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1
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Jones PC, Von Hoff DD. Vitamin A Metabolism and Resistance of Hepatic Metastases to Immunotherapy. Mol Cancer Ther 2025; 24:345-353. [PMID: 39363636 DOI: 10.1158/1535-7163.mct-24-0367] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2024] [Revised: 08/05/2024] [Accepted: 09/27/2024] [Indexed: 10/05/2024]
Abstract
The liver is an immune-tolerant organ, allowing for organ transplantation with less immune suppression compared with other organs. It also provides fertile soil for tumor metastases, which tend to be more resistant to checkpoint blockade immunotherapy than metastases in other organs. This resistance may result from the sum of incremental evolutionary adaptions in various cell types to prevent overaction to antigens absorbed from the gut into the portal circulation or it might involve a central mechanism. Here, we propose that metabolism of vitamin A, which is highly concentrated in the liver, is a root source of tolerance and resistance of hepatic metastases to checkpoint blockade. Suppression of retinoic acid synthesis from vitamin A with disulfiram may mitigate tolerance and produce enhanced immunotherapy treatment results for patients with liver metastases.
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Affiliation(s)
- Peter C Jones
- Saint John's Cancer Institute, Santa Monica, California
| | - Daniel D Von Hoff
- HonorHealth Research Institute (HHRI), Scottsdale, Arizona
- Translational Genomics Research Institute (TGen) a Part of City of Hope, Phoenix, Arizona
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2
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He XY, Xiong XJ, Liu MJ, Liang JT, Liu FY, Xiao JY, Wu LJ. Dahuang Zhechong Pill Alleviates Liver Fibrosis Progression by Regulating p38 MAPK/NF-κ B/TGF-β1 Pathway. Chin J Integr Med 2024; 30:1113-1120. [PMID: 38888716 DOI: 10.1007/s11655-024-3801-x] [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] [Accepted: 11/06/2023] [Indexed: 06/20/2024]
Abstract
OBJECTIVE To explore the effect and mechanism of Dahuang Zhechong Pill (DHZCP) on liver fibrosis. METHODS Liver fibrosis cell model was induced by transforming growth factor-β (TGF-β) in hepatic stellate cells (HSC-T6). DHZCP medicated serum (DMS) was prepared in rats. HSC-T6 cells were divided into the control (15% normal blank serum culture), TGF-β (15% normal blank serum + 5 ng/mL TGF-β), DHZCP (15% DMS + 5 ng/mL TGF-β), DHZCP+PDTC [15% DMS + 4 mmol/L ammonium pyrrolidine dithiocarbamate (PDTC)+ 5 ng/mL TGF-β], and PDTC groups (4 mmol/L PDTC + 5 ng/mL TGF-β). Cell activity was detected by cell counting kit 8 and levels of tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, IL-6, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) in the cell supernatant were determined by enzyme-linked immunosorbnent assay. Western blot was used to measure the expressions of p38 mitogen-activated protein kinase/nuclear factor kappa B/transforming growth factor-β1 (p38 MAPK/NF-κ B/TGF-β1) pathway related proteins, and the localization and expressions of these proteins were observed by immunofluorescence staining. RESULTS DHZCP improves the viability of cells damaged by TGF-β and reduces inflammatory cytokines and ALT and AST levels in the supernatant of HSC-T6 cells induced with TGF-β (P<0.05 or P<0.01). Compared with the TGF-β group, NF-κ B p65 levels in the DHZCP group were decreased (P<0.05). p38 MAPK and NF-κ B p65 levels in the DHZCP+PDTC were also reduced (P<0.01). Compared with the TGF-β group, the protein expression of Smad2 showed a downward trend in the DHZCP, DHZCP+PDTC, and PDTC groups (all P<0.01), and the decreasing trend of Samd3 was statistically significant only in DHZCP+PDTC group (P<0.01), whereas Smad7 was increased (P<0.05 or P<0.01). CONCLUSION DHZCP can inhibit the process of HSC-T6 cell fibrosis by down-regulating the expression of p38 MAPK/NF-κ B/TGF-β1 pathway.
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Affiliation(s)
- Xiao-Yan He
- School of Public Health, Chengdu University of Traditional Chinese Medicine, Chengdu, 610036, China
| | - Xiao-Jiao Xiong
- Department of Neurology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, 610072, China
| | - Mei-Jun Liu
- Department of Neurology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, 610072, China
| | - Jing-Tao Liang
- Department of Neurology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, 610072, China
| | - Fu-You Liu
- Department of Neurology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, 610072, China
| | - Jing-Yi Xiao
- School of Public Health, Chengdu University of Traditional Chinese Medicine, Chengdu, 610036, China
| | - Li-Juan Wu
- School of Public Health, Chengdu University of Traditional Chinese Medicine, Chengdu, 610036, China.
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Tian Y, Sun D, Liu N, Zhao J, Zhao T, Liu X, Dong X, Dong L, Wang W, Jiao P, Ma J. Biomimetic mesenchymal stem cell membrane-coated nanoparticle delivery of MKP5 inhibits hepatic fibrosis through the IRE/XBP1 pathway. J Nanobiotechnology 2024; 22:741. [PMID: 39609656 PMCID: PMC11606114 DOI: 10.1186/s12951-024-03029-8] [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: 07/31/2024] [Accepted: 11/19/2024] [Indexed: 11/30/2024] Open
Abstract
Hepatic fibrosis is a common disease with high morbidity and mortality rates. The complex and poorly understood mechanisms underlying hepatic fibrosis represent a significant challenge for the development of more effective therapeutic strategies. MKP5 is a potential regulator of multiple fibrotic diseases. However, its precise role and mechanism of action in hepatic fibrosis remains unclear. This study identified a reduction in MKP5 expression in fibrotic liver tissues of mice treated with CCl4 and observed that MKP5 knockout mice exhibited a more pronounced development of hepatic fibrosis. In addition, RNA-seq data indicated activation of protein processing in the endoplasmic reticulum signalling pathway in fibrotic liver tissues of mice lacking MKP5. Mechanistically, MKP5 inhibits the activation of hepatic stellate cells (HSCs) and hepatocyte apoptosis through the regulation of the IRE/XBP1 pathway. Based on these findings, we developed PLGA-MKP5 nanoparticles coated with a mesenchymal stem cell membrane (MSCM). Our results demonstrated that MSCM-PLGA-MKP5 was most effective in attenuating hepatic inflammation and fibrosis in murine models by modulating the IRE/XBP1 axis. This study contributes to the current understanding of the pathogenesis of hepatic fibrosis, suggesting that the targeted delivery of MKP5 via a nano-delivery system may represent a promising therapeutic approach to treat hepatic fibrosis.
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Affiliation(s)
- Yafei Tian
- School of Pharmaceutical Sciences, Jilin University, 1266 Fujin Road, Changchun, 130021, Jilin, China
| | - Dandan Sun
- School of Pharmaceutical Sciences, Jilin University, 1266 Fujin Road, Changchun, 130021, Jilin, China
| | - Na Liu
- School of Pharmaceutical Sciences, Jilin University, 1266 Fujin Road, Changchun, 130021, Jilin, China
| | - Jianan Zhao
- School of Pharmaceutical Sciences, Jilin University, 1266 Fujin Road, Changchun, 130021, Jilin, China
| | - Tongjian Zhao
- School of Pharmaceutical Sciences, Jilin University, 1266 Fujin Road, Changchun, 130021, Jilin, China
| | - Xiaonan Liu
- School of Pharmaceutical Sciences, Jilin University, 1266 Fujin Road, Changchun, 130021, Jilin, China
| | - Xinzhe Dong
- School of Pharmaceutical Sciences, Jilin University, 1266 Fujin Road, Changchun, 130021, Jilin, China
| | - Li Dong
- School of Pharmaceutical Sciences, Jilin University, 1266 Fujin Road, Changchun, 130021, Jilin, China
| | - Wei Wang
- School of Pharmaceutical Sciences, Jilin University, 1266 Fujin Road, Changchun, 130021, Jilin, China
| | - Ping Jiao
- School of Pharmaceutical Sciences, Jilin University, 1266 Fujin Road, Changchun, 130021, Jilin, China.
| | - Jie Ma
- School of Pharmaceutical Sciences, Jilin University, 1266 Fujin Road, Changchun, 130021, Jilin, China.
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4
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Ge M, Zou H, Chen J, Zhang Q, Li C, Yang J, Wu J, Xie X, Liu J, Lei L, Peng S, Nie H. Cellular fibronectin-targeted fluorescent aptamer probes for early detection and staging of liver fibrosis. Acta Biomater 2024:S1742-7061(24)00614-7. [PMID: 39433198 DOI: 10.1016/j.actbio.2024.10.022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2024] [Revised: 10/12/2024] [Accepted: 10/16/2024] [Indexed: 10/23/2024]
Abstract
Liver fibrosis is a key process in the progression of chronic liver disease to cirrhosis. Currently, early diagnosis and precise staging of liver fibrosis remain great challenges. Extracellular matrix (ECM) molecules expressed specifically during liver fibrosis are ideal targets for bioimaging and detection of liver fibrosis. Here, we report that fluorescent probes based on a nucleic acid aptamer (ZY-1) targeting cellular fibronectin (cFN), a critical ECM molecule significantly accumulating during liver fibrosis, are promising bioimaging agents for the staging of liver fibrosis. In the work, the outstanding binding affinity of ZY-1 to cFN was validated through an in vitro model of human-derived hepatic stellate cells (HSCs). Subsequently, we constructed different ZY-1-based fluorescent probes and explored the real-time imaging performance of these fluorescent probes in CCl4-induced mouse models of different liver fibrosis stages. The ZY-1-based fluorescent probes, for the first time, effectively identified and distinguished early-stage liver fibrosis (stage 3 of Ishak 6) from advanced liver fibrosis (stage 5 of Ishak 6). The proof-of-concept study provides compelling evidences that ZY-1-based probes are a promising tool for the early diagnosis and staging of liver fibrosis and paves the way for further development of clinical-related diagnosis strategies for fibrotic diseases of the liver and other organs. STATEMENT OF SIGNIFICANCE: Currently, early diagnosis and accurate staging of liver fibrosis continue to present significant challenges. This study demonstrates that fluorescent probes based on the nucleic acid aptamer ZY-1, which targets cellular fibronectin (cFN)-a crucial extracellular matrix (ECM) molecule that significantly accumulates during liver fibrosis-are promising bioimaging agents for staging liver fibrosis. The ZY-1-based fluorescent probes effectively identified and differentiated early-stage liver fibrosis from advanced liver fibrosis. This proof-of-concept study not only provides compelling evidence that ZY-1-based probes show promise for the early diagnosis and staging of liver fibrosis but also paves the way for further investigations into the use of ZY-1 in detecting other diseases associated with cFN.
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Affiliation(s)
- Mengjun Ge
- Department of Biomedical Sciences, College of Biology, Hunan University, Changsha, China
| | - Haitao Zou
- National Supercomputing Center in Changsha, College of Computer Science and Electronic Engineering, Hunan University, Changsha, China
| | - Jiahao Chen
- Department of Biomedical Sciences, College of Biology, Hunan University, Changsha, China
| | - Qinyao Zhang
- Cell Biology Research Group, Xiangya School of Stomatology, Central South University, Changsha, China
| | - Chang Li
- Department of Radiology, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Jiaxing Yang
- Department of Biomedical Sciences, College of Biology, Hunan University, Changsha, China
| | - Jiumei Wu
- Cell Biology Research Group, Xiangya School of Stomatology, Central South University, Changsha, China
| | - Xing Xie
- Cell Biology Research Group, Xiangya School of Stomatology, Central South University, Changsha, China
| | - Jun Liu
- Department of Radiology, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Lei Lei
- Cell Biology Research Group, Xiangya School of Stomatology, Central South University, Changsha, China.
| | - Shaoliang Peng
- National Supercomputing Center in Changsha, College of Computer Science and Electronic Engineering, Hunan University, Changsha, China
| | - Hemin Nie
- Department of Biomedical Sciences, College of Biology, Hunan University, Changsha, China.
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Xue X, Li Y, Zhang S, Yao Y, Peng C, Li Y. Hydroxysafflor yellow A exerts anti-fibrotic and anti-angiogenic effects through miR-29a-3p/PDGFRB axis in liver fibrosis. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2024; 132:155830. [PMID: 38959553 DOI: 10.1016/j.phymed.2024.155830] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/04/2024] [Revised: 06/03/2024] [Accepted: 06/14/2024] [Indexed: 07/05/2024]
Abstract
BACKGROUND Liver fibrosis is a prevalent pathological process in chronic liver diseases characterized by excessive extracellular matrix (ECM) deposition and abnormal angiogenesis. Notably, hepatic stellate cells (HSCs) are the primary source of ECM. Activated HSCs not only secrete numerous pro-fibrotic cytokines but also are endowed with a pro-angiogenic phenotype to promote pathological angiogenesis. Therefore, targeted modulation of HSCs has emerged as a pivotal strategy for addressing liver fibrosis. Hydroxysafflor yellow A (HSYA) is a homology of medicine and food colourant with good pharmacological activity. However, the precise mechanisms of HSYA against liver fibrosis remain unclear. PURPOSE The objective of this study was to elucidate the impact of HSYA on liver fibrosis and pathological angiogenesis, as well as the underlying mechanisms in vitro and in vivo studies. METHODS The efficacy and mechanisms of HSYA on TGF-β1-induced HSCs and VEGFA-induced endothelial cells were investigated by MTT assay, EdU cell proliferation assay, cell scratch assay, Elisa assay, immunofluorescence assay, molecular docking, cell transfection assay, western blot analysis and RT-qPCR analysis. In CCl4-induced liver fibrosis mice model, H&E, Masson, and Sirius red staining were used to observe histopathology. Serum transaminase activity and liver biochemical indexes were tested by biochemical kit. Immunohistochemical, fluorescence in situ hybridization (FISH), western blot analysis and RT-qPCR analysis were implemented to determine the mechanism of HSYA in vivo. RESULTS Herein, our findings confirmed that HSYA inhibited the proliferation, migration and activation of HSCs, as evidenced by a reduction in cell viability, relative migration rate, EdU staining intensity, and pro-fibrotic mRNAs and proteins expression in vitro. Mechanistically, HSYA played an anti-fibrotic and anti-angiogenic role by partially silencing PDGFRB in activated HSCs, thereby disrupting PDGFRB/MEK/ERK signal transduction and inhibiting the expression of HIF-1α, VEGFA and VEGFR2 proteins. Importantly, PDGFRB was a target gene of miR-29a-3p. Treatment with HSYA reversed the down-regulation of miR-29a-3p and antagonized PDGFRB signaling pathway in TGF-β1-induced HSCs transfected with miR-29a-3p inhibitor. Consistent with our in vitro study, HSYA exhibited a good hepatoprotective effect in CCl4-induced liver fibrosis mice by reducing serum ALT and AST levels, decreasing the contents of four fibrosis indicators (HA, PIIIP, ColIV and LN) and hydroxyproline, and inhibiting the TGF-β1/TGFBR signaling pathway. In terms of mechanisms, HSYA alleviated pathological angiogenesis in fibrotic liver by deactivating PDGFRB signaling pathway and impairing the positive expression of CD31. Subsequently, FISH results further corroborated HSYA affected the activation of HSCs and angiogenesis achieved by the concurrent upregulation of miR-29a-3p and downregulation of α-SMA and VEGFA. Additionally, treatment with HSYA also forged a link between HSCs and endothelial cells, as supported by inhibiting the aberrant proliferation of endothelial cells. CONCLUSION Fundamentally, the current study has illustrated that HSYA ameliorates liver fibrosis by repressing HSCs-mediated pro-fibrotic and pro-angiogenic processes, which is contingent upon the regulatory effect of HSYA on the miR-29a-3p/PDGFRB axis. These findings provide compelling evidence bolstering the potential of HSYA as a therapeutic agent in liver fibrosis.
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Affiliation(s)
- Xinyan Xue
- State Key Laboratory of Southwestern Chinese Medicine Resources, Key Laboratory of Standardization for Chinese Herbal Medicine, Ministry of Education, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Yanzhi Li
- State Key Laboratory of Southwestern Chinese Medicine Resources, Key Laboratory of Standardization for Chinese Herbal Medicine, Ministry of Education, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Shenglin Zhang
- State Key Laboratory of Southwestern Chinese Medicine Resources, Key Laboratory of Standardization for Chinese Herbal Medicine, Ministry of Education, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Yuxin Yao
- State Key Laboratory of Southwestern Chinese Medicine Resources, Key Laboratory of Standardization for Chinese Herbal Medicine, Ministry of Education, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Cheng Peng
- State Key Laboratory of Southwestern Chinese Medicine Resources, Key Laboratory of Standardization for Chinese Herbal Medicine, Ministry of Education, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China.
| | - Yunxia Li
- State Key Laboratory of Southwestern Chinese Medicine Resources, Key Laboratory of Standardization for Chinese Herbal Medicine, Ministry of Education, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China.
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6
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Li Y, Chen L, Papadopoulos V. The mitochondrial translocator protein (TSPO, 18 kDa): A key multifunctional molecule in liver diseases. Biochimie 2024; 224:91-103. [PMID: 38065288 DOI: 10.1016/j.biochi.2023.11.013] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2023] [Revised: 11/23/2023] [Accepted: 11/29/2023] [Indexed: 08/23/2024]
Abstract
Translocator protein (TSPO, 18 kDa), previously known as peripheral-type benzodiazepine receptor, is an evolutionarily conserved and tryptophan-rich 169-amino-acid protein located on the outer mitochondrial membrane. TSPO plays a crucial role in various fundamental physiological functions and cellular processes. Its expression is altered in pathological conditions, thus rendering TSPO a potential tool for diagnostic imaging and an appealing therapeutic target. The investigation of synthetic TSPO ligands as both agonists and antagonists has provided valuable insights into the regulatory mechanisms and functional properties of TSPO. Recently, accumulating evidence has highlighted the significance of TSPO in liver diseases. However, a comprehensive summary of TSPO function in the normal liver and diverse liver diseases is lacking. This review aims to provide an overview of recent advances in understanding TSPO function in both normal liver cells and various liver diseases, with a particular emphasis on its involvement in liver fibrosis and inflammation and addresses the existing knowledge gaps in the field that require further investigation.
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Affiliation(s)
- Yuchang Li
- Department of Pharmacology and Pharmaceutical Sciences, Alfred E. Mann School of Pharmacy and Pharmaceutical Sciences, University of Southern California, Los Angeles, CA 90089, USA.
| | - Liting Chen
- Department of Pharmacology and Pharmaceutical Sciences, Alfred E. Mann School of Pharmacy and Pharmaceutical Sciences, University of Southern California, Los Angeles, CA 90089, USA
| | - Vassilios Papadopoulos
- Department of Pharmacology and Pharmaceutical Sciences, Alfred E. Mann School of Pharmacy and Pharmaceutical Sciences, University of Southern California, Los Angeles, CA 90089, USA.
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7
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Xue X, Li Y, Yao Y, Zhang S, Peng C, Li Y. A comprehensive review of miR-21 in liver disease: Big impact of little things. Int Immunopharmacol 2024; 134:112116. [PMID: 38696909 DOI: 10.1016/j.intimp.2024.112116] [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: 04/10/2024] [Accepted: 04/17/2024] [Indexed: 05/04/2024]
Abstract
microRNAs (miRNAs), a class of non-coding RNA with 20-24 nucleotides, are defined as the powerful regulators for gene expression. miR-21 is a multifunctional miRNA enriched in the circulatory system and multiple organs, which not only serves as a non-invasive biomarker in disease diagnosis, but also participates in many cellular activities. In various chronic liver diseases, the increase of miR-21 affects glycolipid metabolism, viral infection, inflammatory and immune cell activation, hepatic stellate cells activation and tissue fibrosis, and autophagy. Moreover, miR-21 is also a liaison in the deterioration of chronic liver disease to hepatocellular carcinoma (HCC), and it impacts on cell proliferation, apoptosis, migration, invasion, angiogenesis, immune escape, and epithelial-mesenchymal transformation by regulating target genes expression in different signaling pathways. In current research on miRNA therapy, some natural products can exert the hepatoprotective effects depending on the inhibition of miR-21 expression. In addition, miR-21-based therapeutic also play a role in regulating intracellular miR-21 levels and enhancing the efficacy of chemotherapy drugs. Herein, we systemically summarized the recent progress of miR-21 on biosynthesis, biomarker function, molecular mechanism and miRNA therapy in chronic liver disease and HCC, and looked forward to outputting some information to enable it from bench to bedside.
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Affiliation(s)
- Xinyan Xue
- State Key Laboratory of Southwestern Chinese Medicine Resources, Key Laboratory of Standardization for Chinese Herbal Medicine, Ministry of Education, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Yanzhi Li
- State Key Laboratory of Southwestern Chinese Medicine Resources, Key Laboratory of Standardization for Chinese Herbal Medicine, Ministry of Education, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Yuxin Yao
- State Key Laboratory of Southwestern Chinese Medicine Resources, Key Laboratory of Standardization for Chinese Herbal Medicine, Ministry of Education, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Shenglin Zhang
- State Key Laboratory of Southwestern Chinese Medicine Resources, Key Laboratory of Standardization for Chinese Herbal Medicine, Ministry of Education, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Cheng Peng
- State Key Laboratory of Southwestern Chinese Medicine Resources, Key Laboratory of Standardization for Chinese Herbal Medicine, Ministry of Education, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China.
| | - Yunxia Li
- State Key Laboratory of Southwestern Chinese Medicine Resources, Key Laboratory of Standardization for Chinese Herbal Medicine, Ministry of Education, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China.
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8
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Tavakoli Pirzaman A, Alishah A, Babajani B, Ebrahimi P, Sheikhi SA, Moosaei F, Salarfar A, Doostmohamadian S, Kazemi S. The Role of microRNAs in Hepatocellular Cancer: A Narrative Review Focused on Tumor Microenvironment and Drug Resistance. Technol Cancer Res Treat 2024; 23:15330338241239188. [PMID: 38634139 PMCID: PMC11025440 DOI: 10.1177/15330338241239188] [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: 11/22/2023] [Revised: 01/26/2024] [Accepted: 02/26/2024] [Indexed: 04/19/2024] Open
Abstract
Globally, hepatic cancer ranks fourth in terms of cancer-related mortality and is the sixth most frequent kind of cancer. Around 80% of liver cancers are hepatocellular carcinomas (HCC), which are the leading cause of cancer death. It is well known that HCC may develop resistance to the available chemotherapy treatments very fast. One of the biggest obstacles in providing cancer patients with appropriate care is drug resistance. According to reports, more than 90% of cancer-specific fatalities are caused by treatment resistance. By binding to the 3'-untranslated region of target messenger RNAs (mRNAs), microRNAs (miRNAs), a group of noncoding RNAs which are around 17 to 25 nucleotides long, regulate target gene expression. Moreover, they play role in the control of signaling pathways, cell proliferation, and cell death. As a result, miRNAs play an important role in the microenvironment of HCC by changing immune phenotypes, hypoxic conditions, and acidification, as well as angiogenesis and extracellular matrix components. Moreover, changes in miRNA levels in HCC can effectively resist cancer cells to chemotherapy by affecting various cellular processes such as autophagy, apoptosis, and membrane transporter activity. In the current work, we narratively reviewed the role of miRNAs in HCC, with a special focus on tumor microenvironment and drug resistance.
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Affiliation(s)
| | - Ali Alishah
- Student Research Committee, Babol University of Medical Sciences, Babol, Iran
| | - Bahareh Babajani
- Student Research Committee, Babol University of Medical Sciences, Babol, Iran
| | - Pouyan Ebrahimi
- Student Research Committee, Babol University of Medical Sciences, Babol, Iran
| | - Seyyed Ali Sheikhi
- Student Research Committee, Babol University of Medical Sciences, Babol, Iran
| | - Farhad Moosaei
- Student Research Committee, Babol University of Medical Sciences, Babol, Iran
| | | | | | - Sohrab Kazemi
- Cellular and Molecular Biology Research Center, Health Research Center, Babol University of Medical Sciences, Babol, Iran
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Kim HY, Sakane S, Eguileor A, Carvalho Gontijo Weber R, Lee W, Liu X, Lam K, Ishizuka K, Rosenthal SB, Diggle K, Brenner DA, Kisseleva T. The Origin and Fate of Liver Myofibroblasts. Cell Mol Gastroenterol Hepatol 2023; 17:93-106. [PMID: 37743012 PMCID: PMC10665929 DOI: 10.1016/j.jcmgh.2023.09.008] [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: 04/24/2023] [Revised: 09/14/2023] [Accepted: 09/14/2023] [Indexed: 09/26/2023]
Abstract
Liver fibrosis of different etiologies is a serious health problem worldwide. There is no effective therapy available for liver fibrosis except the removal of the underlying cause of injury or liver transplantation. Development of liver fibrosis is caused by fibrogenic myofibroblasts that are not present in the normal liver, but rather activate from liver resident mesenchymal cells in response to chronic toxic or cholestatic injury. Many studies indicate that liver fibrosis is reversible when the causative agent is removed. Regression of liver fibrosis is associated with the disappearance of activated myofibroblasts and resorption of the fibrous scar. In this review, we discuss the results of genetic tracing and cell fate mapping of hepatic stellate cells and portal fibroblasts, their specific characteristics, and potential phenotypes. We summarize research progress in the understanding of the molecular mechanisms underlying the development and reversibility of liver fibrosis, including activation, apoptosis, and inactivation of myofibroblasts.
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Affiliation(s)
- Hyun Young Kim
- Department of Medicine, University of California San Diego School of Medicine, La Jolla, California
| | - Sadatsugu Sakane
- Department of Medicine, University of California San Diego School of Medicine, La Jolla, California
| | - Alvaro Eguileor
- Department of Medicine, University of California San Diego School of Medicine, La Jolla, California
| | - Raquel Carvalho Gontijo Weber
- Department of Medicine, University of California San Diego School of Medicine, La Jolla, California; Department of Surgery, University of California San Diego School of Medicine, La Jolla, California
| | - Wonseok Lee
- Department of Medicine, University of California San Diego School of Medicine, La Jolla, California
| | - Xiao Liu
- Department of Medicine, University of California San Diego School of Medicine, La Jolla, California; Department of Surgery, University of California San Diego School of Medicine, La Jolla, California
| | - Kevin Lam
- Department of Medicine, University of California San Diego School of Medicine, La Jolla, California
| | - Kei Ishizuka
- Department of Medicine, University of California San Diego School of Medicine, La Jolla, California
| | - Sara Brin Rosenthal
- Center for Computational Biology and Bioinformatics, University of California San Diego, La Jolla, California
| | - Karin Diggle
- Department of Medicine, University of California San Diego School of Medicine, La Jolla, California; Department of Surgery, University of California San Diego School of Medicine, La Jolla, California
| | - David A Brenner
- Department of Medicine, University of California San Diego School of Medicine, La Jolla, California; Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California.
| | - Tatiana Kisseleva
- Department of Surgery, University of California San Diego School of Medicine, La Jolla, California.
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Shmarakov IO, Gusarova GA, Islam MN, Marhuenda-Muñoz M, Bhattacharya J, Blaner WS. Retinoids stored locally in the lung are required to attenuate the severity of acute lung injury in male mice. Nat Commun 2023; 14:851. [PMID: 36792627 PMCID: PMC9932169 DOI: 10.1038/s41467-023-36475-3] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Accepted: 02/01/2023] [Indexed: 02/17/2023] Open
Abstract
Retinoids are potent transcriptional regulators that act in regulating cell proliferation, differentiation, and other cellular processes. We carried out studies in male mice to establish the importance of local cellular retinoid stores within the lung alveolus for maintaining its health in the face of an acute inflammatory challenge induced by intranasal instillation of lipopolysaccharide. We also undertook single cell RNA sequencing and bioinformatic analyses to identify roles for different alveolar cell populations involved in mediating these retinoid-dependent responses. Here we show that local retinoid stores and uncompromised metabolism and signaling within the lung are required to lessen the severity of an acute inflammatory challenge. Unexpectedly, our data also establish that alveolar cells other than lipofibroblasts, specifically microvascular endothelial and alveolar epithelial cells, are able to take up lipoprotein-transported retinoid and to accumulate cellular retinoid stores that are directly used to respond to an acute inflammatory challenge.
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Affiliation(s)
- Igor O Shmarakov
- Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, 10032, USA.
- Department of Animal Sciences, School of Environmental and Biological Sciences, Rutgers, The State University of New Jersey, New Brunswick, NJ, 08901, USA.
| | - Galina A Gusarova
- Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, 10032, USA
| | - Mohammad N Islam
- Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, 10032, USA
| | - María Marhuenda-Muñoz
- Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, 10032, USA
- Centro de Investigación Biomédica en Red Fisiopatología de la Obesidad y la Nutrición (CIBEROBN), Instituto de Salud Carlos III, 28029, Madrid, Spain
- Department of Nutrition, Food Science and Gastronomy, School of Pharmacy and Food Sciences and XIA, Institute of Nutrition and Food Safety (INSA-UB), University of Barcelona, 08921, Santa Coloma de Gramenet, Spain
| | - Jahar Bhattacharya
- Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, 10032, USA
| | - William S Blaner
- Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, 10032, USA
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11
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Ali FEM, Abd El-Aziz MK, Sharab EI, Bakr AG. Therapeutic interventions of acute and chronic liver disorders: A comprehensive review. World J Hepatol 2023; 15:19-40. [PMID: 36744165 PMCID: PMC9896501 DOI: 10.4254/wjh.v15.i1.19] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2022] [Revised: 11/17/2022] [Accepted: 12/21/2022] [Indexed: 01/16/2023] Open
Abstract
Liver disorders are one of the most common pathological problems worldwide. It affects more than 1.5 billion worldwide. Many types of hepatic cells have been reported to be involved in the initiation and propagation of both acute and chronic liver diseases, including hepatocytes, Kupffer cells, sinusoidal endothelial cells, and hepatic stellate cells (HSCs). In addition, oxidative stress, cytokines, fibrogenic factors, microRNAs, and autophagy are also involved. Understanding the molecular mechanisms of liver diseases leads to discovering new therapeutic interventions that can be used in clinics. Recently, antioxidant, anti-inflammatory, anti-HSCs therapy, gene therapy, cell therapy, gut microbiota, and nanoparticles have great potential for preventing and treating liver diseases. Here, we explored the recent possible molecular mechanisms involved in the pathogenesis of acute and chronic liver diseases. Besides, we overviewed the recent therapeutic interventions that targeted liver diseases and summarized the recent studies concerning liver disorders therapy.
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Affiliation(s)
- Fares EM Ali
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Al-Azhar University, Assiut Branch, Assiut 71524, Egypt
| | | | - Elham I Sharab
- Faculty of Pharmacy, Al-Azhar University, Assiut Branch, Assiut 71524, Egypt
| | - Adel G Bakr
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Al-Azhar University, Assiut Branch, Assiut 71524, Egypt
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12
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Li L, Zhu Z. Pharmacological modulation of ferroptosis as a therapeutic target for liver fibrosis. Front Pharmacol 2023; 13:1071844. [PMID: 36703745 PMCID: PMC9871257 DOI: 10.3389/fphar.2022.1071844] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2022] [Accepted: 12/29/2022] [Indexed: 01/12/2023] Open
Abstract
Liver fibrosis, which is characterized by the excessive deposition of extracellular matrix (ECM) materials (primarily fibrillar collagen-I), is an abnormal repair reaction and pathological outcome of chronic liver diseases caused by alcohol abuse, non-alcoholic fatty liver disease, and chronic hepatitis B and C virus infections. Liver fibrosis often progresses to liver cirrhosis and hepatocellular carcinoma. Ferroptosis, characterized by lipid peroxidation, is a form of iron-dependent non-apoptotic cell death, and recent studies have reported that ferroptosis contribute to the development of liver fibrosis. Moreover, several agents have demonstrated therapeutic effects in experimental liver fibrosis models by inducing hepatic stellate cell (HSCs) ferroptosis. This review delineates the specific mechanism by which ferroptosis contributes to the development of liver fibrosis. Specifically, we focused on the different types of therapeutic agents that can induce HSCs ferroptosis and summarize their pharmacological effectiveness for liver fibrosis treatment. We suggest that HSCs ferroptosis may be a potential useful target of novel therapies for preventing and treating liver fibrosis.
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Affiliation(s)
- Le Li
- Liver Transplantation Center, Clinical Research Center for Pediatric Liver Transplantation, National Clinical Research Center for Digestive Diseases, Beijing Friendship Hospital, Capital Medical University, Beijing, China,Department of hepatobiliary surgery, Chifeng Municipal Hospital, Chifeng, China
| | - Zhijun Zhu
- Liver Transplantation Center, Clinical Research Center for Pediatric Liver Transplantation, National Clinical Research Center for Digestive Diseases, Beijing Friendship Hospital, Capital Medical University, Beijing, China,*Correspondence: Zhijun Zhu,
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13
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Wu T, Wang M, Ning F, Zhou S, Hu X, Xin H, Reilly S, Zhang X. Emerging role for branched-chain amino acids metabolism in fibrosis. Pharmacol Res 2023; 187:106604. [PMID: 36503000 DOI: 10.1016/j.phrs.2022.106604] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2022] [Revised: 11/24/2022] [Accepted: 12/07/2022] [Indexed: 12/13/2022]
Abstract
Fibrosis is a common pathological feature of organ diseases resulting from excessive production of extracellular matrix, which accounts for significant morbidity and mortality. However, there is currently no effective treatment targeting fibrogenesis. Recently, metabolic alterations are increasingly considered as essential factors underlying fibrogenesis, and especially research on metabolic regulation of amino acids is flourishing. Among them, branched-chain amino acids (BCAAs) are the most abundant essential amino acids, including leucine, isoleucine and valine, which play significant roles in the substance and energy metabolism and their regulation. Dysregulation of BCAAs metabolism has been proven to contribute to numerous diseases. In this review, we summarize the metabolic regulation of fibrosis and the changes in BCAAs metabolism secondary to fibrosis. We also review the effects and mechanisms of the BCAAs intervention, and its therapeutic targeting in hepatic, renal and cardiac fibrosis, with a focus on the fibrosis in liver and associated hepatocellular carcinoma.
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Affiliation(s)
- Tiangang Wu
- Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai 201203, China
| | - Mengling Wang
- Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai 201203, China
| | - Fengling Ning
- Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai 201203, China
| | - Shilin Zhou
- Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai 201203, China
| | - Xuetao Hu
- Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai 201203, China
| | - Hong Xin
- Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai 201203, China; Shanghai Zhangjiang Institute of Medical Innovation, Shanghai 201204, China.
| | - Svetlana Reilly
- Division of Cardiovascular Medicine, Radcliffe Department of Medicine, British Heart Foundation Centre of Research Excellence, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom.
| | - Xuemei Zhang
- Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai 201203, China.
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14
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Masaki T, Iwamoto E, Ikuta K, Kushibiki S. Effects of crude protein and neutral detergent fiber percentages in the diet of Japanese Black steers on rumen fluid properties, blood biochemical properties, and carcass characteristics. Anim Sci J 2023; 94:e13867. [PMID: 37642265 DOI: 10.1111/asj.13867] [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: 03/31/2023] [Revised: 07/01/2023] [Accepted: 07/20/2023] [Indexed: 08/31/2023]
Abstract
The effects of crude protein (CP) and neutral detergent fiber (NDF) percentages in the diet of Japanese Black steers on rumen fluid properties, blood biochemical properties, and carcass characteristics were examined. Twelve 13-month-old Japanese Black steers were used for this study and slaughtered at 30 months of age. Steers were assigned to a control group (n = 6) and test group (n = 6) and were fed a concentrate containing 12.9%-13.9% CP and 26.5%-29.8% NDF or 9.1%-9.6% CP and 29.9%-31.2% NDF, respectively. Lipopolysaccharide activity levels in rumen fluid were lower in the test group than in the control group. Plasma urea nitrogen concentration and activities of aspartate aminotransferase and γ-glutamyltransferase remained lower in the test group than in the control group. In contrast, plasma vitamin A concentrations remained higher in the test group than in the control group. Carcass characteristics did not significantly differ between the two groups. These results suggest that dietary CP and NDF percentages in feed for Japanese Black steers older than 13 months of age affected rumen fluid properties and blood biochemical properties, indicating a reduced load on the liver with a small effect on carcass characteristics.
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Affiliation(s)
- Tatsunori Masaki
- Hyogo Prefectural Technology Center for Agriculture, Forestry and Fisheries, Hyogo Prefecture, Kasai, Hyogo, Japan
- Doctoral Program in Advanced Agricultural Technology and Sciences, Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Ibaraki, Japan
| | - Eiji Iwamoto
- Hyogo Prefectural Technology Center for Agriculture, Forestry and Fisheries, Hyogo Prefecture, Kasai, Hyogo, Japan
| | - Kentaro Ikuta
- Awaji Agricultural Technology Institute, Hyogo Prefectural Technology Center for Agriculture, Forestry and Fisheries, Hyogo Prefecture Research Center, Minamiawaji, Hyogo, Japan
| | - Shiro Kushibiki
- Doctoral Program in Advanced Agricultural Technology and Sciences, Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Ibaraki, Japan
- Dairy Cattle Nutrition and Breeding Group, Institute of Livestock and Grassland Science, National Agriculture and Food Research Organization (NARO), Tsukuba, Ibaraki, Japan
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15
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Yepmo M, Potier JB, Pinget M, Grabarz A, Bouzakri K, Dumond Bourie A. Discussing the role of circular RNA in the pathogenesis of non-alcoholic fatty liver disease and its complications. Front Endocrinol (Lausanne) 2022; 13:1035159. [PMID: 36407314 PMCID: PMC9667057 DOI: 10.3389/fendo.2022.1035159] [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: 09/02/2022] [Accepted: 10/17/2022] [Indexed: 01/24/2023] Open
Abstract
Circular RNAs (circRNAs) are class of non-coding RNA, which are characterized by a covalently closed loop structure. Functionally they can act on cellular physiology, notably by sponging microRNAs (miR), regulating gene expression or interacting with binding protein. To date, circRNAs might represent an interesting, underexploited avenue for new target discovery for therapeutic applications, especially in the liver. The first characteristic of non-alcoholic fatty liver disease (NAFLD) is hepatic cholesterol accumulation, followed by its advanced form of the affection, nonalcoholic steatohepatitis (NASH), due to the occurrence of lobular inflammation, irreversible fibrosis, and in some cases hepatocellular carcinoma (HCC). Therefore, studies have investigated the importance of the dysregulation of circRNAs in the onset of metabolic disorders. In this review, we summarize the potential role of circRNAs in the development of metabolic diseases associated with the liver such as NAFLD or NASH, and their potential to become therapeutic strategies for these pathologies.
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Affiliation(s)
- Melissa Yepmo
- Centre européen d’étude du Diabète, Unité Mixte de Recherche de l’Université de Strasbourg « Diabète et Thérapeutique », Strasbourg, France
| | - Jean-Baptiste Potier
- Centre européen d’étude du Diabète, Unité Mixte de Recherche de l’Université de Strasbourg « Diabète et Thérapeutique », Strasbourg, France
- ILONOV, Strasbourg, France
| | - Michel Pinget
- Centre européen d’étude du Diabète, Unité Mixte de Recherche de l’Université de Strasbourg « Diabète et Thérapeutique », Strasbourg, France
| | | | - Karim Bouzakri
- Centre européen d’étude du Diabète, Unité Mixte de Recherche de l’Université de Strasbourg « Diabète et Thérapeutique », Strasbourg, France
- ILONOV, Strasbourg, France
| | - Aurore Dumond Bourie
- Centre européen d’étude du Diabète, Unité Mixte de Recherche de l’Université de Strasbourg « Diabète et Thérapeutique », Strasbourg, France
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16
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Nishio T, Koyama Y, Fuji H, Ishizuka K, Iwaisako K, Taura K, Hatano E, Brenner DA, Kisseleva T. The Role of Mesothelin in Activation of Portal Fibroblasts in Cholestatic Liver Injury. BIOLOGY 2022; 11:1589. [PMID: 36358290 PMCID: PMC9687690 DOI: 10.3390/biology11111589] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 09/21/2022] [Revised: 10/18/2022] [Accepted: 10/27/2022] [Indexed: 11/05/2022]
Abstract
Fibrosis is a common consequence of abnormal wound healing, which is characterized by infiltration of myofibroblasts and formation of fibrous scar. In liver fibrosis, activated Hepatic Stellate Cells (aHSCs) and activated Portal Fibroblasts (aPFs) are the major contributors to the origin of hepatic myofibroblasts. aPFs are significantly involved in the pathogenesis of cholestatic fibrosis, suggesting that aPFs may be a primary target for anti-fibrotic therapy in cholestatic injury. aPFs are distinguishable from aHSCs by specific markers including mesothelin (Msln), Mucin 16 (Muc16), and Thymus cell antigen 1 (Thy1, CD90) as well as fibulin 2, elastin, Gremlin 1, ecto-ATPase nucleoside triphosphate diphosphohydrolase 2. Msln plays a critical role in activation of PFs, via formation of Msln-Muc16-Thy1 complex that regulates TGFβ1/TGFβRI-mediated fibrogenic signaling. The opposing pro- and anti-fibrogenic effects of Msln and Thy1 are key components of the TGFβ1-induced activation pathway in aPFs. In addition, aPFs and activated lung and kidney fibroblasts share similarities across different organs with expression of common markers and activation cascade including Msln-Thy1 interaction. Here, we summarize the potential function of Msln in activation of PFs and development of cholestatic fibrosis, offering a novel perspective for anti-fibrotic therapy targeting Msln.
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Affiliation(s)
- Takahiro Nishio
- Department of Medicine, University of California San Diego, 9500 Gilman Drive, #0063, La Jolla, CA 92093, USA
- Department of Surgery, University of California San Diego, 9500 Gilman Drive, #0063, La Jolla, CA 92093, USA
- Department of Surgery, Graduate School of Medicine, Kyoto University, 54 Kawaharacho Shogoin, Sakyo-ku, Kyoto 606-8507, Japan
| | - Yukinori Koyama
- Department of Medicine, University of California San Diego, 9500 Gilman Drive, #0063, La Jolla, CA 92093, USA
- Department of Surgery, Graduate School of Medicine, Kyoto University, 54 Kawaharacho Shogoin, Sakyo-ku, Kyoto 606-8507, Japan
| | - Hiroaki Fuji
- Department of Medicine, University of California San Diego, 9500 Gilman Drive, #0063, La Jolla, CA 92093, USA
- Department of Surgery, University of California San Diego, 9500 Gilman Drive, #0063, La Jolla, CA 92093, USA
| | - Kei Ishizuka
- Department of Medicine, University of California San Diego, 9500 Gilman Drive, #0063, La Jolla, CA 92093, USA
- Department of Surgery, University of California San Diego, 9500 Gilman Drive, #0063, La Jolla, CA 92093, USA
| | - Keiko Iwaisako
- Department of Medical Life Systems, Faculty of Life and Medical Sciences, Doshisha University, 1-3 Tataramiyakodani, Kyotanabe 610-0394, Japan
| | - Kojiro Taura
- Department of Surgery, Graduate School of Medicine, Kyoto University, 54 Kawaharacho Shogoin, Sakyo-ku, Kyoto 606-8507, Japan
- Department of Gastroenterological Surgery and Oncology, Kitano Hospital Medical Research Institute, 2-4-20 Ogimachi, Kita-ku, Osaka 530-8480, Japan
| | - Etsuro Hatano
- Department of Surgery, Graduate School of Medicine, Kyoto University, 54 Kawaharacho Shogoin, Sakyo-ku, Kyoto 606-8507, Japan
| | - David A. Brenner
- Department of Medicine, University of California San Diego, 9500 Gilman Drive, #0063, La Jolla, CA 92093, USA
| | - Tatiana Kisseleva
- Department of Surgery, University of California San Diego, 9500 Gilman Drive, #0063, La Jolla, CA 92093, USA
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17
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Activated Hepatic Stellate Cells Promote the M1 to M2 Macrophage Transformation and Liver Fibrosis by Elevating the Histone Acetylation Level. DISEASE MARKERS 2022; 2022:9883831. [PMID: 36133436 PMCID: PMC9484931 DOI: 10.1155/2022/9883831] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/18/2022] [Revised: 08/09/2022] [Accepted: 08/13/2022] [Indexed: 11/18/2022]
Abstract
Liver fibrosis results from the formation of fibrous scars of hepatic stellate cells by various chronic liver diseases. Considering that the liver is the most important metabolic organ in the human body, exploring the metabolic characteristics of liver fibrosis is expected to discover new markers and therapeutic targets. In this study, we first used mouse model to verify that both lactate content and histone acetylation levels were significantly increased in hepatic fibrosis mice. At the same time, it was confirmed that activated hepatic stellate cells (HSCs) cocultured with M1 macrophages can promote their transformation into M2 macrophages in hepatic stellate cell line and primary hepatic stellate cells. In addition, the addition of lactic acid to the medium in which M1 cells are cultured can promote their transformation into M2 macrophages. Therefore, we concluded that activated HSCs can promote the transformation of M1 to M2 macrophages through lactate accumulation, thereby causing liver fibrosis.
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18
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Hung CT, Tsai YW, Wu YS, Yeh CF, Yang KC. The novel role of ER protein TXNDC5 in the pathogenesis of organ fibrosis: mechanistic insights and therapeutic implications. J Biomed Sci 2022; 29:63. [PMID: 36050716 PMCID: PMC9438287 DOI: 10.1186/s12929-022-00850-x] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2022] [Accepted: 08/25/2022] [Indexed: 11/17/2022] Open
Abstract
Fibrosis-related disorders account for an enormous burden of disease-associated morbidity and mortality worldwide. Fibrosis is defined by excessive extracellular matrix deposition at fibrotic foci in the organ tissue following injury, resulting in abnormal architecture, impaired function and ultimately, organ failure. To date, there lacks effective pharmacological therapy to target fibrosis per se, highlighting the urgent need to identify novel drug targets against organ fibrosis. Recently, we have discovered the critical role of a fibroblasts-enriched endoplasmic reticulum protein disulfide isomerase (PDI), thioredoxin domain containing 5 (TXNDC5), in cardiac, pulmonary, renal and liver fibrosis, showing TXNDC5 is required for the activation of fibrogenic transforming growth factor-β signaling cascades depending on its catalytic activity as a PDI. Moreover, deletion of TXNDC5 in fibroblasts ameliorates organ fibrosis and preserves organ function by inhibiting myofibroblasts activation, proliferation and extracellular matrix production. In this review, we detailed the molecular and cellular mechanisms by which TXNDC5 promotes fibrogenesis in various tissue types and summarized potential therapeutic strategies targeting TXNDC5 to treat organ fibrosis.
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Affiliation(s)
- Chen-Ting Hung
- Department and Graduate Institute of Pharmacology, National Taiwan University College of Medicine, No. 1, Sec. 1, Ren-Ai Rd, 1150R, Taipei, 100, Taiwan
| | - Yi-Wei Tsai
- Department and Graduate Institute of Pharmacology, National Taiwan University College of Medicine, No. 1, Sec. 1, Ren-Ai Rd, 1150R, Taipei, 100, Taiwan
| | - Yu-Shuo Wu
- Department and Graduate Institute of Pharmacology, National Taiwan University College of Medicine, No. 1, Sec. 1, Ren-Ai Rd, 1150R, Taipei, 100, Taiwan
| | - Chih-Fan Yeh
- Division of Cardiology, Department of Internal Medicine and Cardiovascular Center, National Taiwan University Hospital, Taipei, Taiwan
| | - Kai-Chien Yang
- Department and Graduate Institute of Pharmacology, National Taiwan University College of Medicine, No. 1, Sec. 1, Ren-Ai Rd, 1150R, Taipei, 100, Taiwan. .,Division of Cardiology, Department of Internal Medicine and Cardiovascular Center, National Taiwan University Hospital, Taipei, Taiwan. .,Research Center for Developmental Biology & Regenerative Medicine, National Taiwan University, Taipei, Taiwan. .,Center for Frontier Medicine, National Taiwan University Hospital, Taipei, Taiwan. .,Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan. .,Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
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19
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Li YG, Yu ZJ, Li A, Ren ZG. Gut microbiota alteration and modulation in hepatitis B virus-related fibrosis and complications: Molecular mechanisms and therapeutic inventions. World J Gastroenterol 2022; 28:3555-3572. [PMID: 36161048 PMCID: PMC9372803 DOI: 10.3748/wjg.v28.i28.3555] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2022] [Revised: 06/06/2022] [Accepted: 06/24/2022] [Indexed: 02/06/2023] Open
Abstract
Hepatitis B virus (HBV) has posed a threat to public health, mainly resulting in liver damage. With long-term accumulation of extracellular matrix, patients with chronic hepatitis B are at high risk of developing into liver fibrosis and cirrhosis and even life-threatening hepatic carcinoma. The occurrence of complications such as spontaneous bacterial peritonitis and hepatic encephalopathy greatly increases disability and mortality. With deeper understanding of the bidirectional interaction between the liver and the gut (gut-liver axis), there is a growing consensus that the human health closely relates to the gut microbiota. Supported by animal and human studies, the gut microbiota alters as the HBV-related liver fibrosis initials and progresses, characterized as the decrease of the ratio between “good” and “potentially pathogenic” microbes. When the primary disease is controlled via antiviral treatment, the gut microbiota dysfunction tends to be improved. Conversely, the recovery of gut microbiota can promote the regression of liver fibrosis. Therapeutic strategies targeted on gut microbiota (rifaximin, probiotics, engineered probiotics and fecal microbiota transplantation) have been applied to animal models and patients, obtaining satisfactory results.
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Affiliation(s)
- Yao-Guang Li
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
- Gene Hospital of Henan Province, Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
| | - Zu-Jiang Yu
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
- Gene Hospital of Henan Province, Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
| | - Ang Li
- Gene Hospital of Henan Province, Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
| | - Zhi-Gang Ren
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
- Jinan Microecological Biomedicine Shandong Laboratory, Jinan 250000, Shandong Province, China
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20
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Qorbani M, Seif E, Heshmat R, Ghonbalani ZN, Basiry P, Kazemian E, Kelishadi R. Association of Serum Retinol Concentrations With Metabolic Syndrome Components in Iranian Children and Adolescents: The CASPIAN-V Study. Front Nutr 2022; 9:807634. [PMID: 35634391 PMCID: PMC9137422 DOI: 10.3389/fnut.2022.807634] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2021] [Accepted: 04/19/2022] [Indexed: 11/15/2022] Open
Abstract
Background As a fat-soluble vitamin, vitamin A plays a crucial role in adipogenesis, lipolysis, insulin resistance, and obesity. However, it is still unclear whether they are associated with cardiometabolic risk factors in children and adolescents. The current study aimed to determine the association between serum retinol concentration and the cluster of metabolic syndrome components among children and adolescents. Methods This nationwide cross-sectional study was performed on 2,518 students aged 7–18 years from the Childhood and Adolescence Surveillance and Prevention of Adult Non- communicable disease (CASPIAN-V) study. Students were selected via multistage cluster sampling method from 30 provinces of Iran in 2015. Multivariable logistic regression was used to assess the association of serum retinol concentration with metabolic syndrome (MetS) components. Results Overall, the mean (SD) age of study participants was 12.16 (3.04) years, and 44.9% (n = 1,166) of them were girls. The mean serum retinol concentration was 1.48 ± 1.55 μmol/L and vitamin A deficiency was observed among 19.7% (95% CI: 18.2–21.3) of study subjects. The results of the logistic regression analysis showed that increasing serum retinol concentrations were associated with an increased likelihood of developing obesity (OR: 1.12, 95% CI: 1.04, 1.20), abdominal obesity (OR: 1.07, 95% CI: 1.01, 1.14), low high-density lipoprotein cholesterol (HDL-C) (OR: 1.10, 95% CI: 1.04, 1.16) and high fasting blood glucose (FBG) (OR: 1.21, 95% CI: 1.10, 1.35), whereas it was associated with a decreased odds of developing high blood pressure (OR: 0.82, 95% CI: 0.73, 0.93). Nevertheless, there was no statistically significant association between metabolic syndrome itself and retinol concentration (OR: 1.02, 95% CI: 0.88, 1.18). Conclusion We found that serum retinol concentration was positively associated with metabolic syndrome components such as obesity, low HDL-C, and high FBG, but not with metabolic syndrome itself.
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Affiliation(s)
- Mostafa Qorbani
- Non-Communicable Diseases Research Center, Alborz University of Medical Sciences, Karaj, Iran
- Chronic Diseases Research Center, Endocrinology and Metabolism Population Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Ehsan Seif
- Chronic Diseases Research Center, Endocrinology and Metabolism Population Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Ramin Heshmat
- Chronic Diseases Research Center, Endocrinology and Metabolism Population Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Zahra Nouri Ghonbalani
- Social Determinants of Health Research Center, Alborz University of Medical Sciences, Karaj, Iran
| | - Pouria Basiry
- Student Research Committee, Alborz University of Medical Sciences, Karaj, Iran
| | - Elham Kazemian
- Non-Communicable Diseases Research Center, Alborz University of Medical Sciences, Karaj, Iran
- *Correspondence: Elham Kazemian
| | - Roya Kelishadi
- Child Growth and Development Research Center, Research Institute for Primordial Prevention of Non-Communicable Disease, Isfahan University of Medical Sciences, Isfahan, Iran
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21
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Liu XY, Li D, Li TY, Wu YL, Piao JS, Piao MG. Vitamin A - modified Betulin polymer micelles with hepatic targeting capability for hepatic fibrosis protection. Eur J Pharm Sci 2022; 174:106189. [DOI: 10.1016/j.ejps.2022.106189] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2022] [Revised: 04/11/2022] [Accepted: 04/12/2022] [Indexed: 12/12/2022]
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22
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Shen X, Zhao J, Wang Q, Chen P, Hong Y, He X, Chen D, Liu H, Wang Y, Cai X. The Invasive Potential of Hepatoma Cells Induced by Radiotherapy is Related to the Activation of Stellate Cells and Could be Inhibited by EGCG Through the TLR4 Signaling Pathway. Radiat Res 2022; 197:365-375. [PMID: 35051295 DOI: 10.1667/rade-21-00129.1] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2021] [Accepted: 11/29/2021] [Indexed: 11/03/2022]
Abstract
Post-radiotherapy recurrence and metastasis of liver cancer were thought to arise from the invasion and metastasis of residual hepatocellular carcinoma cells, but it has now been shown to be closely related to the increased metastatic potential of residual liver cancer cells mediated by radiotherapy. The changes of liver microenvironment after radiotherapy also provide a favorable condition for promoting the metastatic potential of hepatocellular carcinoma. Studies have shown that radiation-induced activation of hepatic stellate cells (HSCs) is one of the main changes in the microenvironment of hepatocellular carcinoma. Therefore, we hypothesized that activated HSCs are involved in regulating the metastatic capacity of residual cancer cells after radiotherapy. The present study observed that 48 h co-culture of three human hepatoma cell lines (MHCC97-L, Hep-3B, LM3) with a irradiated human HSC line (LX-2) in a transwell chamber could significantly improve the invasion of the human hepatoma cells; and the culture supernatant of activated HSCs could also enhance the invasion of the hepatoma cells. In contrast, co-culture with irradiated hepatoma cells enhanced the invasion of LX-2 cells. In vitro, irradiation enhanced the activation phenotype and the toll like receptor 4 (TLR4) signaling pathway of LX-2 cells or primary mouse HSCs, which upregulated intercellular cell adhesion molecule-1 (ICAM1), laminin receptor (67 LR), Interleukin- 6 (IL-6), and CX3C chemokine ligand 1 (CX3CL1) and downregulated toll-interacting proteins. The compound (-)-epigallocatechin-3-gallate (EGCG) inhibited signal transduction of activated TLR4 and radiation-induced invasion of LX-2 cells by binding to 67 LR. These observations indicated that the enhancement of the metastatic potential of hepatoma cells after irradiation was relevant to the activation of HSCs, and the activation of TLR4 signaling pathway was involved in this process, which was inhibited by EGCG. Our results will help enhance the therapeutic efficacy of liver cancer stereotactic body radiation therapy to prevent and decrease the risks of post-radiotherapy recurrence and metastasis.
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Affiliation(s)
- Xiaoyun Shen
- Key Laboratory of Endoscopic Technology Research, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310016, P.R. China
| | - Jia Zhao
- Key Laboratory of Endoscopic Technology Research, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310016, P.R. China
| | - Qi Wang
- Key Laboratory of Endoscopic Technology Research, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310016, P.R. China
| | - Ping Chen
- Key Laboratory of Endoscopic Technology Research, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310016, P.R. China
| | - Yiyang Hong
- Key Laboratory of Endoscopic Technology Research, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310016, P.R. China
| | - Xiaoyan He
- Key Laboratory of Endoscopic Technology Research, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310016, P.R. China
| | - Dafang Chen
- Key Laboratory of Endoscopic Technology Research, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310016, P.R. China
| | - Hui Liu
- Key Laboratory of Endoscopic Technology Research, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310016, P.R. China
| | - Yifan Wang
- Key Laboratory of Endoscopic Technology Research, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310016, P.R. China
| | - Xiujun Cai
- Key Laboratory of Endoscopic Technology Research, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310016, P.R. China
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23
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Fuji H, Miller G, Nishio T, Koyama Y, Lam K, Zhang V, Loomba R, Brenner D, Kisseleva T. The role of Mesothelin signaling in Portal Fibroblasts in the pathogenesis of cholestatic liver fibrosis. Front Mol Biosci 2021; 8:790032. [PMID: 34966784 PMCID: PMC8710774 DOI: 10.3389/fmolb.2021.790032] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2021] [Accepted: 11/15/2021] [Indexed: 01/18/2023] Open
Abstract
Liver fibrosis develops in response to chronic toxic or cholestatic injury, and is characterized by apoptosis of damaged hepatocytes, development of inflammatory responses, and activation of Collagen Type I producing myofibroblasts that make liver fibrotic. Two major cell types, Hepatic Stellate Cells (HSCs) and Portal Fibroblasts (PFs) are the major source of hepatic myofibroblasts. Hepatotoxic liver injury activates Hepatic Stellate Cells (aHSCs) to become myofibroblasts, while cholestatic liver injury activates both aHSCs and Portal Fibroblasts (aPFs). aPFs comprise the major population of myofibroblasts at the onset of cholestatic injury, while aHSCs are increasingly activated with fibrosis progression. Here we summarize our current understanding of the role of aPFs in the pathogenesis of cholestatic fibrosis, their unique features, and outline the potential mechanism of targeting aPFs in fibrotic liver.
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Affiliation(s)
- Hiroaki Fuji
- Department of Medicine, University of California San Diego, La Jolla, CA, United States
- Department of Surgery, University of California San Diego, La Jolla, CA, United States
| | - Grant Miller
- Department of Medicine, University of California San Diego, La Jolla, CA, United States
- Department of Surgery, University of California San Diego, La Jolla, CA, United States
| | - Takahiro Nishio
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Yukinori Koyama
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Kevin Lam
- Department of Medicine, University of California San Diego, La Jolla, CA, United States
- Department of Surgery, University of California San Diego, La Jolla, CA, United States
| | - Vivian Zhang
- Department of Medicine, University of California San Diego, La Jolla, CA, United States
- Department of Surgery, University of California San Diego, La Jolla, CA, United States
| | - Rohit Loomba
- Department of Medicine, University of California San Diego, La Jolla, CA, United States
| | - David Brenner
- Department of Medicine, University of California San Diego, La Jolla, CA, United States
| | - Tatiana Kisseleva
- Department of Surgery, University of California San Diego, La Jolla, CA, United States
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24
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Sarohan AR, Kızıl M, İnkaya AÇ, Mahmud S, Akram M, Cen O. A novel hypothesis for COVID-19 pathogenesis: Retinol depletion and retinoid signaling disorder. Cell Signal 2021; 87:110121. [PMID: 34438017 PMCID: PMC8380544 DOI: 10.1016/j.cellsig.2021.110121] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2021] [Revised: 08/18/2021] [Accepted: 08/19/2021] [Indexed: 02/08/2023]
Abstract
The SARS-CoV-2 virus has caused a worldwide COVID-19 pandemic. In less than a year and a half, more than 200 million people have been infected and more than four million have died. Despite some improvement in the treatment strategies, no definitive treatment protocol has been developed. The pathogenesis of the disease has not been clearly elucidated yet. A clear understanding of its pathogenesis will help develop effective vaccines and drugs. The immunopathogenesis of COVID-19 is characteristic with acute respiratory distress syndrome and multiorgan involvement with impaired Type I interferon response and hyperinflammation. The destructive systemic effects of COVID-19 cannot be explained simply by the viral tropism through the ACE2 and TMPRSS2 receptors. In addition, the recently identified mutations cannot fully explain the defect in all cases of Type I interferon synthesis. We hypothesize that retinol depletion and resulting impaired retinoid signaling play a central role in the COVID-19 pathogenesis that is characteristic for dysregulated immune system, defect in Type I interferon synthesis, severe inflammatory process, and destructive systemic multiorgan involvement. Viral RNA recognition mechanism through RIG-I receptors can quickly consume a large amount of the body's retinoid reserve, which causes the retinol levels to fall below the normal serum levels. This causes retinoid insufficiency and impaired retinoid signaling, which leads to interruption in Type I interferon synthesis and an excessive inflammation. Therefore, reconstitution of the retinoid signaling may prove to be a valid strategy for management of COVID-19 as well for some other chronic, degenerative, inflammatory, and autoimmune diseases.
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Affiliation(s)
- Aziz Rodan Sarohan
- Department of Obstetrics and Gynecology, Medicina Plus Medical Center, 75. Yıl Mah., İstiklal Cad. 1305 Sk., No: 16 Sultangazi, İstanbul, Turkey.
| | - Murat Kızıl
- Department of Chemistry, Faculty of Science, Dicle University. Diyarbakır, Turkey
| | - Ahmet Çağkan İnkaya
- Department of Infectious Diseases and Clinical Microbiology, Faculty of Medicine, Hacettepe University, Ankara 06230, Turkey
| | - Shokhan Mahmud
- Department of Pharmacognosy, College of Pharmacy, Hawler Medical University, Erbil, Kurdistan Region, Iraq
| | - Muhammad Akram
- Department of Eastern Medicine Government College, University Faisalabad, Pakistan
| | - Osman Cen
- Department of Microbiology and Immunology, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States of America; Department of Natural Sciences and Engineering, John Wood College, Quincy, IL, United States of America
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25
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Sufleţel RT, Melincovici CS, Gheban BA, Toader Z, Mihu CM. Hepatic stellate cells - from past till present: morphology, human markers, human cell lines, behavior in normal and liver pathology. ROMANIAN JOURNAL OF MORPHOLOGY AND EMBRYOLOGY 2021; 61:615-642. [PMID: 33817704 PMCID: PMC8112759 DOI: 10.47162/rjme.61.3.01] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
Hepatic stellate cell (HSC), initially analyzed by von Kupffer, in 1876, revealed to be an extraordinary mesenchymal cell, essential for both hepatocellular function and lesions, being the hallmark of hepatic fibrogenesis and carcinogenesis. Apart from their implications in hepatic injury, HSCs play a vital role in liver development and regeneration, xenobiotic response, intermediate metabolism, and regulation of immune response. In this review, we discuss the current state of knowledge regarding HSCs morphology, human HSCs markers and human HSC cell lines. We also summarize the latest findings concerning their roles in normal and liver pathology, focusing on their impact in fibrogenesis, chronic viral hepatitis and liver tumors.
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Affiliation(s)
- Rada Teodora Sufleţel
- Discipline of Histology, Department of Morphological Sciences, Iuliu Haţieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania;
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26
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Kisseleva T, Brenner D. Molecular and cellular mechanisms of liver fibrosis and its regression. Nat Rev Gastroenterol Hepatol 2021; 18:151-166. [PMID: 33128017 DOI: 10.1038/s41575-020-00372-7] [Citation(s) in RCA: 1025] [Impact Index Per Article: 256.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/23/2020] [Indexed: 01/18/2023]
Abstract
Chronic liver injury leads to liver inflammation and fibrosis, through which activated myofibroblasts in the liver secrete extracellular matrix proteins that generate the fibrous scar. The primary source of these myofibroblasts are the resident hepatic stellate cells. Clinical and experimental liver fibrosis regresses when the causative agent is removed, which is associated with the elimination of these activated myofibroblasts and resorption of the fibrous scar. Understanding the mechanisms of liver fibrosis regression could identify new therapeutic targets to treat liver fibrosis. This Review summarizes studies of the molecular mechanisms underlying the reversibility of liver fibrosis, including apoptosis and the inactivation of hepatic stellate cells, the crosstalk between the liver and the systems that orchestrate the recruitment of bone marrow-derived macrophages (and other inflammatory cells) driving fibrosis resolution, and the interactions between various cell types that lead to the intracellular signalling that induces fibrosis or its regression. We also discuss strategies to target hepatic myofibroblasts (for example, via apoptosis or inactivation) and the myeloid cells that degrade the matrix (for example, via their recruitment to fibrotic liver) to facilitate fibrosis resolution and liver regeneration.
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Affiliation(s)
- Tatiana Kisseleva
- Department of Surgery, University of California, San Diego, La Jolla, CA, USA.
| | - David Brenner
- Department of Medicine, University of California, San Diego, La Jolla, CA, USA
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27
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Xu F, Tautenhahn HM, Dirsch O, Dahmen U. Modulation of Autophagy: A Novel "Rejuvenation" Strategy for the Aging Liver. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2021; 2021:6611126. [PMID: 33628363 PMCID: PMC7889356 DOI: 10.1155/2021/6611126] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/09/2020] [Revised: 12/08/2020] [Accepted: 01/23/2021] [Indexed: 12/11/2022]
Abstract
Aging is a natural life process which leads to a gradual decline of essential physiological processes. For the liver, it leads to alterations in histomorphology (steatosis and fibrosis) and function (protein synthesis and energy generation) and affects central hepatocellular processes (autophagy, mitochondrial respiration, and hepatocyte proliferation). These alterations do not only impair the metabolic capacity of the liver but also represent important factors in the pathogenesis of malignant liver disease. Autophagy is a recycling process for eukaryotic cells to degrade dysfunctional intracellular components and to reuse the basic substances. It plays a crucial role in maintaining cell homeostasis and in resisting environmental stress. Emerging evidence shows that modulating autophagy seems to be effective in improving the age-related alterations of the liver. However, autophagy is a double-edged sword for the aged liver. Upregulating autophagy alleviates hepatic steatosis and ROS-induced cellular stress and promotes hepatocyte proliferation but may aggravate hepatic fibrosis. Therefore, a well-balanced autophagy modulation strategy might be suitable to alleviate age-related liver dysfunction. Conclusion. Modulation of autophagy is a promising strategy for "rejuvenation" of the aged liver. Detailed knowledge regarding the most devastating processes in the individual patient is needed to effectively counteract aging of the liver without causing obvious harm.
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Affiliation(s)
- Fengming Xu
- Department of General, Visceral and Vascular Surgery, Jena University Hospital, Jena 07747, Germany
| | - Hans-Michael Tautenhahn
- Department of General, Visceral and Vascular Surgery, Jena University Hospital, Jena 07747, Germany
| | - Olaf Dirsch
- Institute of Pathology, Klinikum Chemnitz gGmbH, Chemnitz 09111, Germany
| | - Uta Dahmen
- Department of General, Visceral and Vascular Surgery, Jena University Hospital, Jena 07747, Germany
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28
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Meijer EM, van Dijk CGM, Kramann R, Verhaar MC, Cheng C. Implementation of Pericytes in Vascular Regeneration Strategies. TISSUE ENGINEERING PART B-REVIEWS 2021; 28:1-21. [PMID: 33231500 DOI: 10.1089/ten.teb.2020.0229] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
For the survival and integration of complex large-sized tissue-engineered (TE) organ constructs that exceed the maximal nutrients and oxygen diffusion distance required for cell survival, graft (pre)vascularization to ensure medium or blood supply is crucial. To achieve this, the morphology and functionality of the microcapillary bed should be mimicked by incorporating vascular cell populations, including endothelium and mural cells. Pericytes play a crucial role in microvascular function, blood vessel stability, angiogenesis, and blood pressure regulation. In addition, tissue-specific pericytes are important in maintaining specific functions in different organs, including vitamin A storage in the liver, renin production in the kidneys and maintenance of the blood-brain-barrier. Together with their multipotential differentiation capacity, this makes pericytes the preferred cell type for application in TE grafts. The use of a tissue-specific pericyte cell population that matches the TE organ may benefit organ function. In this review, we provide an overview of the literature for graft (pre)-vascularization strategies and highlight the possible advantages of using tissue-specific pericytes for specific TE organ grafts. Impact statement The use of a tissue-specific pericyte cell population that matches the tissue-engineered (TE) organ may benefit organ function. In this review, we provide an overview of the literature for graft (pre)vascularization strategies and highlight the possible advantages of using tissue-specific pericytes for specific TE organ grafts.
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Affiliation(s)
- Elana M Meijer
- Department of Nephrology and Hypertension, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Christian G M van Dijk
- Department of Nephrology and Hypertension, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Rafael Kramann
- Division of Nephrology and Institute of Experimental Medicine and Systems Biology, University Hospital RWTH Aachen, Aachen, Germany.,Department of Internal Medicine, Nephrology and Transplantation, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Marianne C Verhaar
- Department of Nephrology and Hypertension, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Caroline Cheng
- Department of Nephrology and Hypertension, University Medical Center Utrecht, Utrecht, The Netherlands.,Experimental Cardiology, Department of Cardiology, Thorax Center Erasmus University Medical Center, Rotterdam, The Netherlands
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29
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Qi X, Yang M, Stenberg J, Dey R, Fogwe L, Alam MS, Kimchi ET, Staveley-O'Carroll KF, Li G. Gut microbiota mediated molecular events and therapy in liver diseases. World J Gastroenterol 2020; 26:7603-7618. [PMID: 33505139 PMCID: PMC7789060 DOI: 10.3748/wjg.v26.i48.7603] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2020] [Revised: 11/24/2020] [Accepted: 12/06/2020] [Indexed: 02/06/2023] Open
Abstract
Gut microbiota is a community of microorganisms that reside in the gastrointestinal tract. An increasing number of studies has demonstrated that the gut-liver axis plays a critical role in liver homeostasis. Dysbiosis of gut microbiota can cause liver diseases, including nonalcoholic fatty liver disease and alcoholic liver disease. Preclinical and clinical investigations have substantiated that the metabolites and other molecules derived from gut microbiota and diet interaction function as mediators to cause liver fibrosis, cirrhosis, and final cancer. This effect has been demonstrated to be associated with dysregulation of intrahepatic immunity and liver metabolism. Targeting these findings have led to the development of novel preventive and therapeutic strategies. Here, we review the cellular and molecular mechanisms underlying gut microbiota-mediated impact on liver disease. We also summarize the advancement of gut microbiota-based therapeutic strategies in the control of liver diseases.
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Affiliation(s)
- Xiaoqiang Qi
- Department of Surgery, University of Missouri, Columbia, MO 65212, United States
- Ellis Fischel Cancer Center, University of Missouri, Columbia, MO 65212, United States
- VA Hospital, Harry S Truman Memorial VA Hospital, Columbia, MO 65201, United States
| | - Ming Yang
- Department of Surgery, University of Missouri, Columbia, MO 65212, United States
- Ellis Fischel Cancer Center, University of Missouri, Columbia, MO 65212, United States
- VA Hospital, Harry S Truman Memorial VA Hospital, Columbia, MO 65201, United States
| | - Joseph Stenberg
- Department of Surgery, University of Missouri, Columbia, MO 65212, United States
| | - Rahul Dey
- Department of Surgery, University of Missouri, Columbia, MO 65212, United States
| | - Leslie Fogwe
- Department of Surgery, University of Missouri, Columbia, MO 65212, United States
| | | | - Eric T Kimchi
- Department of Surgery, University of Missouri, Columbia, MO 65212, United States
- Ellis Fischel Cancer Center, University of Missouri, Columbia, MO 65212, United States
- VA Hospital, Harry S Truman Memorial VA Hospital, Columbia, MO 65201, United States
| | - Kevin F Staveley-O'Carroll
- Department of Surgery, University of Missouri, Columbia, MO 65212, United States
- Ellis Fischel Cancer Center, University of Missouri, Columbia, MO 65212, United States
- VA Hospital, Harry S Truman Memorial VA Hospital, Columbia, MO 65201, United States
| | - Guangfu Li
- Department of Surgery, University of Missouri, Columbia, MO 65212, United States
- Ellis Fischel Cancer Center, University of Missouri, Columbia, MO 65212, United States
- VA Hospital, Harry S Truman Memorial VA Hospital, Columbia, MO 65201, United States
- Department of Molecular Microbiology and Immunology, University of Missouri, Columbia, MO 65212, United States
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30
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Donati C, Cencetti F, Bernacchioni C, Vannuzzi V, Bruni P. Role of sphingosine 1-phosphate signalling in tissue fibrosis. Cell Signal 2020; 78:109861. [PMID: 33253915 DOI: 10.1016/j.cellsig.2020.109861] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2020] [Revised: 11/23/2020] [Accepted: 11/24/2020] [Indexed: 02/06/2023]
Abstract
Fibrosis is characterized by the excessive accumulation of extracellular matrix components, leading to loss of tissue function in affected organs. Although the majority of fibrotic diseases have different origins, they have in common a persistent inflammatory stimulus and lymphocyte-monocyte interactions that determine the production of numerous fibrogenic cytokines. Treatment to contrast fibrosis is urgently needed, since some fibrotic diseases lead to systemic fibrosis and represent a major cause of death. In this article, the role of the bioactive sphingolipid sphingosine 1-phosphate (S1P) and its signalling pathway in the fibrosis of different tissue contexts is extensively reviewed, highlighting that it may represent an innovative and promising pharmacological therapeutic target for treating this devastating multifaceted disease. In multiple tissues S1P influences different aspects of fibrosis modulating the recruitment of inflammatory cells, as well as cell proliferation, migration and transdifferentiation into myofibroblasts, the cell type mainly involved in fibrosis development. Moreover, at the level of fibrotic lesions, S1P metabolism is profoundly influenced by multiple cross-talk with profibrotic mediators, such as transforming growth factor β, thus finely regulating the development of fibrosis. This article is part of a Special Issue entitled "Physiological and pathological roles of bioactive sphingolipids".
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Affiliation(s)
- Chiara Donati
- Department of Experimental and Clinical Biomedical Sciences "M. Serio", University of Florence, viale GB Morgagni 50, 50134 Florence, Italy.
| | - Francesca Cencetti
- Department of Experimental and Clinical Biomedical Sciences "M. Serio", University of Florence, viale GB Morgagni 50, 50134 Florence, Italy
| | - Caterina Bernacchioni
- Department of Experimental and Clinical Biomedical Sciences "M. Serio", University of Florence, viale GB Morgagni 50, 50134 Florence, Italy
| | - Valentina Vannuzzi
- Department of Experimental and Clinical Biomedical Sciences "M. Serio", University of Florence, viale GB Morgagni 50, 50134 Florence, Italy
| | - Paola Bruni
- Department of Experimental and Clinical Biomedical Sciences "M. Serio", University of Florence, viale GB Morgagni 50, 50134 Florence, Italy
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31
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Friend or Foe: Lipid Droplets as Organelles for Protein and Lipid Storage in Cellular Stress Response, Aging and Disease. Molecules 2020; 25:molecules25215053. [PMID: 33143278 PMCID: PMC7663626 DOI: 10.3390/molecules25215053] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Revised: 10/20/2020] [Accepted: 10/22/2020] [Indexed: 02/06/2023] Open
Abstract
Lipid droplets (LDs) were considered as a mere lipid storage organelle for a long time. Recent evidence suggests that LDs are in fact distinct and dynamic organelles with a specialized proteome and functions in many cellular roles. As such, LDs contribute to cellular signaling, protein and lipid homeostasis, metabolic diseases and inflammation. In line with the multitude of functions, LDs interact with many cellular organelles including mitochondria, peroxisomes, lysosomes, the endoplasmic reticulum and the nucleus. LDs are highly mobile and dynamic organelles and impaired motility disrupts the interaction with other organelles. The reduction of interorganelle contacts results in a multitude of pathophysiologies and frequently in neurodegenerative diseases. Contacts not only supply lipids for β-oxidation in mitochondria and peroxisomes, but also may include the transfer of toxic lipids as well as misfolded and harmful proteins to LDs. Furthermore, LDs assist in the removal of protein aggregates when severe proteotoxic stress overwhelms the proteasomal system. During imbalance of cellular lipid homeostasis, LDs also support cellular detoxification. Fine-tuning of LD function is of crucial importance and many diseases are associated with dysfunctional LDs. We summarize the current understanding of LDs and their interactions with organelles, providing a storage site for harmful proteins and lipids during cellular stress, aging inflammation and various disease states.
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32
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Hessmann E, Buchholz SM, Demir IE, Singh SK, Gress TM, Ellenrieder V, Neesse A. Microenvironmental Determinants of Pancreatic Cancer. Physiol Rev 2020; 100:1707-1751. [DOI: 10.1152/physrev.00042.2019] [Citation(s) in RCA: 86] [Impact Index Per Article: 17.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) belongs to the most lethal solid tumors in humans. A histological hallmark feature of PDAC is the pronounced tumor microenvironment (TME) that dynamically evolves during tumor progression. The TME consists of different non-neoplastic cells such as cancer-associated fibroblasts, immune cells, endothelial cells, and neurons. Furthermore, abundant extracellular matrix components such as collagen and hyaluronic acid as well as matricellular proteins create a highly dynamic and hypovascular TME with multiple biochemical and physical interactions among the various cellular and acellular components that promote tumor progression and therapeutic resistance. In recent years, intensive research efforts have resulted in a significantly improved understanding of the biology and pathophysiology of the TME in PDAC, and novel stroma-targeted approaches are emerging that may help to improve the devastating prognosis of PDAC patients. However, none of anti-stromal therapies has been approved in patients so far, and there is still a large discrepancy between multiple successful preclinical results and subsequent failure in clinical trials. Furthermore, recent findings suggest that parts of the TME may also possess tumor-restraining properties rendering tailored therapies even more challenging.
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Affiliation(s)
- Elisabeth Hessmann
- Department of Gastroenterology, Gastrointestinal Oncology, and Endocrinology, University Medical Centre Goettingen, Georg August University, Goettingen, Germany; Department of Surgery, Klinikum rechts der Isar, Technische Universität München, School of Medicine Munich, Munich, Germany; Sonderforschungsbereich/Collaborative Research Centre 1321 Modeling and Targeting Pancreatic Cancer, Munich, Germany; Deutsches Konsortium für Translationale Krebsforschung (DKTK) Munich Site, Munich, Germany; and
| | - Soeren M. Buchholz
- Department of Gastroenterology, Gastrointestinal Oncology, and Endocrinology, University Medical Centre Goettingen, Georg August University, Goettingen, Germany; Department of Surgery, Klinikum rechts der Isar, Technische Universität München, School of Medicine Munich, Munich, Germany; Sonderforschungsbereich/Collaborative Research Centre 1321 Modeling and Targeting Pancreatic Cancer, Munich, Germany; Deutsches Konsortium für Translationale Krebsforschung (DKTK) Munich Site, Munich, Germany; and
| | - Ihsan Ekin Demir
- Department of Gastroenterology, Gastrointestinal Oncology, and Endocrinology, University Medical Centre Goettingen, Georg August University, Goettingen, Germany; Department of Surgery, Klinikum rechts der Isar, Technische Universität München, School of Medicine Munich, Munich, Germany; Sonderforschungsbereich/Collaborative Research Centre 1321 Modeling and Targeting Pancreatic Cancer, Munich, Germany; Deutsches Konsortium für Translationale Krebsforschung (DKTK) Munich Site, Munich, Germany; and
| | - Shiv K. Singh
- Department of Gastroenterology, Gastrointestinal Oncology, and Endocrinology, University Medical Centre Goettingen, Georg August University, Goettingen, Germany; Department of Surgery, Klinikum rechts der Isar, Technische Universität München, School of Medicine Munich, Munich, Germany; Sonderforschungsbereich/Collaborative Research Centre 1321 Modeling and Targeting Pancreatic Cancer, Munich, Germany; Deutsches Konsortium für Translationale Krebsforschung (DKTK) Munich Site, Munich, Germany; and
| | - Thomas M. Gress
- Department of Gastroenterology, Gastrointestinal Oncology, and Endocrinology, University Medical Centre Goettingen, Georg August University, Goettingen, Germany; Department of Surgery, Klinikum rechts der Isar, Technische Universität München, School of Medicine Munich, Munich, Germany; Sonderforschungsbereich/Collaborative Research Centre 1321 Modeling and Targeting Pancreatic Cancer, Munich, Germany; Deutsches Konsortium für Translationale Krebsforschung (DKTK) Munich Site, Munich, Germany; and
| | - Volker Ellenrieder
- Department of Gastroenterology, Gastrointestinal Oncology, and Endocrinology, University Medical Centre Goettingen, Georg August University, Goettingen, Germany; Department of Surgery, Klinikum rechts der Isar, Technische Universität München, School of Medicine Munich, Munich, Germany; Sonderforschungsbereich/Collaborative Research Centre 1321 Modeling and Targeting Pancreatic Cancer, Munich, Germany; Deutsches Konsortium für Translationale Krebsforschung (DKTK) Munich Site, Munich, Germany; and
| | - Albrecht Neesse
- Department of Gastroenterology, Gastrointestinal Oncology, and Endocrinology, University Medical Centre Goettingen, Georg August University, Goettingen, Germany; Department of Surgery, Klinikum rechts der Isar, Technische Universität München, School of Medicine Munich, Munich, Germany; Sonderforschungsbereich/Collaborative Research Centre 1321 Modeling and Targeting Pancreatic Cancer, Munich, Germany; Deutsches Konsortium für Translationale Krebsforschung (DKTK) Munich Site, Munich, Germany; and
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Wang W, Huang X, Fan X, Yan J, Luan J. Progress in evaluating the status of hepatitis C infection based on the functional changes of hepatic stellate cells (Review). Mol Med Rep 2020; 22:4116-4124. [PMID: 33000255 DOI: 10.3892/mmr.2020.11516] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2020] [Accepted: 08/18/2020] [Indexed: 11/06/2022] Open
Abstract
Hepatitis C virus (HCV) infection is a global public health problem. Cirrhosis and hepatocellular carcinoma are the main causes of death in patients with chronic hepatitis C (CHC) infection. Liver fibrosis is an important cause of cirrhosis and end‑stage liver disease after CHC infection. Along with the course of infection, liver fibrosis exhibits a progressive exacerbation. Hepatic stellate cells (HSCs) are involved in both physiological and pathological processes of the liver. During the chronic liver injury process, the activated HSCs transform into myofibroblasts, which are important cells in the development of liver fibrosis. At present, HCV infection still lacks specific markers for the accurate detection of the disease condition and progression. Therefore, the present review focused on HSCs, which are closely related to HCV‑infected liver fibrosis, and analyzed the changes in the HSCs, including their surface‑specific markers, cytokine production, activation, cell function and morphological structure. The present review aimed to propose novel diagnostic markers, at both the cellular and molecular level, which would be of great significance for the timely diagnosis of the disease. According to this aim, the characteristic changes of HSCs during HCV infection were reviewed in the present article.
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Affiliation(s)
- Wei Wang
- Department of Blood Transfusion Medicine, School of Medicine, Jinling Hospital, Nanjing University, Nanjing, Jiangsu 210002, P.R. China
| | - Xuelian Huang
- Department of Blood Transfusion Medicine, School of Medicine, Jinling Hospital, Nanjing University, Nanjing, Jiangsu 210002, P.R. China
| | - Xuzhou Fan
- Department of Blood Transfusion Medicine, School of Medicine, Jinling Hospital, Nanjing University, Nanjing, Jiangsu 210002, P.R. China
| | - Jingmei Yan
- Department of Blood Transfusion Medicine, School of Medicine, Jinling Hospital, Nanjing University, Nanjing, Jiangsu 210002, P.R. China
| | - Jianfeng Luan
- Department of Blood Transfusion Medicine, School of Medicine, Jinling Hospital, Nanjing University, Nanjing, Jiangsu 210002, P.R. China
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Thuy LTT, Hai H, Kawada N. Role of cytoglobin, a novel radical scavenger, in stellate cell activation and hepatic fibrosis. Clin Mol Hepatol 2020; 26:280-293. [PMID: 32492766 PMCID: PMC7364355 DOI: 10.3350/cmh.2020.0037] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2020] [Revised: 03/09/2020] [Accepted: 03/13/2020] [Indexed: 12/17/2022] Open
Abstract
Cytoglobin (Cygb), a stellate cell-specific globin, has recently drawn attention due to its association with liver fibrosis. In the livers of both humans and rodents, Cygb is expressed only in stellate cells and can be utilized as a marker to distinguish stellate cells from hepatic fibroblast-derived myofibroblasts. Loss of Cygb accelerates liver fibrosis and cancer development in mouse models of chronic liver injury including diethylnitrosamine-induced hepatocellular carcinoma, bile duct ligation-induced cholestasis, thioacetamide-induced hepatic fibrosis, and choline-deficient L-amino acid-defined diet-induced non-alcoholic steatohepatitis. This review focuses on the history of research into the role of reactive oxygen species and nitrogen species in liver fibrosis and discusses the current perception of Cygb as a novel radical scavenger with an emphasis on its role in hepatic stellate cell activation and fibrosis.
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Affiliation(s)
- Le Thi Thanh Thuy
- Department of Hepatology, Graduate School of Medicine, Osaka City University, Osaka, Japan
| | - Hoang Hai
- Department of Hepatology, Graduate School of Medicine, Osaka City University, Osaka, Japan
| | - Norifumi Kawada
- Department of Hepatology, Graduate School of Medicine, Osaka City University, Osaka, Japan
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35
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Ishay Y, Nachman D, Khoury T, Ilan Y. The role of the sphingolipid pathway in liver fibrosis: an emerging new potential target for novel therapies. Am J Physiol Cell Physiol 2020; 318:C1055-C1064. [PMID: 32130072 DOI: 10.1152/ajpcell.00003.2020] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Sphingolipids (SL) are a family of bioactive lipids and a major cellular membrane structural component. SLs include three main compounds: ceramide (Cer), sphingosine (Sp), and sphingosine-1-phosphate (S-1P), all of which have emerging roles in biological functions in cells, especially in the liver. They are under investigation in various liver diseases, including cirrhosis and end-stage liver disease. In this review, we provide an overview on the role of SLs in liver pathobiology and focus on their potential role in the development of hepatic fibrosis. We describe recent evidence and suggest SLs are a promising potential therapeutic target for the treatment of liver disease and fibrosis.
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Affiliation(s)
- Yuval Ishay
- Department of Internal Medicine A, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
| | - Dean Nachman
- Department of Internal Medicine A, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
| | - Tawfik Khoury
- Gastroenterology and Liver Units, Department of Medicine, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
| | - Yaron Ilan
- Gastroenterology and Liver Units, Department of Medicine, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
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36
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Chen Z, Jain A, Liu H, Zhao Z, Cheng K. Targeted Drug Delivery to Hepatic Stellate Cells for the Treatment of Liver Fibrosis. J Pharmacol Exp Ther 2019; 370:695-702. [PMID: 30886124 PMCID: PMC6806344 DOI: 10.1124/jpet.118.256156] [Citation(s) in RCA: 71] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2018] [Accepted: 03/04/2019] [Indexed: 12/17/2022] Open
Abstract
Liver fibrosis is caused by excessive accumulation of extracellular matrix during chronic liver injuries. Although clinical evidence suggests that liver fibrosis can be reversed, there is no standard therapy for liver fibrosis. Moreover, there is a lack of diagnostic tools to detect early-stage liver fibrosis. Activation of hepatic stellate cells (HSCs) is the key step during liver fibrogenesis, and its mechanism has been extensively studied by various cell culture and animal models. Targeted delivery of therapeutic agents to activated HSCs is therefore critical for the successful treatment of liver fibrosis. A number of protein markers have been found to be overexpressed in activated HSCs, and their ligands have been used to specifically deliver various antifibrotic agents. In this review, we summarize these HSC-specific protein markers and their ligands for targeted delivery of antifibrotic agents.
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Affiliation(s)
- Zhijin Chen
- Division of Pharmacology and Pharmaceutical Science, School of Pharmacy, University of Missouri-Kansas City, Kansas City, Missouri
| | - Akshay Jain
- Division of Pharmacology and Pharmaceutical Science, School of Pharmacy, University of Missouri-Kansas City, Kansas City, Missouri
| | - Hao Liu
- Division of Pharmacology and Pharmaceutical Science, School of Pharmacy, University of Missouri-Kansas City, Kansas City, Missouri
| | - Zhen Zhao
- Division of Pharmacology and Pharmaceutical Science, School of Pharmacy, University of Missouri-Kansas City, Kansas City, Missouri
| | - Kun Cheng
- Division of Pharmacology and Pharmaceutical Science, School of Pharmacy, University of Missouri-Kansas City, Kansas City, Missouri
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37
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Haemmerle G, Lass A. Genetically modified mouse models to study hepatic neutral lipid mobilization. Biochim Biophys Acta Mol Basis Dis 2019; 1865:879-894. [PMID: 29883718 PMCID: PMC6887554 DOI: 10.1016/j.bbadis.2018.06.001] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2018] [Revised: 05/25/2018] [Accepted: 06/01/2018] [Indexed: 02/07/2023]
Abstract
Excessive accumulation of triacylglycerol is the common denominator of a wide range of clinical pathologies of liver diseases, termed non-alcoholic fatty liver disease. Such excessive triacylglycerol deposition in the liver is also referred to as hepatic steatosis. Although liver steatosis often resolves over time, it eventually progresses to steatohepatitis, liver fibrosis and cirrhosis, with associated complications, including liver failure, hepatocellular carcinoma and ultimately death of affected individuals. From the disease etiology it is obvious that a tight regulation between lipid uptake, triacylglycerol synthesis, hydrolysis, secretion and fatty acid oxidation is required to prevent triacylglycerol deposition in the liver. In addition to triacylglycerol, also a tight control of other neutral lipid ester classes, i.e. cholesteryl esters and retinyl esters, is crucial for the maintenance of a healthy liver. Excessive cholesteryl ester accumulation is a hallmark of cholesteryl ester storage disease or Wolman disease, which is associated with premature death. The loss of hepatic vitamin A stores (retinyl ester stores of hepatic stellate cells) is incidental to the onset of liver fibrosis. Importantly, this more advanced stage of liver disease usually does not resolve but progresses to life threatening stages, i.e. liver cirrhosis and cancer. Therefore, understanding the enzymes and pathways that mobilize hepatic neutral lipid esters is crucial for the development of strategies and therapies to ameliorate pathophysiological conditions associated with derangements of hepatic neutral lipid ester stores, including liver steatosis, steatohepatitis, and fibrosis. This review highlights the physiological roles of enzymes governing the mobilization of neutral lipid esters at different sites in liver cells, including cytosolic lipid droplets, endoplasmic reticulum, and lysosomes. This article is part of a Special Issue entitled Molecular Basis of Disease: Animal models in liver disease.
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Affiliation(s)
- Guenter Haemmerle
- Institute of Molecular Biosciences, University of Graz, Heinrichstraße 31/II, 8010 Graz, Austria.
| | - Achim Lass
- Institute of Molecular Biosciences, University of Graz, Heinrichstraße 31/II, 8010 Graz, Austria; BioTechMed-Graz, Austria.
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38
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Chen L, Brenner DA, Kisseleva T. Combatting Fibrosis: Exosome-Based Therapies in the Regression of Liver Fibrosis. Hepatol Commun 2019; 3:180-192. [PMID: 30766956 PMCID: PMC6357832 DOI: 10.1002/hep4.1290] [Citation(s) in RCA: 68] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2018] [Accepted: 10/24/2018] [Indexed: 12/14/2022] Open
Abstract
Hepatic fibrosis results from chronic injury and inflammation in the liver and leads to cirrhosis, liver failure, and portal hypertension. Understanding the molecular mechanisms underlying hepatic fibrosis has advanced the prospect of developing therapies for regression of the disease. Resolution of fibrosis requires a reduction of proinflammatory and fibrogenic cytokines, a decrease in extracellular matrix (ECM) protein production, an increase in collagenase activity, and finally, a disappearance of activated myofibroblasts. Exosomes are nanovesicles of endocytic origin secreted by most cell types. They epigenetically reprogram and alter the phenotype of their recipient cells and hold great promise for the reversal of fibrosis. Recent studies have shown that exosomes function as conduits for intercellular transfer and contain all the necessary components to induce resolution of fibrosis, including the ability to (1) inhibit macrophage activation and cytokine secretion, (2) remodel ECM production and decrease fibrous scars, and (3) inactivate hepatic stellate cells, a major myofibroblast population. Here, we discuss the research involving the regression of hepatic fibrosis. We focus on the newly discovered roles of exosomes during fibrogenesis and as a therapy for fibrosis reversal. We also emphasize the novel discoveries of exosome-based antifibrotic treatments in vitro and in vivo.
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Affiliation(s)
- Li Chen
- Department of MedicineUniversity of California San DiegoLa JollaCA
| | - David A. Brenner
- Department of MedicineUniversity of California San DiegoLa JollaCA
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Yokomori H, Ando W, Oda M. Caveolin-1 is related to lipid droplet formation in hepatic stellate cells in human liver. Acta Histochem 2019; 121:113-118. [PMID: 30446170 DOI: 10.1016/j.acthis.2018.10.008] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2018] [Revised: 10/19/2018] [Accepted: 10/19/2018] [Indexed: 11/30/2022]
Abstract
Caveolins (CAVs) regulate intracellular cholesterol transport by a complex process involving caveolae, endoplasmic reticulum (ER), and the Golgi network. Hepatic stellate cells (HSCs) are the central site for retinoid storage in the liver and indeed the entire body. Herein, we attempted to elucidate the ultrastructural localization and expression of caveolin-1 (CAV-1) in human HSCs during the progression of liver cirrhosis (LC). Normal and hepatitis C-related cirrhotic liver samples were prepared using a modified perfusion-fixation method to fix organelle structures and molecules in their in vivo positions, and examined using immunoelectron microscopy. In control liver specimens, CAV-1 was minimally associated with low electron density lipid droplets (LDs) segregated around zones 1-2, and specifically associated with membranes surrounding LDs. CAV-1 was segregated in high-density LDs, consistent with the formation of membrane-enclosed lipid-rich vesicular structures, as well as caveolae on plasma membranes around zones 2-3. In cirrhotic liver specimens, CAV-1 molecules were inserted into the cytoplasmic leaflets of ER membranes for transportation to LDs. Thus, CAV-1 transport to LDs might represent an intracellular pathway from the ER in cirrhotic liver tissue.
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Affiliation(s)
- Hiroaki Yokomori
- Department of Internal Medicine, Kitasato University Medical Center, Saitama, Japan.
| | - Wataru Ando
- Department of Clinical Pharmacy, School of Pharmacy, Kitasato University, Tokyo, Japan
| | - Masaya Oda
- Organized Center of Clinical Medicine, Sanno Medical Center, International University of Health and Welfare, Tokyo, Japan
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40
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Peng DQ, Lee JS, Kim WS, Kim YS, Bae MH, Jo YH, Oh YK, Baek YC, Hwang SG, Lee HG. Effect of vitamin A restriction on carcass traits and blood metabolites in Korean native steers. ANIMAL PRODUCTION SCIENCE 2019. [DOI: 10.1071/an17733] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
The objective of the present study was to determine the effect of vitamin A restriction on serum metabolites and carcass performance in Korean native steers during a fattening period. In Study 1, 61 steers were divided into three groups and supplied diets with concentrate and roughage containing 890 IU/kg of provitamin A and then supplemented with either 8000 IU (control), 3000 IU (T1) or 0 IU (T2) of premix vitamin A per kilogram of dry matter. In Study 2, 19 steers were divided into two groups and provided with the same basic diets then supplemented with 8000 IU (control) or 0 IU (T) of premix vitamin A per kilogram of dry matter. In Study 1, we found that serum vitamin A concentrations were significantly (P < 0.05) lower in the T2 group, along with significant (P < 0.05) increases in blood urea nitrogen, albumin, creatinine and non-esterified fatty acid concentrations. In Study 2, the T group had a higher (P < 0.05) skeletal muscle mRNA expression levels of myogenic factor 6 and a trend for the greater yield grade (P=0.095). However, marbling scores in the study showed no significant. Therefore, vitamin A restriction with vitamin premix during the fattening period was associated with a trend for a higher yield grade, but marbling scores that were not significantly higher. Metabolic parameters in this stage could be used as indicators in future metabolic studies and as early health status markers in Korean native steers.
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41
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Oral vitamin-A-coupled valsartan nanomedicine: High hepatic stellate cell receptors accessibility and prolonged enterohepatic residence. J Control Release 2018; 283:32-44. [PMID: 29792888 DOI: 10.1016/j.jconrel.2018.05.021] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2018] [Revised: 05/14/2018] [Accepted: 05/18/2018] [Indexed: 12/12/2022]
Abstract
So far, liver fibrosis still has no clinically-approved treatment. The loss of stored vitamin-A (VA) in hepatic stellate cells (HSCs), the main regulators to hepatic fibrosis, can be applied as a mechanism for their targeting. Valsartan is a good candidate for this approach; it is a marketed oral-therapy with inverse- and partial-agonistic activity to the over-expressed angiotensin-II type1 receptor (AT1R) and depleted nuclear peroxisome proliferator-activated receptor-gamma (PPAR-γ), respectively, in activated HSCs. However, efficacy on AT1R and PPAR-γ necessitates high drug permeability which is lacking in valsartan. In the current study, liposomes were used as nanocarriers for valsartan to improve its permeability and hence efficacy. They were coupled to VA and characterized for HSCs-targeting. Tracing of orally-administered fluorescently-labeled VA-coupled liposomes in normal rats and their fluorescence intensity quantification in different organs convincingly demonstrated their intestinal entrapment. On the other hands, their administration to rats with induced fibrosis revealed preferential hepatic, and less intestinal, accumulation which lasted up to six days. This indicated their uptake by intestinal stellate cells that acted as a depot for their release over time. Confocal microscopical examination of immunofluorescently-stained HSCs in liver sections, with considerable formula accumulation, confirmed HSCs-targeting and nuclear uptake. Consequently, VA-coupled valsartan-loaded liposomes (VLC)-therapy resulted in profound re-expression of hepatic Mas-receptor and PPAR-γ, potent reduction of fibrogenic mediators' level and nearly normal liver function tests. Therefore, VLC epitomizes a promising antifibrotic therapy with exceptional extended action and additional PPAR-γ agonistic activity.
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42
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Bae M, Park YK, Lee JY. Food components with antifibrotic activity and implications in prevention of liver disease. J Nutr Biochem 2017; 55:1-11. [PMID: 29268106 DOI: 10.1016/j.jnutbio.2017.11.003] [Citation(s) in RCA: 55] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2017] [Revised: 09/18/2017] [Accepted: 11/11/2017] [Indexed: 12/26/2022]
Abstract
Increasing prevalence of nonalcoholic fatty liver disease (NAFLD) in parallel with the obesity epidemic has been a major public health concern. NAFLD is the most common chronic liver disease in the United States, ranging from fatty liver to steatohepatitis, fibrosis and cirrhosis in the liver. In response to chronic liver injury, fibrogenesis in the liver occurs as a protective response; however, prolonged and dysregulated fibrogenesis can lead to liver fibrosis, which can further progress to cirrhosis and eventually hepatocellular carcinoma. Interplay of hepatocytes, macrophages and hepatic stellate cells (HSCs) in the hepatic inflammatory and oxidative milieu is critical for the development of NAFLD. In particular, HSCs play a major role in the production of extracellular matrix proteins. Studies have demonstrated that bioactive food components and natural products, including astaxanthin, curcumin, blueberry, silymarin, coffee, vitamin C, vitamin E, vitamin D, resveratrol, quercetin and epigallocatechin-3-gallate, have antifibrotic effects in the liver. This review summarizes current knowledge of the mechanistic insight into the antifibrotic actions of the aforementioned bioactive food components.
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Affiliation(s)
- Minkyung Bae
- Department of Nutritional Sciences, University of Connecticut, Storrs, CT 06269, USA
| | - Young-Ki Park
- Department of Nutritional Sciences, University of Connecticut, Storrs, CT 06269, USA
| | - Ji-Young Lee
- Department of Nutritional Sciences, University of Connecticut, Storrs, CT 06269, USA; Department of Food and Nutrition, Kyung Hee University, Seoul, South Korea.
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43
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Opitz L, Kling KM, Brandenberger C, Mühlfeld C. Lipid-body containing interstitial cells (lipofibroblasts) in the lungs of various mouse strains. J Anat 2017; 231:970-977. [PMID: 28786110 DOI: 10.1111/joa.12677] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/28/2017] [Indexed: 11/26/2022] Open
Abstract
Pulmonary alveolar septa are thought to contain at least two types of fibroblasts that are termed myofibroblasts and lipofibroblasts based on their morphological characteristics. Lipofibroblasts possess cytoplasmic lipid inclusions (lipid bodies or droplets) and are involved in several important functions, such as surfactant synthesis, development, vitamin A storage and presumably regeneration. As vitamin A was shown to reduce pulmonary emphysema in several but not all mouse and rat strains, we hypothesized that these strain differences might be explained by a differential occurrence of lipofibroblasts and their lipid bodies in various mouse strains. Therefore, mouse lungs of six strains (NMRI, BALB/c, C3H/HeJ, C57BL/6J, C57BL/6N and FVB/N) were investigated by light and electron microscopic stereology to quantify the amount of lipid bodies and the composition of alveolar septa. Lipofibroblasts were observed qualitatively by transmission electron microscopy in every investigated mouse strain. The total volume and the volume-weighted mean volume of lipid bodies were similar in all mouse strains. The results on the composition of the interalveolar septa did not show major differences between the groups. The only mouse strain that differed significantly from the other strains was the NMRI strain because the lungs had a higher volume and consequently many of the morphological parameters were also larger than in the other groups. In conclusion, the present study showed that lipofibroblasts are a common cell type in the mouse lung across various strains. Therefore, the mere presence or absence of lipofibroblasts does not explain differences in the pulmonary regenerative potential among mouse strains.
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Affiliation(s)
- Luka Opitz
- Institute of Functional and Applied Anatomy, Hannover Medical School, Hannover, Germany
| | - Katharina Maria Kling
- Institute of Functional and Applied Anatomy, Hannover Medical School, Hannover, Germany
| | - Christina Brandenberger
- Institute of Functional and Applied Anatomy, Hannover Medical School, Hannover, Germany.,Cluster of Excellence REBIRTH (From Regenerative Biology to Reconstructive Therapy), Hannover, Germany.,Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), German Center for Lung Research (DZL), Hannover, Germany
| | - Christian Mühlfeld
- Institute of Functional and Applied Anatomy, Hannover Medical School, Hannover, Germany.,Cluster of Excellence REBIRTH (From Regenerative Biology to Reconstructive Therapy), Hannover, Germany.,Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), German Center for Lung Research (DZL), Hannover, Germany
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44
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Welte MA, Gould AP. Lipid droplet functions beyond energy storage. Biochim Biophys Acta Mol Cell Biol Lipids 2017; 1862:1260-1272. [PMID: 28735096 PMCID: PMC5595650 DOI: 10.1016/j.bbalip.2017.07.006] [Citation(s) in RCA: 353] [Impact Index Per Article: 44.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2017] [Revised: 07/17/2017] [Accepted: 07/17/2017] [Indexed: 02/07/2023]
Abstract
Lipid droplets are cytoplasmic organelles that store neutral lipids and are critically important for energy metabolism. Their function in energy storage is firmly established and increasingly well characterized. However, emerging evidence indicates that lipid droplets also play important and diverse roles in the cellular handling of lipids and proteins that may not be directly related to energy homeostasis. Lipid handling roles of droplets include the storage of hydrophobic vitamin and signaling precursors, and the management of endoplasmic reticulum and oxidative stress. Roles of lipid droplets in protein handling encompass functions in the maturation, storage, and turnover of cellular and viral polypeptides. Other potential roles of lipid droplets may be connected with their intracellular motility and, in some cases, their nuclear localization. This diversity highlights that lipid droplets are very adaptable organelles, performing different functions in different biological contexts. This article is part of a Special Issue entitled: Recent Advances in Lipid Droplet Biology edited by Rosalind Coleman and Matthijs Hesselink.
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Affiliation(s)
- Michael A Welte
- Department of Biology, University of Rochester, Rochester, NY, United States.
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45
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McDaniel K, Huang L, Sato K, Wu N, Annable T, Zhou T, Ramos-Lorenzo S, Wan Y, Huang Q, Francis H, Glaser S, Tsukamoto H, Alpini G, Meng F. The let-7/Lin28 axis regulates activation of hepatic stellate cells in alcoholic liver injury. J Biol Chem 2017; 292:11336-11347. [PMID: 28536261 DOI: 10.1074/jbc.m116.773291] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2016] [Revised: 05/20/2017] [Indexed: 12/11/2022] Open
Abstract
The let-7/Lin28 axis is associated with the regulation of key cellular regulatory genes known as microRNAs in various human disorders and cancer development. This study evaluated the role of the let-7/Lin28 axis in regulating a mesenchymal phenotype of hepatic stellate cells in alcoholic liver injury. We identified that ethanol feeding significantly down-regulated several members of the let-7 family in mouse liver, including let-7a and let-7b. Similarly, the treatment of human hepatic stellate cells (HSCs) with lipopolysaccharide (LPS) and transforming growth factor-β (TGF-β) significantly decreased the expressions of let-7a and let-7b. Conversely, overexpression of let-7a and let-7b suppressed the myofibroblastic activation of cultured human HSCs induced by LPS and TGF-β, as evidenced by repressed ACTA2 (α-actin 2), COL1A1 (collagen 1A1), TIMP1 (TIMP metallopeptidase inhibitor 1), and FN1 (fibronectin 1); this supports the notion that HSC activation is controlled by let-7. A combination of bioinformatics, dual-luciferase reporter assay, and Western blot analysis revealed that Lin28B and high-mobility group AT-hook (HMGA2) were the direct targets of let-7a and let-7b. Furthermore, Lin28B deficiency increased the expression of let-7a/let-7b as well as reduced HSC activation and liver fibrosis in mice with alcoholic liver injury. This feedback regulation of let-7 by Lin28B is verified in hepatic stellate cells isolated by laser capture microdissection from the model. The identification of the let-7/Lin28 axis as an important regulator of HSC activation as well as its upstream modulators and down-stream targets will provide insights into the involvement of altered microRNA expression in contributing to the pathogenesis of alcoholic liver fibrosis and novel therapeutic approaches for human alcoholic liver diseases.
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Affiliation(s)
- Kelly McDaniel
- From the Division of Research, Central Texas Veterans Health Care System, Temple, Texas 76504.,Digestive Disease Research Center, Department of Medicine, Baylor Scott & White Digestive Disease Research Center, Texas A&M Health Science Center, and Baylor Scott & White Hospital, Temple, Texas 76504.,Research Institute, Baylor Scott & White Health, Temple, Texas 76504
| | - Li Huang
- Department of Hepatobiliary Surgery, First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China
| | - Keisaku Sato
- Digestive Disease Research Center, Department of Medicine, Baylor Scott & White Digestive Disease Research Center, Texas A&M Health Science Center, and Baylor Scott & White Hospital, Temple, Texas 76504
| | - Nan Wu
- Digestive Disease Research Center, Department of Medicine, Baylor Scott & White Digestive Disease Research Center, Texas A&M Health Science Center, and Baylor Scott & White Hospital, Temple, Texas 76504
| | - Tami Annable
- Research Institute, Baylor Scott & White Health, Temple, Texas 76504.,Temple Bioscience District, Temple, Texas 76504
| | - Tianhao Zhou
- From the Division of Research, Central Texas Veterans Health Care System, Temple, Texas 76504.,Digestive Disease Research Center, Department of Medicine, Baylor Scott & White Digestive Disease Research Center, Texas A&M Health Science Center, and Baylor Scott & White Hospital, Temple, Texas 76504
| | | | - Ying Wan
- Digestive Disease Research Center, Department of Medicine, Baylor Scott & White Digestive Disease Research Center, Texas A&M Health Science Center, and Baylor Scott & White Hospital, Temple, Texas 76504.,Research Institute, Baylor Scott & White Health, Temple, Texas 76504.,Department of Pathophysiology, Key Laboratory for Shock and Microcirculation Research of Guangdong Province, Southern Medical University, Guangzhou 510515, China, and
| | - Qiaobing Huang
- Department of Pathophysiology, Key Laboratory for Shock and Microcirculation Research of Guangdong Province, Southern Medical University, Guangzhou 510515, China, and
| | - Heather Francis
- From the Division of Research, Central Texas Veterans Health Care System, Temple, Texas 76504.,Digestive Disease Research Center, Department of Medicine, Baylor Scott & White Digestive Disease Research Center, Texas A&M Health Science Center, and Baylor Scott & White Hospital, Temple, Texas 76504.,Research Institute, Baylor Scott & White Health, Temple, Texas 76504
| | - Shannon Glaser
- From the Division of Research, Central Texas Veterans Health Care System, Temple, Texas 76504.,Digestive Disease Research Center, Department of Medicine, Baylor Scott & White Digestive Disease Research Center, Texas A&M Health Science Center, and Baylor Scott & White Hospital, Temple, Texas 76504
| | - Hidekazu Tsukamoto
- Southern California Research Center for Alcoholic Liver and Pancreatic Diseases (ALPD) and Cirrhosis, Keck School of Medicine of the University of Southern California and Department of Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, California 90089
| | - Gianfranco Alpini
- From the Division of Research, Central Texas Veterans Health Care System, Temple, Texas 76504, .,Digestive Disease Research Center, Department of Medicine, Baylor Scott & White Digestive Disease Research Center, Texas A&M Health Science Center, and Baylor Scott & White Hospital, Temple, Texas 76504
| | - Fanyin Meng
- From the Division of Research, Central Texas Veterans Health Care System, Temple, Texas 76504, .,Digestive Disease Research Center, Department of Medicine, Baylor Scott & White Digestive Disease Research Center, Texas A&M Health Science Center, and Baylor Scott & White Hospital, Temple, Texas 76504.,Research Institute, Baylor Scott & White Health, Temple, Texas 76504
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Salas-Villalobos T, Lozano-Sepúlveda S, Rincón-Sánchez A, Govea-Salas M, Rivas-Estilla A. Mechanisms involved in liver damage resolution after hepatitis C virus clearance. MEDICINA UNIVERSITARIA 2017. [DOI: 10.1016/j.rmu.2017.05.005] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
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Katsumata LW, Miyajima A, Itoh T. Portal fibroblasts marked by the surface antigen Thy1 contribute to fibrosis in mouse models of cholestatic liver injury. Hepatol Commun 2017; 1:198-214. [PMID: 29404454 PMCID: PMC5721447 DOI: 10.1002/hep4.1023] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/04/2016] [Accepted: 02/09/2017] [Indexed: 12/23/2022] Open
Abstract
Liver fibrosis, a condition that is characterized by excessive production and accumulation of extracellular matrix, including collagen, is the most common outcome of chronic liver injuries of different etiologies. Vitamin A‐storing hepatic stellate cells (HSCs) are considered to be the main source of this collagen production, with activation in response to liver injury. In contrast, the contribution of other cell types to this fibrogenic response remains largely elusive due to the lack of specific surface markers to identify and isolate these cells for detailed analysis. Here, we identify a mesenchymal population of thymus cell antigen 1 (Thy1)+ CD45− cells (Thy1 MCs) in the mouse liver; these cells reside near the portal vein in vivo and indicate profibrogenic characteristics in vitro, shown by their expression of collagen and α‐smooth muscle actin. Flow cytometric analysis of mouse liver nonparenchymal cells revealed that vitamin A storage and Thy1 expression were mutually exclusive, indicating that Thy1 MCs are distinct from HSCs. Importantly, Thy1 MCs reacted and contributed to the development of liver fibrosis specifically in mouse models of cholestatic liver injury. With the occurrence of cholestatic liver injury, collagen‐producing Thy1 MCs expanded in cell number and inhibited collagen degradation through up‐regulation of matrix metalloproteinase inhibitor Timp1 expression, thereby promoting the accumulation of extracellular matrix in the periportal area. Conclusion: This study establishes Thy1 as a useful cell surface marker to prospectively identify and isolate periportal fibroblasts and further highlights a significant contribution of these cells to the pathogenesis of liver fibrosis caused by cholestatic liver injuries. We suggest that Thy1 MCs may be an interesting therapeutic target for treating liver fibrosis in addition to the well‐characterized HSCs. (Hepatology Communications 2017;1:198‐214)
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Affiliation(s)
- Len William Katsumata
- Laboratory of Cell Growth and Differentiation Institute of Molecular and Cellular Biosciences, University of Tokyo Tokyo Japan
| | - Atsushi Miyajima
- Laboratory of Cell Growth and Differentiation Institute of Molecular and Cellular Biosciences, University of Tokyo Tokyo Japan
| | - Tohru Itoh
- Laboratory of Cell Growth and Differentiation Institute of Molecular and Cellular Biosciences, University of Tokyo Tokyo Japan
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48
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The stellate cell system (vitamin A-storing cell system). Anat Sci Int 2017; 92:387-455. [PMID: 28299597 DOI: 10.1007/s12565-017-0395-9] [Citation(s) in RCA: 67] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2016] [Accepted: 02/15/2017] [Indexed: 01/18/2023]
Abstract
Past, present, and future research into hepatic stellate cells (HSCs, also called vitamin A-storing cells, lipocytes, interstitial cells, fat-storing cells, or Ito cells) are summarized and discussed in this review. Kupffer discovered black-stained cells in the liver using the gold chloride method and named them stellate cells (Sternzellen in German) in 1876. Wake rediscovered the cells in 1971 using the same gold chloride method and various modern histological techniques including electron microscopy. Between their discovery and rediscovery, HSCs disappeared from the research history. Their identification, the establishment of cell isolation and culture methods, and the development of cellular and molecular biological techniques promoted HSC research after their rediscovery. In mammals, HSCs exist in the space between liver parenchymal cells (PCs) or hepatocytes and liver sinusoidal endothelial cells (LSECs) of the hepatic lobule, and store 50-80% of all vitamin A in the body as retinyl ester in lipid droplets in the cytoplasm. SCs also exist in extrahepatic organs such as pancreas, lung, and kidney. Hepatic (HSCs) and extrahepatic stellate cells (EHSCs) form the stellate cell (SC) system or SC family; the main storage site of vitamin A in the body is HSCs in the liver. In pathological conditions such as liver fibrosis, HSCs lose vitamin A, and synthesize a large amount of extracellular matrix (ECM) components including collagen, proteoglycan, glycosaminoglycan, and adhesive glycoproteins. The morphology of these cells also changes from the star-shaped HSCs to that of fibroblasts or myofibroblasts.
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Rogler CE, Matarlo JS, Kosmyna B, Fulop D, Rogler LE. Knockdown of miR-23, miR-27, and miR-24 Alters Fetal Liver Development and Blocks Fibrosis in Mice. Gene Expr 2017; 17:99-114. [PMID: 27938504 PMCID: PMC8751183 DOI: 10.3727/105221616x693891] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
MicroRNAs (miRNAs) regulate cell fate selection and cellular differentiation. miRNAs of the miR23b polycistron (miR-23b, miR-27b, and miR-24) target components of the TGF-β signaling pathway and affect murine bile ductular and hepatocyte cell fate selection in vitro. Here we show that miR-23b polycistron miRNAs directly target murine Smad4, which is required for TGF-β signaling. Injection of antagomirs against these miRNAs directly into E16.5 murine fetuses caused increased cytokeratin expression in sinusoids and primitive ductular elements throughout the parenchyma of newborn mice. Similar antagomir injection in newborn mice increased bile ductular differentiation in the liver periphery and reduced hepatocyte proliferation. Antagomir injection in newborn Alb/TGF-β1 transgenic mice that develop fibrosis inhibited the development of fibrosis, and injection of older mice caused the resolution of existing fibrosis. Furthermore, murine stellate cell activation, including ColA1 and ACTA2 expression, is regulated by miR-23b cluster miRNAs. In summary, knockdown of miR-23b cluster miRNAs in fetal and newborn liver promotes bile duct differentiation and can block or revert TGF-β-induced liver fibrosis that is dependent on stellate cell activation. These data may find practical application in the highly needed development of therapies for the treatment of fibrosis.
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Affiliation(s)
- Charles E. Rogler
- Division of Gastroenterology and Liver Disease, Department of Medicine, Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Joe S. Matarlo
- Division of Gastroenterology and Liver Disease, Department of Medicine, Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Brian Kosmyna
- Division of Gastroenterology and Liver Disease, Department of Medicine, Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Daniel Fulop
- Division of Gastroenterology and Liver Disease, Department of Medicine, Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Leslie E. Rogler
- Division of Gastroenterology and Liver Disease, Department of Medicine, Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, NY, USA
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50
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Napoli JL. Cellular retinoid binding-proteins, CRBP, CRABP, FABP5: Effects on retinoid metabolism, function and related diseases. Pharmacol Ther 2017; 173:19-33. [PMID: 28132904 DOI: 10.1016/j.pharmthera.2017.01.004] [Citation(s) in RCA: 178] [Impact Index Per Article: 22.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Cellular binding-proteins (BP), including CRBP1, CRBP2, CRABP1, CRABP2, and FABP5, shepherd the poorly aqueous soluble retinoids during uptake, metabolism and function. Holo-BP promote efficient use of retinol, a scarce but essential nutrient throughout evolution, by sheltering it and its major metabolite all-trans-retinoic acid from adventitious interactions with the cellular milieu, and by imposing specificity of delivery to enzymes, nuclear receptors and other partners. Apo-BP reflect cellular retinoid status and modify activities of retinoid metabolon enzymes, or exert non-canonical actions. High ligand binding affinities and the nature of ligand sequestration necessitate external factors to prompt retinoid release from holo-BP. One or more of cross-linking, kinetics, and colocalization have identified these factors as RDH, RALDH, CYP26, LRAT, RAR and PPARβ/δ. Michaelis-Menten and other kinetic approaches verify that BP channel retinoids to select enzymes and receptors by protein-protein interactions. Function of the BP and enzymes that constitute the retinoid metabolon depends in part on retinoid exchanges unique to specific pairings. The complexity of these exchanges configure retinol metabolism to meet the diverse functions of all-trans-retinoic acid and its ability to foster contrary outcomes in different cell types, such as inducing apoptosis, differentiation or proliferation. Altered BP expression affects retinoid function, for example, by impairing pancreas development resulting in abnormal glucose and energy metabolism, promoting predisposition to breast cancer, and fostering more severe outcomes in prostate cancer, ovarian adenocarcinoma, and glioblastoma. Yet, the extent of BP interactions with retinoid metabolon enzymes and their impact on retinoid physiology remains incompletely understood.
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Affiliation(s)
- Joseph L Napoli
- Department of Nutritional Sciences and Toxicology, University of California, Berkeley, CA 94720, United States.
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