wnt signaling regulates hepatobiliary repair following cholestatic liver injury in mice. Hepatology 2016; 64:1652-1666. [PMID: 27533619 PMCID: PMC5074849 DOI: 10.1002/hep.28774] [Citation(s) in RCA: 77] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2016] [Accepted: 08/04/2016] [Indexed: 12/15/2022]
Abstract
UNLABELLED Hepatic repair is directed chiefly by the proliferation of resident mature epithelial cells. Furthermore, if predominant injury is to cholangiocytes, the hepatocytes can transdifferentiate to cholangiocytes to assist in the repair and vice versa, as shown by various fate-tracing studies. However, the molecular bases of reprogramming remain elusive. Using two models of biliary injury where repair occurs through cholangiocyte proliferation and hepatocyte transdifferentiation to cholangiocytes, we identify an important role of Wnt signaling. First we identify up-regulation of specific Wnt proteins in the cholangiocytes. Next, using conditional knockouts of Wntless and Wnt coreceptors low-density lipoprotein-related protein 5/6, transgenic mice expressing stable β-catenin, and in vitro studies, we show a role of Wnt signaling through β-catenin in hepatocyte to biliary transdifferentiation. Last, we show that specific Wnts regulate cholangiocyte proliferation, but in a β-catenin-independent manner. CONCLUSION Wnt signaling regulates hepatobiliary repair after cholestatic injury in both β-catenin-dependent and -independent manners. (Hepatology 2016;64:1652-1666).
Collapse
Affiliation(s)
- Hirohisa Okabe
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA,Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Jing Yang
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA
| | - Kyle Sylakowski
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA
| | - Mladen Yovchev
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA
| | - Yoshitaka Miyagawa
- Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA
| | - Shanmugam Nagarajan
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA
| | - Maria Chikina
- Department of Computational and Systems Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA
| | - Michael Thompson
- Department of Pediatrics, Nationwide Children’s Hospital, Columbus, OH
| | - Michael Oertel
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA
| | - Hideo Baba
- Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Satdarshan P Monga
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA,Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA
| | | |
Collapse
|
|
47
|
Sakamoto K, Khai NC, Wang Y, Irie R, Takamatsu H, Matsufuji H, Kosai KI. Heparin-binding epidermal growth factor-like growth factor and hepatocyte growth factor inhibit cholestatic liver injury in mice through different mechanisms. Int J Mol Med 2016; 38:1673-1682. [PMID: 27779646 PMCID: PMC5117744 DOI: 10.3892/ijmm.2016.2784] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2016] [Accepted: 09/02/2016] [Indexed: 12/23/2022] Open
Abstract
In contrast to hepatocyte growth factor (HGF), the therapeutic potential and pathophysiologic roles of heparin-binding epidermal growth factor-like growth factor (HB-EGF) in liver diseases remain relatively unknown. To address the lack of effective pharmacologic treatments for cholestatic liver injuries, as well as to clarify the biologic features of these growth factors, we explored the effects of HB-EGF and HGF in mice with cholestatic liver injury induced by bile duct ligation (BDL). The mice were assessed 3, 5 and/or 14 days after BDL (acute, subacute and/or chronic phases, respectively) and intravenous injection of adenoviral vector expressing LacZ (control), HB-EGF, HGF, or HB-EGF and HGF. HB-EGF, HGF, or a combination of the growth factors exerted potent antioncotic (antinecrotic), antiapoptotic, anticholestatic, and regenerative effects on hepatocytes in vivo, whereas no robust antiapoptotic or regenerative effects were detected in interlobular bile ducts. Based on serum transaminase levels, the acute protective effects of HB-EGF on hepatocytes were greater than those of HGF. On the other hand, liver fibrosis and cholestasis during the chronic phase were more potently inhibited by HGF compared with HB-EGF. Compared with either growth factor alone, combining HB-EGF and HGF produced greater anticholestatic and regenerative effects during the chronic phase. Taken together, these findings suggest that HB-EGF and HGF inhibited BDL-induced cholestatic liver injury, predominantly by exerting acute cytoprotective and chronic antifibrotic effects, respectively; combining the growth factors enhanced the anticholestatic effects and liver regeneration during the chronic phase. Our results contribute to a better understanding of the pathophysiologic roles of HB-EGF and HGF, as well as to the development of novel effective therapies for cholestatic liver injuries.
Collapse
Affiliation(s)
- Kouichi Sakamoto
- Department of Gene Therapy and Regenerative Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima 890-8544, Japan
| | - Ngin Cin Khai
- Department of Gene Therapy and Regenerative Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima 890-8544, Japan
| | - Yuqing Wang
- Department of Gene Therapy and Regenerative Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima 890-8544, Japan
| | - Rie Irie
- Department of Gene Therapy and Regenerative Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima 890-8544, Japan
| | - Hideo Takamatsu
- Department of Pediatric Surgery, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima 890-8544, Japan
| | - Hiroshi Matsufuji
- Department of Pediatric Surgery, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima 890-8544, Japan
| | - Ken-Ichiro Kosai
- Department of Gene Therapy and Regenerative Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima 890-8544, Japan
| |
Collapse
|
|
48
|
Hu HH, Liu J, Lin YL, Luo WS, Chu YJ, Chang CL, Jen CL, Lee MH, Lu SN, Wang LY, You SL, Yang HI, Chen CJ. The rs2296651 (S267F) variant on NTCP (SLC10A1) is inversely associated with chronic hepatitis B and progression to cirrhosis and hepatocellular carcinoma in patients with chronic hepatitis B. Gut 2016; 65:1514-21. [PMID: 26642861 DOI: 10.1136/gutjnl-2015-310686] [Citation(s) in RCA: 76] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2015] [Accepted: 11/09/2015] [Indexed: 02/06/2023]
Abstract
OBJECTIVE The sodium taurocholate co-transporting polypeptide (NTCP), encoded by SLC10A1, was recently identified as a receptor for HBV. We assessed the association of the p.Ser267Phe variant (rs2296651) with chronic hepatitis B (CHB) serostatus, cirrhosis and hepatocellular carcinoma (HCC) in patients with CHB. DESIGN The variant was genotyped in 3801 patients with CHB and 3801 matched hepatitis B surface antigen (HBsAg) seronegative individuals. ORs with 95% CIs for the variant's association with CHB, cirrhosis and HCC were estimated using logistic regression. RESULTS In patients with CHB, the S267F variant was observed in 515 (18.5%) controls, 40 (17.2%) cirrhosis only cases, 49 (13.2%) non-cirrhotic HCC cases, and 52 (12.7%) cirrhotic-HCC cases. After adjustment for known risk factors, S267F was significantly associated with decreased risk for cirrhosis (OR 0.65 (95% CI 0.49 to 0.86), p=0.002) and HCC (OR 0.55 (95% CI 0.42 to 0.72), p<0.001). This association persisted for non-cirrhotic and cirrhotic-HCC. Compared with patients with HBV DNA levels greater than 10(5) copies/mL who carried the GG genotype, patients who had undetectable HBV DNA and the GA or AA genotypes had a 25-fold decreased risk of developing HCC (OR 0.04 (95% CI 0.02 to 0.11), p<0.001). The AA genotype was also associated with HBsAg seronegativity (OR 0.13 (95% CI 0.05 to 0.34), p<0.001). CONCLUSIONS The SLC10A1 (NTCP) S267F variant is independently associated with decreased risk of cirrhosis and HCC, and resistance to CHB infection. Together with serum HBV DNA levels, S267F may help to identify patients with CHB with very low risk of HCC.
Collapse
Affiliation(s)
- Hui-Han Hu
- Genomics Research Center, Academia Sinica, Taipei, Taiwan
| | - Jessica Liu
- Genomics Research Center, Academia Sinica, Taipei, Taiwan
| | - Yu-Ling Lin
- Genomics Research Center, Academia Sinica, Taipei, Taiwan
| | - Wun-Sheng Luo
- Genomics Research Center, Academia Sinica, Taipei, Taiwan
| | - Yu-Ju Chu
- Genomics Research Center, Academia Sinica, Taipei, Taiwan
| | - Chia-Lin Chang
- Genomics Research Center, Academia Sinica, Taipei, Taiwan
| | - Chin-Lan Jen
- Genomics Research Center, Academia Sinica, Taipei, Taiwan
| | - Mei-Hsuan Lee
- Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan
| | - Sheng-Nan Lu
- Department of Gastroenterology, Chang-Gung Memorial Hospital, Kaohsiung, Taiwan
| | - Li-Yu Wang
- Department of Medicine, Mackay Medical College, New Taipei City, Taiwan
| | - San-Lin You
- Genomics Research Center, Academia Sinica, Taipei, Taiwan
| | - Hwai-I Yang
- Genomics Research Center, Academia Sinica, Taipei, Taiwan Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan
| | - Chien-Jen Chen
- Genomics Research Center, Academia Sinica, Taipei, Taiwan Graduate Institute of Epidemiology and Preventative Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan
| | | |
Collapse
|
|
49
|
Turk O, Badak B, Ates E, Dundar E, Sutken E. The role of growth factors on hepatic damage in rats with obstructive jaundice. SPRINGERPLUS 2016; 5:1274. [PMID: 27540507 PMCID: PMC4975730 DOI: 10.1186/s40064-016-2919-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/20/2015] [Accepted: 07/27/2016] [Indexed: 01/20/2023]
Abstract
In this study, we investigated the affect and the role of growth factors on liver damage. 110 Sprague–Dawley rats were divided into 11 groups: a sham group, a control group, HGF, EGF, IGF, TGF groups of irreversible jaundiced rats and a control group and HGF, EGF, IGF, and TGF groups of reversible jaundiced rats (n = 10). In the irreversible jaundiced groups, the common bile duct was explorated, double ligated, and cut. 150 μg/kg/day HGF, 5 μg/kg/day EGF, 5 μg/kg/day IGF, and 5 μg/kg/day TGF β-1 were injected intraperitoneally after the seventh post-operative day. In the reversible jaundiced group, the common bile duct was ligated and the ligation was resolved on the seventh post-operative day. For 5 days, growth factors were injected at the same dose. Ductal proliferation scores significantly decreased after growth factor administration in the EGF-A and TGF-A groups. Furthermore, ductal proliferation was decreased in the TGF-B group. As a result of this study, HGF was effective in the irreversible jaundiced groups and ineffective in the reversible jaundice groups. EGF was effective in the reversible jaundiced groups and ineffective in the irreversible jaundiced groups. In both the irreversible jaundiced and reversible jaundiced groups, IGF was ineffective, although TGF β-1 was effective. We believe that these results arise from the positive effects of effective doses of growth factor on liver damage.
Collapse
Affiliation(s)
- Ozgur Turk
- Department of General Surgery, Private Esentepe Hospital, Bursa, Turkey
| | - Bartu Badak
- Department of General Surgery, Eskisehir Osmangazi University Medical Faculty, Eskisehir, Turkey
| | - Ersin Ates
- Department of General Surgery, Eskisehir Osmangazi University Medical Faculty, Eskisehir, Turkey
| | - Emine Dundar
- Department of Pathology, Eskisehir Osmangazi University Medical Faculty, Eskisehir, Turkey
| | - Emine Sutken
- Department of Biochemistry, Eskisehir Osmangazi University Medical Faculty, Eskisehir, Turkey
| |
Collapse
|
|
50
|
Yao L, Chen W, Han C, Wu T. Microsomal prostaglandin E synthase-1 protects against Fas-induced liver injury. Am J Physiol Gastrointest Liver Physiol 2016; 310:G1071-80. [PMID: 27102561 PMCID: PMC4935489 DOI: 10.1152/ajpgi.00327.2015] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/17/2015] [Accepted: 04/17/2016] [Indexed: 01/31/2023]
Abstract
Microsomal prostaglandin E synthase-1 (mPGES-1) is the terminal enzyme for the synthesis of prostaglandin E2 (PGE2), a proproliferative and antiapoptotic lipid molecule important for tissue regeneration and injury repair. In this study, we developed transgenic (Tg) mice with targeted expression of mPGES-1 in the liver to assess Fas-induced hepatocyte apoptosis and acute liver injury. Compared with wild-type (WT) mice, the mPGES-1 Tg mice showed less liver hemorrhage, lower serum alanine transaminase (ALT) and aspartate transaminase (AST) levels, less hepatic necrosis/apoptosis, and lower level of caspase cascade activation after intraperitoneal injection of the anti-Fas antibody Jo2. Western blotting analysis revealed increased expression and activation of the serine/threonine kinase Akt and associated antiapoptotic molecules in the liver tissues of Jo2-treated mPGES-1 Tg mice. Pretreatment with the mPGES-1 inhibitor (MF63) or the Akt inhibitor (Akt inhibitor V) restored the susceptibility of the mPGES-1 Tg mice to Fas-induced liver injury. Our findings provide novel evidence that mPGES-1 prevents Fas-induced liver injury through activation of Akt and related signaling and suggest that induction of mPGES-1 or treatment with PGE2 may represent important therapeutic strategy for the prevention and treatment of Fas-associated liver injuries.
Collapse
Affiliation(s)
| | | | | | - Tong Wu
- Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, Louisiana
| |
Collapse
|