|
1
|
Zhong X, Sun Y, Lin Y, Deng S, Wang H, Zhou X, Lu J, Zheng Y, Luo R, Huang M, Song J. Ginsenoside Rd protects against acute liver injury by regulating the autophagy NLRP3 inflammasome pathway. Sci Rep 2025; 15:3569. [PMID: 39875579 PMCID: PMC11775168 DOI: 10.1038/s41598-025-87991-9] [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: 09/29/2024] [Accepted: 01/23/2025] [Indexed: 01/30/2025] Open
Abstract
Ginsenoside Rd (Rd) is a bioactive compound predominantly found in Panax ginseng C.A. Meyer and Panax notoginseng (Burkill) F.H. Chen ex C.H. Chow, both species belonging to genus Panax in the Araliaceae family. However, its hepatic protective effect against acute liver injury and related mechanistic action remain unexplored. To investigate the protective effect of Rd against thioacetamide (TAA)-induced acute liver injury and assess its underlying regulatory mechanisms related to autophagy and inflammation. Forty-eight 8 weeks old C57BL/6 mice were treated with saline (control or model group), Rd (12.5 mg/kg, 25 mg/kg or 50 mg/kg), and diammonium glycyrrhizinate (DG, 30 mg/kg) for three days. Then the mice were stimulated with TAA to establish acute liver injury model, excluding the control group. HSC-T6 cells were treated with Rd at concentrations of 2.5, 5, or 10 µM, for 12 h with or without Lipopolysaccharide (LPS) stimulation at 100 ng/mL. Immunofluorescence staining, qPCR and Western blot were employed to analyze the expressions of genes and proteins associated with inflammation and autophagy. To validate the role of Rd in regulating autophagy and inflammation, the autophagy inducers, rapamycin and GSK621, were utilised in reverse validation experiments in cells. Rd exhibited significant hepatic protective effects in mice by reducing the serum levels of Aspartate aminotransferase (AST), Alanine aminotransferase (ALT), Glutathione S-transferase (GST) and Lactate dehydrogenase (LDH) with acute liver injury. It exhibited strong anti-inflammatory effect by reducing inflammation associated protein, such as cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), nod-like receptor protein 3 (NLRP3), associated speck-like protein containing a CARD (ASC), interleukin-18 (IL-18) and interleukin-1β(IL-1β) proteins and the mRNA expression levels of COX-2, Tumor Necrosis Factor α (TNF α), interleukin-6 (IL-6) and iNOS were decreased in liver tissue. And Rd inhibited LPS-induced inflammation by reducing the expression of COX-2 and NLRP3 in HSC-T6 cells. Moreover, not only in vivo but also in vitro, Rd downregulated the expression of LC3II, Beclin1, phosphorylation-AMP-activated protein kinase (p-AMPK), phosphorylation-ULK1 (p-ULK1) and upregulated the expression of p62 and phosphorylation-mechanistic target of rapamycin (p-mTOR) to suppress autophagy via the AMPK/mTOR/ULK1 pathway. Finally, the inhibitory effects of Rd on autophagy and inflammation in HSC-T6 cells were partially blocked by rapamycin and GSK621. Rd is a promising therapeutic agent to protect liver against TAA-induced acute liver injury by regulating the autophagy-NLRP3 inflammasome pathway.
Collapse
Affiliation(s)
- Xiaomei Zhong
- The Affiliated People's Hospital, Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, 350108, China
| | - Yibin Sun
- Kaifeng Hospital of Traditional Chinese Medicine, Kaifeng, 475000, China
| | - Yanxiang Lin
- The Affiliated People's Hospital, College of Pharmacy, Fujian University of Traditional Chinese Medicine, Fuzhou, 350108, China
| | - Shan Deng
- The Affiliated People's Hospital, College of Pharmacy, Fujian University of Traditional Chinese Medicine, Fuzhou, 350108, China
| | - Huan Wang
- The Affiliated People's Hospital, College of Pharmacy, Fujian University of Traditional Chinese Medicine, Fuzhou, 350108, China
| | - Xian Zhou
- NICM Health Research Institute, Western Sydney University, Westmead, NSW, 2006, Australia
| | - Jinjian Lu
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Avenida da Universidade, Taipa, Macao, China
| | - Yanfang Zheng
- The Affiliated People's Hospital, College of Pharmacy, Fujian University of Traditional Chinese Medicine, Fuzhou, 350108, China.
| | - Ruoyin Luo
- School of Pharmacy and Pharmaceutical Sciences, Ulster University, Belfast, UK.
| | - Mingqing Huang
- The Affiliated People's Hospital, College of Pharmacy, Fujian University of Traditional Chinese Medicine, Fuzhou, 350108, China.
| | - Jianyuan Song
- Department of Radiation Oncology, Fujian Medical University Union Hospital, Fuzhou, 350001, Fujian, China.
| |
Collapse
|
|
2
|
Markowska J, Kasprzak-Drozd K, Niziński P, Dragan M, Kondracka A, Gondek E, Oniszczuk T, Oniszczuk A. Quercetin: A Promising Candidate for the Management of Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD). Molecules 2024; 29:5245. [PMID: 39598636 PMCID: PMC11596905 DOI: 10.3390/molecules29225245] [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: 09/30/2024] [Revised: 10/30/2024] [Accepted: 11/04/2024] [Indexed: 11/29/2024] Open
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) represents a chronic liver disease. The development of MASLD is influenced by a multitude of diseases associated with modern lifestyles, including but not limited to diabetes mellitus, hypertension, hyperlipidaemia and obesity. These conditions are often consequences of the adoption of unhealthy habits, namely a sedentary lifestyle, a lack of physical activity, poor dietary choices and excessive alcohol consumption. The treatment of MASLD is primarily based on modifying the patient's lifestyle and pharmacological intervention. Despite the absence of FDA-approved pharmacological agents for the treatment of MASLD, several potential therapeutic modalities have demonstrated efficacy in reversing the histopathological features of the disease. Among the botanical ingredients belonging to the flavonoid group is quercetin (QE). QE has been demonstrated to possess a number of beneficial physiological effects, including anti-inflammatory, anticancer and antifungal properties. Additionally, it functions as a natural antioxidant. Preclinical evidence indicates that QE may play a beneficial role in reducing liver damage and improving metabolic health. Early human studies also suggest that QE may be an effective treatment for MASLD due to its antioxidant, anti-inflammatory, and lipid-regulating properties. This review aims to summarize the available information on the therapeutic effects of QE in MASLD.
Collapse
Affiliation(s)
- Julia Markowska
- Science Circle of the Department of Inorganic Chemistry, Medical University of Lublin, Dr. Witolda Chodźki 4a, 20-093 Lublin, Poland; (J.M.); (M.D.)
| | - Kamila Kasprzak-Drozd
- Department of Inorganic Chemistry, Medical University of Lublin, Dr. Witolda Chodźki 4a, 20-093 Lublin, Poland;
| | - Przemysław Niziński
- Department of Pharmacology, Medical University of Lublin, Radziwiłłowska 11, 20-080 Lublin, Poland;
| | - Magdalena Dragan
- Science Circle of the Department of Inorganic Chemistry, Medical University of Lublin, Dr. Witolda Chodźki 4a, 20-093 Lublin, Poland; (J.M.); (M.D.)
| | - Adrianna Kondracka
- Department of Obstetrics and Pathology of Pregnancy, Medical University of Lublin, 20-081 Lublin, Poland;
| | - Ewa Gondek
- Department of Food Engineering and Process Management, Institute of Food Science, Warsaw University of Life Sciences, Nowoursynowska 159C, 02-776 Warsaw, Poland
| | - Tomasz Oniszczuk
- Department of Thermal Technology and Food Process Engineering, University of Life Sciences in Lublin, Głęboka 31, 20-612 Lublin, Poland;
| | - Anna Oniszczuk
- Department of Inorganic Chemistry, Medical University of Lublin, Dr. Witolda Chodźki 4a, 20-093 Lublin, Poland;
| |
Collapse
|
|
3
|
Le TV, Truong NH, Holterman AXL. Autophagy modulates physiologic and adaptive response in the liver. LIVER RESEARCH 2023; 7:304-320. [PMID: 39958781 PMCID: PMC11792069 DOI: 10.1016/j.livres.2023.12.001] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/06/2023] [Revised: 07/20/2023] [Accepted: 11/14/2023] [Indexed: 01/03/2025]
Abstract
Autophagy is a physiological process that is ubiquitous and essential to the disposal or recycling of damaged cellular organelles and misfolded proteins to maintain organ homeostasis and survival. Its importance in the regulation of liver function in normal and pathological conditions is increasingly recognized. This review summarizes how autophagy regulates epithelial cell- and non-epithelial cell-specific function in the liver and how it differentially participates in hepatic homeostasis, hepatic injury response to stress-induced liver damage such as cholestasis, sepsis, non-alcoholic and alcohol-associated liver disease, viral hepatitis, hepatic fibrosis, hepatocellular and cholangiocellular carcinoma, and aging. Autophagy-based interventional studies for liver diseases that are currently registered in clinicatrials.gov are summarized. Given the broad and multidirectional autophagy response in the liver, a more refined understanding of the liver cell-specific autophagy activities in a context-dependent manner is necessary.
Collapse
Affiliation(s)
- Trinh Van Le
- Laboratory of Stem Cell Research and Application, University of Science-VNUHCM, Ho Chi Minh City, Vietnam
- Vietnam National University, Ho Chi Minh City, Vietnam
| | - Nhung Hai Truong
- Faculty of Biology and Biotechnology, University of Science-VNUHCM, Ho Chi Minh City, Vietnam
| | - Ai Xuan L. Holterman
- Department of Pediatrics and Surgery, University of Illinois College of Medicine, Chicago and Peoria, IL, USA
| |
Collapse
|
|
4
|
Li Y, Xu J, Chen W, Wang X, Zhao Z, Li Y, Zhang L, Jiao J, Yang Q, Ding Q, Yang P, Wei L, Chen Y, Chen Y, Ruan XZ, Zhao L. Hepatocyte CD36 modulates UBQLN1-mediated proteasomal degradation of autophagic SNARE proteins contributing to septic liver injury. Autophagy 2023; 19:2504-2519. [PMID: 37014234 PMCID: PMC10392739 DOI: 10.1080/15548627.2023.2196876] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2022] [Revised: 02/27/2023] [Accepted: 03/24/2023] [Indexed: 04/05/2023] Open
Abstract
Macroautophagy/autophagy plays a protective role in sepsis-induced liver injury. As a member of class B scavenger receptors, CD36 plays important roles in various disorders, such as atherosclerosis and fatty liver disease. Here we found that the expression of CD36 in hepatocytes was increased in patients and a mouse model with sepsis, accompanied by impaired autophagy flux. Furthermore, hepatocyte cd36 knockout (cd36-HKO) markedly improved liver injury and the impairment of autophagosome-lysosome fusion in lipopolysaccharide (LPS)-induced septic mice. Ubqln1 (ubiquilin 1) overexpression (OE) in hepatocyte blocked the protective effect of cd36-HKO on LPS-induced liver injury in mice. Mechanistically, with LPS stimulation, CD36 on the plasma membrane was depalmitoylated and distributed to the lysosome, where CD36 acted as a bridge molecule linking UBQLN1 to soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins and hence promoting the proteasomal degradation of SNARE proteins, resulting in fusion impairment. Overall, our data reveal that CD36 is essential for modulating the proteasomal degradation of autophagic SNARE proteins in a UBQLN1-dependent manner. Targeting CD36 in hepatocytes is effective for improving autophagic flux in sepsis and therefore represents a promising therapeutic strategy for clinical treatment of septic liver injury.Abbreviations: AAV8: adeno-associated virus 8; AOSC: acute obstructive suppurative cholangitis; ATP1A1: ATPase, Na+/K+ transporting, alpha 1 polypeptide; CASP3: caspase 3; CASP8: caspase 8; CCL2: chemokine (C-C motif) ligand 2; cd36-HKO: hepatocyte-specific cd36 knockout; Co-IP: co-immunoprecipitation; CQ: chloroquine; Cys: cysteine; GOT1: glutamic-oxaloacetic transaminase 1, soluble; GPT: glutamic-pyruvic transaminase, soluble; IL1B: interleukin 1 beta; IL6: interleukin 6; KO: knockout; LAMP1: lysosomal associated membrane protein 1; LDH, lactate dehydrogenase; LPS: lipopolysaccharide; LYPLA1: lysophospholipase 1; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; OE: overexpression; qPCR: quantitative polymerase chain reaction; SNAP29: synaptosome associated protein 29; SNARE: soluble N-ethylmaleimide-sensitive factor attachment protein receptor; SQSTM1/p62: sequestosome 1; STX17: syntaxin 17; TNF: tumor necrosis factor; TRIM: tripartite motif-containing; UBA: ubiquitin-associated; UBL: ubiquitin-like; UBQLN: ubiquilin; VAMP8: vesicle associated membrane protein 8; WT: wild-type.
Collapse
Affiliation(s)
- Yanping Li
- Centre for Lipid Research & Chongqing Key Laboratory of Metabolism on Lipid and Glucose, Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, the Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Jingyuan Xu
- Centre for Lipid Research & Chongqing Key Laboratory of Metabolism on Lipid and Glucose, Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, the Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Weiting Chen
- Centre for Lipid Research & Chongqing Key Laboratory of Metabolism on Lipid and Glucose, Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, the Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Xingxing Wang
- Centre for Lipid Research & Chongqing Key Laboratory of Metabolism on Lipid and Glucose, Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, the Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Zhibo Zhao
- Centre for Lipid Research & Chongqing Key Laboratory of Metabolism on Lipid and Glucose, Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, the Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Yuqi Li
- Centre for Lipid Research & Chongqing Key Laboratory of Metabolism on Lipid and Glucose, Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, the Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Linkun Zhang
- Centre for Lipid Research & Chongqing Key Laboratory of Metabolism on Lipid and Glucose, Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, the Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Junkui Jiao
- Centre for Lipid Research & Chongqing Key Laboratory of Metabolism on Lipid and Glucose, Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, the Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Qin Yang
- Centre for Lipid Research & Chongqing Key Laboratory of Metabolism on Lipid and Glucose, Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, the Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Qiuying Ding
- Centre for Lipid Research & Chongqing Key Laboratory of Metabolism on Lipid and Glucose, Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, the Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Ping Yang
- Centre for Lipid Research & Chongqing Key Laboratory of Metabolism on Lipid and Glucose, Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, the Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Li Wei
- Centre for Lipid Research & Chongqing Key Laboratory of Metabolism on Lipid and Glucose, Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, the Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Yao Chen
- Centre for Lipid Research & Chongqing Key Laboratory of Metabolism on Lipid and Glucose, Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, the Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Yaxi Chen
- Centre for Lipid Research & Chongqing Key Laboratory of Metabolism on Lipid and Glucose, Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, the Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Xiong Z. Ruan
- Centre for Lipid Research & Chongqing Key Laboratory of Metabolism on Lipid and Glucose, Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, the Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
- John Moorhead Research Laboratory, Centre for Nephrology, University College London Medical School, London, England, UK
| | - Lei Zhao
- Centre for Lipid Research & Chongqing Key Laboratory of Metabolism on Lipid and Glucose, Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, the Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| |
Collapse
|
|
5
|
Yang Y, Tian T, Li S, Li N, Luo H, Jiang Y. LncRNA 220: A Novel Long Non-Coding RNA Regulates Autophagy and Apoptosis in Kupffer Cells via the miR-5101/PI3K/AKT/mTOR Axis in LPS-Induced Endotoxemic Liver Injury in Mice. Int J Mol Sci 2023; 24:11210. [PMID: 37446388 PMCID: PMC10342868 DOI: 10.3390/ijms241311210] [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: 05/06/2023] [Revised: 06/21/2023] [Accepted: 06/30/2023] [Indexed: 07/15/2023] Open
Abstract
Sepsis is a severe medical condition distinguished by immune systematic dysfunction and multiple organic injury, or even failure, resulting from an acute systemic inflammatory response. Acute liver injury (ALI) could be considered as a notable inflammatory outcome of sepsis. Studies have demonstrated the essential roles played by long non-coding RNAs (lncRNAs) in mediating the processes of various diseases, including their ability to engage in interactions with microRNAs (miRNAs) as complexes of competing endogenous RNA (ceRNA) to modulate signaling pathways. In this study, a newly discovered lncRNA, named 220, was identified to function in regulating autophagy and apoptosis in Kupffer cells treated with lipopolysaccharide (LPS). This was achieved through sponging miR-5101 as a ceRNA complex, as identified via high-throughput sequencing. The expression of 220 was found to be significantly different in the hepatic tissues of endotoxemic mice that were treated with LPS for 8 h, ultimately modulating the ALI process. Our studies have collectively demonstrated that 220 is a novel regulator that acts on LPS-induced autophagy and apoptosis in Kupffer cells, thereby mediating the ALI process induced by LPS. Furthermore, the validation of our findings using clinical databases suggests that 220 could potentially serve as a molecular target of clinical, diagnostic, and therapeutic significance in septic liver injury.
Collapse
Affiliation(s)
| | | | | | | | | | - Yong Jiang
- Guangdong Provincial Key Laboratory of Proteomics, State Key Laboratory of Organ Failure Research, Department of Pathophysiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China; (Y.Y.); (T.T.); (S.L.); (N.L.); (H.L.)
| |
Collapse
|
|
6
|
Wang YT, Sansone A, Smirnov A, Stallings CL, Orvedahl A. Myeloid autophagy genes protect mice against fatal TNF- and LPS-induced cytokine storm syndromes. Autophagy 2023; 19:1114-1127. [PMID: 36056542 PMCID: PMC10012903 DOI: 10.1080/15548627.2022.2116675] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2020] [Revised: 08/19/2022] [Accepted: 08/19/2022] [Indexed: 02/09/2023] Open
Abstract
ABBREVIATIONS ATG5: autophagy related 5; ATG7: autophagy related 7; ATG14: autophagy related 14; ATG16L1: autophagy related 16-like 1 (S. cerevisiae); BECN1: beclin 1, autophagy related; CASP1: caspase 1; CASP4/CASP11: caspase 4, apoptosis-related cysteine peptidase; CIM: conditionally immortalized macrophage; CLP: cecal ligation and puncture; CSS: cytokine storm syndrome; DC: dendritic cell; IFNG/IFNγ: interferon gamma; IFNGR1: interferon gamma receptor 1; ip: intraperitoneal; iv: intravenous; IL12/p70: interleukin 12, p70 heterodimer; IL18: Interleukin 18; ITGAX/CD11c: integrin alpha X; LAP: LC3-associated phagocytosis; LPS: lipopolysaccharide; LYZ2/LYSM: lysozyme 2; MAP1LC3A/LC3: microtubule-associated protein 1 light chain 3 alpha; RB1CC1/FIP200: RB1-inducible coiled-coil 1; S100A8/MRP8: S100 calcium binding protein A8 (calgranulin A); TICAM1/TRIF: TIR domain containing adaptor molecule 1; TLR4: toll-like receptor 4; TNF: tumor necrosis factor.
Collapse
Affiliation(s)
- Ya-Ting Wang
- Center for Infectious Disease Research, Department of Basic Medical Sciences, Tsinghua University School of Medicine, Beijing, Haidian, China
| | - Amy Sansone
- Department of Pediatrics, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
| | - Asya Smirnov
- Department of Molecular Microbiology, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
| | - Christina L. Stallings
- Department of Molecular Microbiology, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
| | - Anthony Orvedahl
- Department of Pediatrics, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
- Department of Pathology and Immunology, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
| |
Collapse
|
|
7
|
Zhang X, Liu H, Hashimoto K, Yuan S, Zhang J. The gut–liver axis in sepsis: interaction mechanisms and therapeutic potential. Crit Care 2022; 26:213. [PMID: 35831877 PMCID: PMC9277879 DOI: 10.1186/s13054-022-04090-1] [Citation(s) in RCA: 58] [Impact Index Per Article: 19.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2022] [Accepted: 07/09/2022] [Indexed: 12/20/2022] Open
Abstract
Sepsis is a potentially fatal condition caused by dysregulation of the body's immune response to an infection. Sepsis-induced liver injury is considered a strong independent prognosticator of death in the critical care unit, and there is anatomic and accumulating epidemiologic evidence that demonstrates intimate cross talk between the gut and the liver. Intestinal barrier disruption and gut microbiota dysbiosis during sepsis result in translocation of intestinal pathogen-associated molecular patterns and damage-associated molecular patterns into the liver and systemic circulation. The liver is essential for regulating immune defense during systemic infections via mechanisms such as bacterial clearance, lipopolysaccharide detoxification, cytokine and acute-phase protein release, and inflammation metabolic regulation. When an inappropriate immune response or overwhelming inflammation occurs in the liver, the impaired capacity for pathogen clearance and hepatic metabolic disturbance can result in further impairment of the intestinal barrier and increased disruption of the composition and diversity of the gut microbiota. Therefore, interaction between the gut and liver is a potential therapeutic target. This review outlines the intimate gut–liver cross talk (gut–liver axis) in sepsis.
Collapse
|
|
8
|
Dou X, Yan D, Liu S, Gao L, Shan A. Thymol Alleviates LPS-Induced Liver Inflammation and Apoptosis by Inhibiting NLRP3 Inflammasome Activation and the AMPK-mTOR-Autophagy Pathway. Nutrients 2022; 14:nu14142809. [PMID: 35889766 PMCID: PMC9319298 DOI: 10.3390/nu14142809] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2022] [Revised: 07/05/2022] [Accepted: 07/06/2022] [Indexed: 01/17/2023] Open
Abstract
Thymol is a natural antibacterial agent found in the essential oil extracted from thyme, which has been proven to be beneficial in food and medicine. Meanwhile, the NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome and autophagy have been reported to play key roles in the progression of liver injury. However, the effects of thymol on the NLRP3 inflammasome and autophagy in protecting the liver remain unclear. The present study used a mouse model with liver injury induced by lipopolysaccharides (LPS) to investigate the regulatory mechanisms of thymol. We found that thymol alleviated LPS-induced liver structural damage, as judged by reduced inflammatory cell infiltration and improved structure. In addition, elevated levels of the liver damage indicators (alanine transaminase (ALT), aspartate transaminase (AST), and total bilirubin (TBIL)) dropped after thymol administration. The mRNA and protein expression of inflammatory cytokines (tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-22), apoptosis-related genes (caspase3 and caspase9), and the activity of apoptosis-related genes (caspase3 and caspase9) were increased in LPS-treated livers, whereas the changes were alleviated after thymol administration. Thymol inhibited LPS-induced increment in lactate dehydrogenase (LDH) activity in primary hepatocytes of the mouse. In addition, thymol protected mice from liver injury by inhibiting NLRP3 inflammasome activation induced by LPS. Mechanistically, the present study indicates that thymol has liver protective activity resulting from the modulation of the AMP-activated protein kinase—mammalian target of rapamycin (AMPK–mTOR) to regulate the autophagy pathway, hence curbing inflammation.
Collapse
|
|
9
|
Guo FF, Meng FG, Zhang XN, Zeng T. Spermidine inhibits LPS-induced pro-inflammatory activation of macrophages by acting on Nrf2 signaling but not autophagy. J Funct Foods 2022. [DOI: 10.1016/j.jff.2022.105115] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
|
|
10
|
Wang H, Zhu J, Wei L, Wu S, Shang L, Ye X, Li S. TSLP protects against sepsis-induced liver injury by inducing autophagy via activation of the PI3K/Akt/STAT3 pathway. Pathol Res Pract 2022; 236:153979. [PMID: 35751928 DOI: 10.1016/j.prp.2022.153979] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2022] [Revised: 06/04/2022] [Accepted: 06/11/2022] [Indexed: 11/16/2022]
Abstract
BACKGROUND Liver injury is the main factor in multiple organ failure caused by sepsis. Thymic stromal lymphopoietin (TSLP) is derived from epithelial cells and plays an important role in inflammation, allergies and cancer. The role of TSLP in sepsis-induced liver injury (SILI) is unclear. The purpose of this study was to investigate the effect of TSLP on sepsis-induced liver injury and to clarify the mechanism. METHODS Wild-type (WT) mice and TSLPR knockout (TSLPR-/-) mice were subjected to cecal ligation and puncture (CLP) to generate a SILI model. Liver injury was assessed by measuring the levels of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), histologic liver injury scores, hepatocyte death, and liver inflammatory factors. Signal pathways were explored in vivo to identify possible mechanisms for TSLP in SILI. RESULTS The expression of TSLP and TSLPR increased during SILI. Deletion of TSLPR exacerbated liver injury in terms of serum ALT, AST, histologic liver injury scores, and liver inflammatory factors. Compared with controls, administration of exogenous recombinant mouse TSLP reduced liver injury in WT mice during SILI, but failed to reduce liver injury in TSLPR-/- mice. TSLP induced autophagy in hepatocytes during SILI. Mechanistically, Akt and STAT3 were activated in WT mice during SILI. The opposite results were observed in TSLPR-/- mice. In addition, the protective effects of TSLP in WT mice were blocked by PI3K inhibitor, LY294002, during SILI. CONCLUSION These results suggest that TSLP can improve liver injury caused by sepsis and its specific mechanism may be related to inducing autophagy through the PI3K/Akt/STAT3 signaling pathway.
Collapse
Affiliation(s)
- He Wang
- Department of Emergency, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, China
| | - Jijin Zhu
- Department of Emergency, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, China
| | - Liuzi Wei
- Department of Emergency, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, China
| | - Shaolei Wu
- Department of Emergency, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, China
| | - Liming Shang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, China
| | - Xinping Ye
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, China
| | - Shilai Li
- Department of Emergency, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, China.
| |
Collapse
|
|
11
|
Cingolani F, Liu Y, Shen Y, Wen J, Farris AB, Czaja MJ. Redundant Functions of ERK1 and ERK2 Maintain Mouse Liver Homeostasis Through Down-Regulation of Bile Acid Synthesis. Hepatol Commun 2022; 6:980-994. [PMID: 34936222 PMCID: PMC9035584 DOI: 10.1002/hep4.1867] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/24/2021] [Revised: 10/22/2021] [Accepted: 11/03/2021] [Indexed: 11/07/2022] Open
Abstract
Activation of extracellular signal-regulated kinase (ERK) 1/2 promotes hepatocyte proliferation in response to growth stimuli, but whether constitutive hepatocyte ERK1/2 signaling functions in liver physiology is unknown. To examine the role of ERK1/2 in hepatic homeostasis, the effects of a knockout of Erk1 and/or Erk2 in mouse liver were examined. The livers of mice with a global Erk1 knockout or a tamoxifen-inducible, hepatocyte-specific Erk2 knockout were normal. In contrast, Erk1/2 double-knockout mice developed hepatomegaly and hepatitis by serum transaminases, histology, terminal deoxynucleotide transferase-mediated deoxyuridine triphosphate nick end-labeling, and assays of hepatic inflammation. Liver injury was associated with biochemical evidence of cholestasis with increased serum and hepatic bile acids and led to hepatic fibrosis and mortality. RNA sequencing and polymerase chain reaction analysis of double-knockout mouse livers revealed that the rate-limiting bile acid synthesis gene Cyp7a1 (cholesterol 7α-hydroxylase) was up-regulated in concert with decreased expression of the transcriptional repressor short heterodimer partner. Elevated bile acids were the mechanism of liver injury, as bile acid reduction by SC-435, an inhibitor of the ileal apical sodium-dependent bile acid transporter, prevented liver injury. Conclusion: Constitutive ERK1 and ERK2 signaling has a redundant but critical physiological function in the down-regulation of hepatic bile acid synthesis to maintain normal liver homeostasis.
Collapse
Affiliation(s)
- Francesca Cingolani
- Division of Digestive DiseasesDepartment of MedicineEmory University School of MedicineAtlantaGAUSA
| | - Yunshan Liu
- Division of Digestive DiseasesDepartment of MedicineEmory University School of MedicineAtlantaGAUSA
| | - Yang Shen
- Division of Digestive DiseasesDepartment of MedicineEmory University School of MedicineAtlantaGAUSA
| | - Jing Wen
- Division of Digestive DiseasesDepartment of MedicineEmory University School of MedicineAtlantaGAUSA
| | - Alton B. Farris
- Department of Pathology & Laboratory MedicineEmory University School of MedicineAtlantaGAUSA
| | - Mark J. Czaja
- Division of Digestive DiseasesDepartment of MedicineEmory University School of MedicineAtlantaGAUSA
| |
Collapse
|
|
12
|
Kumar P, Liu Y, Shen Y, Maher JJ, Cingolani F, Czaja MJ. Mouse liver injury induces hepatic macrophage FGF23 production. PLoS One 2022; 17:e0264743. [PMID: 35231062 PMCID: PMC8887750 DOI: 10.1371/journal.pone.0264743] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2021] [Accepted: 02/15/2022] [Indexed: 01/22/2023] Open
Abstract
Fibroblast growth factor 23 (FGF23) is a bone marrow cell produced hormone that functions in the intestine and kidney to regulate phosphate homeostasis. Increased serum FGF23 is a well-established predictor of mortality in renal disease, but recent findings linking increased levels to hepatic and cardiac diseases have suggested that other organs are sources of FGF23 or targets of its effects. The potential ability of the liver to produce FGF23 in response to hepatocellular injury was therefore examined. Very low levels of Fgf23 mRNA and FGF23 protein were detected in normal mouse liver, but the amounts increased markedly during acute liver injury from the hepatotoxin carbon tetrachloride. Serum levels of intact FGF23 were elevated during liver injury from carbon tetrachloride. Chronic liver injury induced by a high fat diet or elevated bile acids also increased hepatic FGF23 levels. Stimulation of toll-like receptor (TLR) 4-driven inflammation by gut-derived lipopolysaccharide (LPS) underlies many forms of liver injury, and LPS induced Fgf23 in the liver as well as in other organs. The LPS-inducible cytokines IL-1β and TNF increased hepatic Fgf23 expression as did a TLR2 agonist Pam2CSK3. Analysis of Fgf23 expression and FGF23 secretion in different hepatic cell types involved in liver injury identified the resident liver macrophage or Kupffer cell as a source of hepatic FGF23. LPS and cytokines selectively induced the hormone in these cells but not in hepatocytes or hepatic stellate cells. FGF23 failed to exert any autocrine effect on the inflammatory state of Kupffer cells but did trigger proinflammatory activation of hepatocytes. During liver injury inflammatory factors induce Kupffer cell production of FGF23 that may have a paracrine proinflammatory effect on hepatocytes. Liver-produced FGF23 may have systemic hormonal effects as well that influence diseases in in other organs.
Collapse
Affiliation(s)
- Pradeep Kumar
- Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, United States of America
| | - Yunshan Liu
- Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, United States of America
| | - Yang Shen
- Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, United States of America
| | - Jacquelyn J. Maher
- Department of Medicine and Liver Center, University of California, San Francisco, San Francisco, California, United States of America
| | - Francesca Cingolani
- Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, United States of America
| | - Mark J. Czaja
- Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, United States of America
- * E-mail:
| |
Collapse
|
|
13
|
Zhang Y, Chen L, Luo Y, Wang K, Liu X, Xiao Z, Zhao G, Yao Y, Lu Z. Pink1/Parkin-Mediated Mitophagy Regulated the Apoptosis of Dendritic Cells in Sepsis. Inflammation 2022; 45:1374-1387. [PMID: 35129770 DOI: 10.1007/s10753-022-01628-x] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Revised: 12/23/2021] [Accepted: 01/12/2022] [Indexed: 12/29/2022]
Abstract
Dendritic cells (DCs) are vital antigen-presenting cells (APCs) in the immune system, whose apoptosis is closely related to the development of sepsis. Mitophagy is one of the necessary forms of selective autophagy that removes damaged or dysfunctional mitochondria to regulate immunity and inflammation. However, its effect on the apoptosis of DC in sepsis remains unknown. Here, we showed that sepsis activated the apoptosis and mitophagy of DC, and mitophagy had an anti-apoptotic effect on sepsis-induced DC apoptosis. In this study, we used cecal ligation and puncture (CLP) to simulate the pathophysiological state of sepsis. Apoptosis and mitophagy of DC were significantly enhanced in CPL mice compared with controls, and in the Pink1-KO (Pink1-knockout) mice CLP model, the level of apoptosis in DC was further increased while the level of mitophagy was decreased. In addition, more severe mitochondrial dysfunction was exhibited in DC of Pink1-KO mice CLP model compared to wild-type (WT) mice. The results suggest that Pink1/Parkin-mediated mitophagy is activated during sepsis and has an anti-apoptotic effect on DC, which regulates immune functions.
Collapse
Affiliation(s)
- Yaolu Zhang
- Department of Emergency, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
- Key Laboratory of Emergency & Disaster Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Longwang Chen
- Department of Emergency, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
- Key Laboratory of Emergency & Disaster Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Yinan Luo
- Department of Emergency, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
- Department of Critical Care Medicine, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Kang Wang
- Department of Emergency, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
- Key Laboratory of Emergency & Disaster Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Xinyong Liu
- Department of Emergency, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
- Key Laboratory of Emergency & Disaster Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Zhong Xiao
- Department of Emergency, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
- Key Laboratory of Emergency & Disaster Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Guangju Zhao
- Department of Emergency, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
- Key Laboratory of Emergency & Disaster Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Yongming Yao
- Trauma Research Center, Fourth Medical of the Chinese PLA General Hospital, Beijing, China.
| | - Zhongqiu Lu
- Department of Emergency, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
- Key Laboratory of Emergency & Disaster Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
| |
Collapse
|
|
14
|
Wang Y, Pandak WM, Lesnefsky EJ, Hylemon PB, Ren S. 25-Hydroxycholesterol 3-Sulfate Recovers Acetaminophen Induced Acute Liver Injury via Stabilizing Mitochondria in Mouse Models. Cells 2021; 10:3027. [PMID: 34831255 PMCID: PMC8616185 DOI: 10.3390/cells10113027] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Revised: 10/29/2021] [Accepted: 11/03/2021] [Indexed: 12/20/2022] Open
Abstract
Acetaminophen (APAP) overdose is one of the most frequent causes of acute liver failure (ALF). N-acetylcysteine (NAC) is currently being used as part of the standard care in the clinic but its usage has been limited in severe cases, in which liver transplantation becomes the only treatment option. Therefore, there still is a need for a specific and effective therapy for APAP induced ALF. In the current study, we have demonstrated that treatment with 25-Hydroxycholesterol 3-Sulfate (25HC3S) not only significantly reduced mortality but also decreased the plasma levels of liver injury markers, including LDH, AST, and ALT, in APAP overdosed mouse models. 25HC3S also decreased the expression of those genes involved in cell apoptosis, stabilized mitochondrial polarization, and significantly decreased the levels of oxidants, malondialdehyde (MDA), and reactive oxygen species (ROS). Whole genome bisulfite sequencing analysis showed that 25HC3S increased demethylation of 5mCpG in key promoter regions and thereby increased the expression of those genes involved in MAPK-ERK and PI3K-Akt signaling pathways. We concluded that 25HC3S may alleviate APAP induced liver injury via up-regulating the master signaling pathways and maintaining mitochondrial membrane polarization. The results suggest that 25HC3S treatment facilitates the recovery and significantly decreases the mortality of APAP induced acute liver injury and has a synergistic effect with NAC in propylene glycol (PG) for the injury.
Collapse
Affiliation(s)
| | | | | | | | - Shunlin Ren
- Department of Internal Medicine, McGuire Veterans Affairs Medical Center, Virginia Commonwealth University, Richmond, VA 23249, USA; (Y.W.); (W.M.P.); (E.J.L.); (P.B.H.)
| |
Collapse
|
|
15
|
Shen Y, Cingolani F, Malik SA, Wen J, Liu Y, Czaja MJ. Sex-Specific Regulation of Interferon-γ Cytotoxicity in Mouse Liver by Autophagy. Hepatology 2021; 74:2745-2758. [PMID: 34118081 PMCID: PMC8542567 DOI: 10.1002/hep.32010] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Revised: 05/18/2021] [Accepted: 06/09/2021] [Indexed: 12/22/2022]
Abstract
BACKGROUND AND AIMS Interferon-γ (IFNγ) is a central activator of immune responses in the liver and other organs. IFNγ triggers tissue injury and inflammation in immune diseases, which occur predominantly in females for unknown reasons. Recent findings that autophagy regulates hepatotoxicity from proinflammatory cytokines led to an examination of whether defective hepatocyte autophagy underlies sex-specific liver injury and inflammation induced by IFNγ. APPROACH AND RESULTS A lentiviral autophagy-related 5 (Atg5) knockdown was performed to decrease autophagy-sensitized alpha mouse liver (AML 12) hepatocytes to death from IFNγ in combination with IL-1β or TNF. Death was necrosis attributable to impaired energy homeostasis and adenosine triphosphate depletion. Male mice with decreased autophagy from a tamoxifen-inducible, hepatocyte-specific Atg5 knockout were resistant to IFNγ hepatotoxicity whereas female knockout mice developed liver injury and inflammation. Female mice had increased IFNγ-induced signal transducer and activator of transcription 1 (STAT1) levels compared to males. Blocking STAT1, but not interferon regulatory factor 1, signaling prevented IFNγ-induced hepatocyte death in autophagy-deficient AML12 cells and female mice. The mechanism of death is STAT1-induced overexpression of nitric oxide synthase 2 (NOS2) as in vitro hepatocyte death and in vivo liver injury were blocked by NOS2 inhibition. CONCLUSIONS Decreased hepatocyte autophagy sensitizes mice to IFNγ-induced liver injury and inflammation through overactivation of STAT1 signaling that causes NOS2 overexpression. Hepatotoxicity is restricted to female mice, suggesting that sex-specific effects of defective autophagy may underlie the increased susceptibility of females to IFNγ-mediated immune diseases.
Collapse
Affiliation(s)
- Yang Shen
- Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, GA
| | - Francesca Cingolani
- Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, GA
| | - Shoaib Ahmad Malik
- Department of Biochemistry, Sargodha Medical College, Sargodha, Pakistan
| | - Jing Wen
- Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, GA
| | - Yunshan Liu
- Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, GA
| | - Mark J. Czaja
- Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, GA
| |
Collapse
|
|
16
|
Lou J, Yang X, Shan W, Jin Z, Ding J, Hu Y, Liao Q, Du Q, Xie R, Xu J. Effects of calcium‑permeable ion channels on various digestive diseases in the regulation of autophagy (Review). Mol Med Rep 2021; 24:680. [PMID: 34318907 DOI: 10.3892/mmr.2021.12319] [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: 12/03/2020] [Accepted: 05/07/2021] [Indexed: 12/09/2022] Open
Abstract
Autophagy is a process of degradation and catabolism in cells. By removing damaged or dysfunctional organelles, autophagy interacts with the ubiquitin‑proteasome degradation system to jointly regulate cell function and energy homeostasis. Since autophagy plays a key role in physiology, disorders of the autophagy mechanism are associated with various diseases. Therefore, thorough understanding of the autophagy regulatory mechanism are crucially important in the diagnosis and treatment of diseases. To date, ion channels may affect the development and treatment of diseases by regulating autophagy, especially calcium‑permeable ion channels, in the process of digestive system diseases. However, the mechanism by which calcium ions and their channels regulate autophagy is still poorly understood, thus emphasizing the need for further research in this field. The present review intends to discuss the association, mechanism and application of calcium ions, their channels and autophagy in the occurrence and development of digestive system diseases.
Collapse
Affiliation(s)
- Jun Lou
- Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563003, P.R. China
| | - Xiaoxu Yang
- Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563003, P.R. China
| | - Weixi Shan
- Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563003, P.R. China
| | - Zhe Jin
- Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563003, P.R. China
| | - Jianhong Ding
- Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563003, P.R. China
| | - Yanxia Hu
- Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563003, P.R. China
| | - Qiushi Liao
- Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563003, P.R. China
| | - Qian Du
- Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563003, P.R. China
| | - Rui Xie
- Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563003, P.R. China
| | - Jingyu Xu
- Department of Gastroenterology, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou 563003, P.R. China
| |
Collapse
|
|
17
|
Lucantoni F, Martínez-Cerezuela A, Gruevska A, Moragrega ÁB, Víctor VM, Esplugues JV, Blas-García A, Apostolova N. Understanding the implication of autophagy in the activation of hepatic stellate cells in liver fibrosis: are we there yet? J Pathol 2021; 254:216-228. [PMID: 33834482 DOI: 10.1002/path.5678] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Revised: 03/29/2021] [Accepted: 04/07/2021] [Indexed: 01/18/2023]
Abstract
Liver fibrosis (LF) occurs as a result of persistent liver injury and can be defined as a pathologic, chronic, wound-healing process in which functional parenchyma is progressively replaced by fibrotic tissue. As a phenomenon involved in the majority of chronic liver diseases, and therefore prevalent, it exerts a significant impact on public health. This impact becomes even more patent given the lack of a specific pharmacological therapy, with LF only being ameliorated or prevented through the use of agents that alleviate the underlying causes. Hepatic stellate cells (HSCs) are fundamental mediators of LF, which, activated in response to pro-fibrotic stimuli, transdifferentiate from a quiescent phenotype into myofibroblasts that deposit large amounts of fibrotic tissue and mediate pro-inflammatory effects. In recent years, much effort has been devoted to understanding the mechanisms through which HSCs are activated or inactivated. Using cell culture and/or different animal models, numerous studies have shown that autophagy is enhanced during the fibrogenic process and have provided specific evidence to pinpoint the fundamental role of autophagy in HSC activation. This effect involves - though may not be limited to - the autophagic degradation of lipid droplets. Several hepatoprotective agents have been shown to reverse the autophagic alteration present in LF, but clinical confirmation of these effects is pending. On the other hand, there is evidence that implicates autophagy in several anti-fibrotic mechanisms in HSCs that stimulate HSC cell cycle arrest and cell death or prevent the generation of pro-fibrotic mediators, including excess collagen accumulation. The objective of this review is to offer a comprehensive analysis of published evidence of the role of autophagy in HSC activation and to provide hints for possible therapeutic targets for the treatment and/or prevention of LF related to autophagy. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.
Collapse
Affiliation(s)
- Federico Lucantoni
- Departamento de Farmacología, Facultad de Medicina, Universidad de Valencia, Valencia, Spain
- FISABIO - Hospital Universitario Doctor Peset, Valencia, Spain
| | | | - Aleksandra Gruevska
- Departamento de Farmacología, Facultad de Medicina, Universidad de Valencia, Valencia, Spain
- FISABIO - Hospital Universitario Doctor Peset, Valencia, Spain
| | - Ángela B Moragrega
- Departamento de Farmacología, Facultad de Medicina, Universidad de Valencia, Valencia, Spain
- FISABIO - Hospital Universitario Doctor Peset, Valencia, Spain
| | - Víctor M Víctor
- FISABIO - Hospital Universitario Doctor Peset, Valencia, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Valencia, Spain
- Departamento de Fisiología, Facultad de Medicina, Universidad de Valencia, Valencia, Spain
| | - Juan V Esplugues
- Departamento de Farmacología, Facultad de Medicina, Universidad de Valencia, Valencia, Spain
- FISABIO - Hospital Universitario Doctor Peset, Valencia, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Valencia, Spain
| | - Ana Blas-García
- FISABIO - Hospital Universitario Doctor Peset, Valencia, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Valencia, Spain
- Departamento de Fisiología, Facultad de Medicina, Universidad de Valencia, Valencia, Spain
| | - Nadezda Apostolova
- Departamento de Farmacología, Facultad de Medicina, Universidad de Valencia, Valencia, Spain
- FISABIO - Hospital Universitario Doctor Peset, Valencia, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Valencia, Spain
| |
Collapse
|
|
18
|
Yu Y, Guo H, Jiang W, Zhang C, Xing C, Chen D, Xu C, Su L. Cyclic GMP-AMP promotes the acute phase response and protects against Escherichia coli infection in mice. Biochem Pharmacol 2021; 188:114541. [PMID: 33812857 DOI: 10.1016/j.bcp.2021.114541] [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: 12/27/2020] [Revised: 03/28/2021] [Accepted: 03/29/2021] [Indexed: 11/25/2022]
Abstract
The acute phase response, as a component of the innate immune system, is part of the first line of defense against invading pathogens. The Stimulator of Interferon Genes (STING) pathway initiates innate immune responses upon recognition of exogenous bacterial and viral DNA. However, whether STING signaling pathway plays any roles in regulating acute phase response during bacterial infection remains unknown. In this study, we used STING-deficient (Tmem173gt) and wildtype mice to investigate acute phase responses to bacterial infection (Escherichia coli, E. coli) and test the effect of exogenous cyclic GMP-AMP (cGAMP, a STING agonist) treatment. Bacterial infection of STING-deficient mice resulted in an increase in mortality and bacterial dissemination. Also, inflammation-induced acute phase response was drastically reduced in STING-deficient mice, showing significant reduction in expression of cytokine TNF-α and acute phase proteins. In contrast, exogenous cGAMP treatment enhanced inflammation-induced acute phase response by increasing the expression of TNF-α and acute phase proteins. Also, cGAMP accelerated bacterial clearance and improved survival rate of wildtype mice, but not STING-deficient mice. Interestingly, cGAMP treatment mitigated bacterial infection induced liver injury in both wildtype and STING-deficient mice. Further in vitro evidence showed that cGAMP treatment retarded TNF-α-mediated hepatocyte apoptosis, potentially accelerating autophagy. Taken together, our results indicated that cGAMP/STING signaling pathway is critical for organism to initiate blood-borne innate immune-responses to defend bacterial infection, and cGAMP is envisaged as a drug candidate for further clinical trial.
Collapse
Affiliation(s)
- Yongsheng Yu
- School of Medicine, Shanghai University, Shanghai, China
| | - Huan Guo
- Institute of Translational Medicine, Shanghai University, Shanghai, China
| | - Wenli Jiang
- Department of Biochemistry and Molecular Biology, The Faculty of Basic Medical Science, Second Military Medical University, Shanghai, China
| | - Chenxi Zhang
- Institute of Translational Medicine, Shanghai University, Shanghai, China
| | - Chunlei Xing
- Institute of Translational Medicine, Shanghai University, Shanghai, China
| | - Dagui Chen
- Institute of Translational Medicine, Shanghai University, Shanghai, China
| | - Can Xu
- Department of Gastroenterology, Changhai Hospital, Second Military Medical University, Shanghai, China.
| | - Li Su
- Institute of Translational Medicine, Shanghai University, Shanghai, China.
| |
Collapse
|
|
19
|
Tran M, Wu J, Wang L, Shin DJ. A Potential Role for SerpinA3N in Acetaminophen-Induced Hepatotoxicity. Mol Pharmacol 2021; 99:277-285. [PMID: 33436521 PMCID: PMC7985612 DOI: 10.1124/molpharm.120.000117] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2020] [Accepted: 12/31/2020] [Indexed: 10/25/2022] Open
Abstract
Acetaminophen (APAP) is a commonly used pain and fever reliever but is also the most frequent cause of drug-induced liver injury. The mechanism pertaining acetaminophen toxicity has been well documented, whereas mechanisms of hepatotoxicity are not well established. Serine (or cysteine) peptidase inhibitor, clade A, member 3N (SerpinA3N), a serine protease inhibitor, is synthesized in the liver but the role of SerpinA3N in relation to APAP-induced liver injury is not known. Wild-type and hepatocyte-specific SerpinA3N knockout (HKO) mice were injected intraperitoneally with a single dose of PBS or APAP (400 mg/kg) for 12 hours, and markers of liver injury, cell death, and inflammation were assessed. SerpinA3N expression was highly induced in mice with APAP overdose. SerpinA3N HKO mice had diminished liver injury and necrosis as shown by lower alanine aminotransferase and interleukin-6 levels, accompanied by suppressed inflammatory cytokines and reduced neutrophil infiltration. The reduced oxidative stress was associated with enhanced antioxidant enzyme capabilities. Taken together, hepatocyte SerpinA3N deficiency reduced APAP-induced liver injury by ameliorating inflammation and modulating the 5' AMP-activated protein kinase-unc-51-like autophagy activating kinase 1 signaling pathway. Our study provides novel insights into a potential role for SerpinA3N in APAP-induced liver injury. SIGNIFICANCE STATEMENT: Our studies indicate that serine (or cysteine) peptidase inhibitor, clade A, member 3N (SerpinA3N) may have a pathophysiological role in modulating acetaminophen (APAP)-induced liver injury. More specifically, mice with hepatic deletion of SerpinA3N suppressed inflammation and liver injury to reduce APAP-induced hepatotoxicity. Controlling the inflammatory response offers possible approaches for novel therapeutics; therefore, understanding the pathophysiological role of SerpinA3N in inducing liver injury may add to the development of more efficacious treatments.
Collapse
Affiliation(s)
- Melanie Tran
- Department of Physiology and Neurobiology, University of Connecticut, Storrs, Connecticut (M.T., J.W., D.-J.S.) and Department of Internal Medicine, Section of Digestive Diseases, Yale University, New Haven, Connecticut (L.W.)
| | - Jianguo Wu
- Department of Physiology and Neurobiology, University of Connecticut, Storrs, Connecticut (M.T., J.W., D.-J.S.) and Department of Internal Medicine, Section of Digestive Diseases, Yale University, New Haven, Connecticut (L.W.)
| | - Li Wang
- Department of Physiology and Neurobiology, University of Connecticut, Storrs, Connecticut (M.T., J.W., D.-J.S.) and Department of Internal Medicine, Section of Digestive Diseases, Yale University, New Haven, Connecticut (L.W.)
| | - Dong-Ju Shin
- Department of Physiology and Neurobiology, University of Connecticut, Storrs, Connecticut (M.T., J.W., D.-J.S.) and Department of Internal Medicine, Section of Digestive Diseases, Yale University, New Haven, Connecticut (L.W.)
| |
Collapse
|
|
20
|
Kouroumalis E, Voumvouraki A, Augoustaki A, Samonakis DN. Autophagy in liver diseases. World J Hepatol 2021; 13:6-65. [PMID: 33584986 PMCID: PMC7856864 DOI: 10.4254/wjh.v13.i1.6] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/09/2020] [Revised: 12/10/2020] [Accepted: 12/26/2020] [Indexed: 02/06/2023] Open
Abstract
Autophagy is the liver cell energy recycling system regulating a variety of homeostatic mechanisms. Damaged organelles, lipids and proteins are degraded in the lysosomes and their elements are re-used by the cell. Investigations on autophagy have led to the award of two Nobel Prizes and a health of important reports. In this review we describe the fundamental functions of autophagy in the liver including new data on the regulation of autophagy. Moreover we emphasize the fact that autophagy acts like a two edge sword in many occasions with the most prominent paradigm being its involvement in the initiation and progress of hepatocellular carcinoma. We also focused to the implication of autophagy and its specialized forms of lipophagy and mitophagy in the pathogenesis of various liver diseases. We analyzed autophagy not only in well studied diseases, like alcoholic and nonalcoholic fatty liver and liver fibrosis but also in viral hepatitis, biliary diseases, autoimmune hepatitis and rare diseases including inherited metabolic diseases and also acetaminophene hepatotoxicity. We also stressed the different consequences that activation or impairment of autophagy may have in hepatocytes as opposed to Kupffer cells, sinusoidal endothelial cells or hepatic stellate cells. Finally, we analyzed the limited clinical data compared to the extensive experimental evidence and the possible future therapeutic interventions based on autophagy manipulation.
Collapse
Affiliation(s)
- Elias Kouroumalis
- Liver Research Laboratory, University of Crete Medical School, Heraklion 71110, Greece
| | - Argryro Voumvouraki
- 1 Department of Internal Medicine, AHEPA University Hospital, Thessaloniki 54636, Greece
| | - Aikaterini Augoustaki
- Department of Gastroenterology and Hepatology, University Hospital of Crete, Heraklion 71110, Greece
| | - Dimitrios N Samonakis
- Department of Gastroenterology and Hepatology, University Hospital of Crete, Heraklion 71110, Greece.
| |
Collapse
|
|
21
|
Roy AC, Chang G, Roy S, Ma N, Gao Q, Shen X. γ-d-Glutamyl-meso-diaminopimelic acid induces autophagy in bovine hepatocytes during nucleotide-binding oligomerization domain 1-mediated inflammation. J Cell Physiol 2020; 236:5212-5234. [PMID: 33368240 DOI: 10.1002/jcp.30227] [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: 03/16/2020] [Revised: 12/06/2020] [Accepted: 12/08/2020] [Indexed: 11/07/2022]
Abstract
Autophagy is a crucial cellular homeostatic process and an important part of the host defense system. Dysfunction in autophagy enhances tissue susceptibility to infection and multiple diseases. However, the role of nucleotide oligomerization domain 1 (NOD1) in autophagy in bovine hepatocytes is not well known. Therefore, our aim was to study the contribution of NOD1 to autophagy during inflammation in response to a specific ligand γ-d-glutamyl-meso-diaminopimelic acid (iE-DAP). To achieve this aim, hepatocytes separated from cows at ∼160 days in milk (DIM) were divided into six groups: the nontreated control (CON) group, the rapamycin-treated (RAP) group as a positive control, the iE-DAP-treated (DAP) group, the 3-MA-treated (MA) group, the rapamycin with 3-MA (RM) group, and the iE-DAP with 3-MA (DM) group. iE-DAP administration significantly increased the mRNA expression of NOD1, ATG16L1, RIPK2, ULK1, AMBRA1, DFCP1, WIPI1, ATG5, ATG7, ATG10, ATG4A, IκBα, NF-κB, CXCL1, IL-8, and STAT6 and significantly decreased PIK3C3. The protein expression of NOD1, p-IκBα, p-NF-κB/p-p65, LC3-II, ATG5, and beclin 1 were significantly upregulated and that of SQSTM1/p62, p-mTOR, and FOXA2 were significantly downregulated in response to iE-DAP. iE-DAP also induced the formation of LC3-GFP autophagic puncta in bovine hepatocytes. We also knocked down the NOD1 with siRNA. NOD1 silencing suppressed the autophagy and inflammation-related genes and proteins. The application of the autophagy inhibitor increased the expression of inflammatory molecules and alleviated autophagy-associated molecules. Taken together, these findings suggest that NOD1 is a key player for regulating both ATG16L1 and RIPK2-ULK1 directed autophagy during inflammation in response to iE-DAP in bovine hepatocytes.
Collapse
Affiliation(s)
- Animesh Chandra Roy
- Ministry of Education Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, Jiangsu, China.,Faculty of Veterinary, Animal and Biomedical Sciences, Sylhet Agricultural University, Sylhet, Bangladesh
| | - Guangjun Chang
- Ministry of Education Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, Jiangsu, China
| | - Shipra Roy
- Ministry of Education Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, Jiangsu, China
| | - Nana Ma
- Ministry of Education Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, Jiangsu, China
| | - Qianyun Gao
- Ministry of Education Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, Jiangsu, China
| | - Xiangzhen Shen
- Ministry of Education Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, Jiangsu, China
| |
Collapse
|
|
22
|
Shao L, Xiong X, Zhang Y, Miao H, Ren Y, Tang X, Song J, Wang C. IL-22 ameliorates LPS-induced acute liver injury by autophagy activation through ATF4-ATG7 signaling. Cell Death Dis 2020; 11:970. [PMID: 33177520 PMCID: PMC7658242 DOI: 10.1038/s41419-020-03176-4] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2019] [Revised: 10/13/2020] [Accepted: 10/15/2020] [Indexed: 12/12/2022]
Abstract
Uncontrollable inflammatory response acts as a driver of sepsis-associated liver injury (SALI). IL-22 plays an important role in regulating inflammatory responses, but its role in SALI remains unknown. The aim of the study was to assess the association of serum IL-22 with SALI in pediatric patients and to enclose the underlying mechanisms of IL-22 involved in lipopolysaccharide (LPS) - induced acute liver injury (ALI) in mice. Serum IL-22 levels in patients with SALI were significantly lower than in septic patients without liver injury, and the area under receiver operating characteristic (ROC) curve of IL-22 for discriminating SALI was 0.765 (95% CI: 0.593-0.937). Pre-administration of recombinant murine IL-22 alleviated LPS-induced ALI in mice, and serum IL-6 levels and the mRNA levels of TNF-α, IL-1β, and IL-6 in livers were decreased in response to IL-22 pre-treatment in mice. More importantly, IL-22 pre-treatment activated hepatic autophagy mediated by activating transcription factor 4 (ATF4)-autophagy-related gene 7 (ATG7) signaling in vivo and in vitro in response to LPS administration. Moreover, knockdown of ATF4 in mice aggravated LPS-induced ALI, which was associated with suppressed ATG7-related autophagy. In addition, the protective effects of IL-22 on LPS-induced ALI was partially blocked by ATF4 knockdown, which was associated with lower expression of LC3II/I in the livers of ATF4 knockdown (HT or Atf4+/-) mice compared with wild-type mice (WT or Atf4+/+) mice. In conclusion, low serum IL-22 level is associated with SALI occurrence, and IL-22 pre-administration activates autophagy in hepatocytes and protects mice against LPS-induced ALI partially related to ATF4-ATG7 signaling pathway.
Collapse
Affiliation(s)
- Lujing Shao
- Department of Critical Care Medicine, Shanghai Children's Hospital, Shanghai Jiao Tong University, Shanghai, 200062, China
- Institute of Pediatric Critical Care, Shanghai Jiao Tong University, Shanghai, 200062, China
| | - Xi Xiong
- Department of Critical Care Medicine, Shanghai Children's Hospital, Shanghai Jiao Tong University, Shanghai, 200062, China
- Institute of Pediatric Critical Care, Shanghai Jiao Tong University, Shanghai, 200062, China
| | - Yucai Zhang
- Department of Critical Care Medicine, Shanghai Children's Hospital, Shanghai Jiao Tong University, Shanghai, 200062, China.
- Institute of Pediatric Critical Care, Shanghai Jiao Tong University, Shanghai, 200062, China.
| | - Huijie Miao
- Department of Critical Care Medicine, Shanghai Children's Hospital, Shanghai Jiao Tong University, Shanghai, 200062, China
- Institute of Pediatric Critical Care, Shanghai Jiao Tong University, Shanghai, 200062, China
| | - Yuqian Ren
- Department of Critical Care Medicine, Shanghai Children's Hospital, Shanghai Jiao Tong University, Shanghai, 200062, China
| | - Xiaomeng Tang
- Department of Critical Care Medicine, Shanghai Children's Hospital, Shanghai Jiao Tong University, Shanghai, 200062, China
- Institute of Pediatric Critical Care, Shanghai Jiao Tong University, Shanghai, 200062, China
| | - Jia Song
- Department of Critical Care Medicine, Shanghai Children's Hospital, Shanghai Jiao Tong University, Shanghai, 200062, China
| | - Chunxia Wang
- Department of Critical Care Medicine, Shanghai Children's Hospital, Shanghai Jiao Tong University, Shanghai, 200062, China.
- Institute of Pediatric Critical Care, Shanghai Jiao Tong University, Shanghai, 200062, China.
| |
Collapse
|
|
23
|
Impaired autophagy increases susceptibility to endotoxin-induced chronic pancreatitis. Cell Death Dis 2020; 11:889. [PMID: 33087696 PMCID: PMC7578033 DOI: 10.1038/s41419-020-03050-3] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2020] [Revised: 08/26/2020] [Accepted: 08/27/2020] [Indexed: 12/11/2022]
Abstract
Chronic pancreatitis (CP) is associated with elevated plasma levels of bacterial lipopolysaccharide (LPS) and we have demonstrated reduced acinar cell autophagy in human CP tissue. Therefore, we investigated the role of autophagy in experimental endotoxin-induced pancreatic injury and aimed to identify LPS in human CP tissue. Pancreatic Atg7-deficient mice were injected with a single sub-lethal dose of LPS. Expression of autophagy, apoptosis, necroptosis, and inflammatory markers was determined 3 and 24 h later utilizing immunoblotting and immunofluorescence. The presence of LPS in pancreatic tissue from mice and from patients and healthy controls was determined using immunohistochemistry, immunoblots, and chromogenic assay. Mice lacking pancreatic autophagy exhibited local signs of inflammation and were particularly sensitive to the toxic effect of LPS injection as compared to control mice. In response to LPS, Atg7Δpan mice exhibited enhanced vacuolization of pancreatic acinar cells, increase in TLR4 expression coupled to enhanced expression of NF-κΒ, JNK, and pro-inflammatory cytokines by acinar cells and enhanced infiltration by myeloid cells (but not Atg7F/F controls). Cell death was enhanced in Atg7Δpan pancreata, but only necroptosis and trypsin activation was further amplified following LPS injection along with elevated pancreatic LPS. The presence of LPS was identified in the pancreata from all 14 CP patients examined but was absent in the pancreata from all 10 normal controls. Altogether, these results support a potential role for metabolic endotoxemia in the pathogenesis of CP. Moreover, the evidence also supports the notion that autophagy plays a major cytoprotective and anti-inflammatory role in the pancreas, and blunting metabolic endotoxemia-induced CP.
Collapse
|
|
24
|
Shen Y, Malik SA, Amir M, Kumar P, Cingolani F, Wen J, Liu Y, Zhao E, Farris AB, Raeman R, Czaja MJ. Decreased Hepatocyte Autophagy Leads to Synergistic IL-1β and TNF Mouse Liver Injury and Inflammation. Hepatology 2020; 72:595-608. [PMID: 32108953 PMCID: PMC8114460 DOI: 10.1002/hep.31209] [Citation(s) in RCA: 55] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2019] [Revised: 01/25/2020] [Accepted: 02/04/2020] [Indexed: 02/06/2023]
Abstract
BACKGROUND AND AIMS The proinflammatory cytokine IL-1β has been implicated in the pathophysiology of nonalcoholic and alcoholic steatohepatitis. How IL-1β promotes liver injury in these diseases is unclear, as no IL-1β receptor-linked death pathway has been identified. Autophagy functions in hepatocyte resistance to injury and death, and findings of decreased hepatic autophagy in many liver diseases suggest a role for impaired autophagy in disease pathogenesis. Recent findings that autophagy blocks mouse liver injury from lipopolysaccharide led to an examination of autophagy's function in hepatotoxicity from proinflammatory cytokines. APPROACH AND RESULTS AML12 cells with decreased autophagy from a lentiviral autophagy-related 5 (Atg5) knockdown were resistant to toxicity from TNF, but sensitized to death from IL-1β, which was markedly amplified by TNF co-treatment. IL-1β/TNF death was necrosis by trypan blue and propidium iodide positivity, absence of mitochondrial death pathway and caspase activation, and failure of a caspase inhibitor or necrostatin-1s to prevent death. IL-1β/TNF depleted autophagy-deficient cells of ATP, and ATP depletion and cell death were prevented by supplementation with the energy substrate pyruvate or oleate. Pharmacological inhibitors and genetic knockdown studies demonstrated that IL-1β/TNF-induced necrosis resulted from lysosomal permeabilization and release of cathepsins B and L in autophagy-deficient cells. Mice with a tamoxifen-inducible, hepatocyte-specific Atg5 knockout were similarly sensitized to cathepsin-dependent hepatocellular injury and death from IL-1β/TNF in combination, but neither IL-1β nor TNF alone. Knockout mice had increased hepatic inflammation, and IL-1β/TNF-treated, autophagy-deficient AML12 cells secreted exosomes with proinflammatory damage-associated molecular patterns. CONCLUSIONS The findings delineate mechanisms by which decreased hepatocyte autophagy promotes IL-1β/TNF-induced necrosis from impaired energy homeostasis and lysosomal permeabilization and inflammation through the secretion of exosomal damage-associated molecular patterns.
Collapse
Affiliation(s)
- Yang Shen
- Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, GA
| | - Shoaib Ahmad Malik
- Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, GA;,Department of Biochemistry, Sargodha Medical College, Sargodha, Pakistan
| | - Muhammad Amir
- Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, GA
| | - Pradeep Kumar
- Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, GA
| | - Francesca Cingolani
- Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, GA
| | - Jing Wen
- Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, GA
| | - Yunshan Liu
- Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, GA
| | - Enpeng Zhao
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Alton B. Farris
- Department of Pathology & Laboratory Medicine, Emory University School of Medicine, Atlanta, GA
| | - Reben Raeman
- Department of Pathology, University of Pittsburgh, Pittsburgh, PA
| | - Mark J. Czaja
- Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, GA
| |
Collapse
|
|
25
|
Blocking Liver Autophagy Accelerates Apoptosis and Mitochondrial Injury in Hepatocytes and Reduces Time to Mortality in a Murine Sepsis Model. Shock 2019; 50:427-434. [PMID: 29076973 DOI: 10.1097/shk.0000000000001040] [Citation(s) in RCA: 44] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Autophagy plays an important role in cell survival, sequestering, and degrading a wide variety of substrates. Although an increase of autophagosomes in liver has been reported in sepsis patients as well as in septic mice, the influence of autophagy on liver injury, the interaction between autophagy, and other types of cell death in sepsis remain unclear. The aim of this study was to elucidate the contribution of liver autophagy to the pathophysiology of sepsis. We performed a cecal ligation and puncture on liver-specific autophagy-deficient (Alb-Cre/Atg5) mice (6-8-week-old male). When compared with controls (C57BL/6), we found a significant accumulation of p62 in the liver and demonstrated a greater number of cleaved caspase-3 immunoreactive hepatocytes in these knockout (KO) mice. Additionally, we confirmed a significant increase in autophagic vacuoles in the control mice relative to KO mice; in contrast, cell shrinkage and nuclear fragmentation (morphological characteristics of apoptosis) were preferentially seen in the KO mice by transmission electron microscopy. Severe mitochondrial damage was also prominent in KO mice, relative to controls, associated with an increase of reactive oxygen species in hepatocytes. Serum aspartate transaminase levels (P = 0.005) and serum interleukin-6 levels (P = 0.020) were significantly increased in the KO mice compared with controls. Deficiency of autophagy in liver significantly decreased survival in the murine sepsis model (P = 0.025). In conclusion, blocking liver autophagy accelerates time to mortality in the murine sepsis model, suggesting that liver autophagy plays a protective role for organ failure through degradation of damaged mitochondria, as well as prevention of apoptosis.
Collapse
|
|
26
|
Yin X, Xin H, Mao S, Wu G, Guo L. The Role of Autophagy in Sepsis: Protection and Injury to Organs. Front Physiol 2019; 10:1071. [PMID: 31507440 PMCID: PMC6716215 DOI: 10.3389/fphys.2019.01071] [Citation(s) in RCA: 69] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2019] [Accepted: 08/05/2019] [Indexed: 12/12/2022] Open
Abstract
Sepsis is a systemic inflammatory disease with infection, and autophagy has been shown to play an important role in sepsis. This review summarizes the main regulatory mechanisms of autophagy in sepsis and its latest research. Recent studies have shown that autophagy can regulate innate immune processes and acquired immune processes, and the regulation of autophagy in different immune cells is different. Mitophagy can select damaged mitochondria and remove it to deal with oxidative stress damage. The process of mitophagy is regulated by other factors. Non-coding RNA is also an important factor in the regulation of autophagy. In addition, more and more studies in recent years have shown that autophagy plays different roles in different organs. It tends to be protective in the lungs, heart, kidneys, and brain, and tends to be damaging in skeletal muscle. We also mentioned that some drugs can regulate autophagy. The process of modulating autophagy through drug intervention appears to be a new potential hope for the treatment of sepsis.
Collapse
Affiliation(s)
- Xin Yin
- Department of Critical Care Medicine, The Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Huang Xin
- Department of Critical Care Medicine, The Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Shuai Mao
- Department of Critical Care Medicine, The Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Guangping Wu
- Department of Critical Care Medicine, The Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Liheng Guo
- Department of Critical Care Medicine, The Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou, China
| |
Collapse
|
|
27
|
Batt J, Herridge MS, Dos Santos CC. From skeletal muscle weakness to functional outcomes following critical illness: a translational biology perspective. Thorax 2019; 74:1091-1098. [PMID: 31431489 DOI: 10.1136/thoraxjnl-2016-208312] [Citation(s) in RCA: 47] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2018] [Revised: 06/25/2019] [Accepted: 07/02/2019] [Indexed: 12/23/2022]
Abstract
Intensive care unit acquired weakness (ICUAW) is now a well-known entity complicating critical illness. It increases mortality and in the critical illness survivor it is associated with physical disability, substantially increased health resource utilisation and healthcare costs. Skeletal muscle wasting is a key driver of ICUAW and physical functional outcomes in both the short and long term. To date, there is no intervention that can universally and consistently prevent muscle loss during critical illness, or enhance its recovery following intensive care unit discharge, to improve physical function. Clinical trials of early mobilisation or exercise training, or enhanced nutritional support have generated inconsistent results and we have no effective pharmacological interventions. This review will delineate our current understanding of the mechanisms underpinning the development and persistence of skeletal muscle loss and dysfunction in the critically ill individual, highlighting recent discoveries and clinical observations, and utilisation of this knowledge in the development of novel therapeutics.
Collapse
Affiliation(s)
- Jane Batt
- Keenan Research Center for Biomedical Science, St Michael's Hospital, Toronto, Ontario, Canada .,Interdepartmental Division of Critical Care Medicine and Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Margaret S Herridge
- Interdepartmental Division of Critical Care Medicine and Department of Medicine, University of Toronto, Toronto, Ontario, Canada.,Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada
| | - Claudia C Dos Santos
- Keenan Research Center for Biomedical Science, St Michael's Hospital, Toronto, Ontario, Canada.,Interdepartmental Division of Critical Care Medicine and Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| |
Collapse
|
|
28
|
Autophagy genes in myeloid cells counteract IFNγ-induced TNF-mediated cell death and fatal TNF-induced shock. Proc Natl Acad Sci U S A 2019; 116:16497-16506. [PMID: 31346084 DOI: 10.1073/pnas.1822157116] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Host inflammatory responses must be tightly regulated to ensure effective immunity while limiting tissue injury. IFN gamma (IFNγ) primes macrophages to mount robust inflammatory responses. However, IFNγ also induces cell death, and the pathways that regulate IFNγ-induced cell death are incompletely understood. Using genome-wide CRISPR/Cas9 screening, we identified autophagy genes as central mediators of myeloid cell survival during the IFNγ response. Hypersensitivity of autophagy gene-deficient cells to IFNγ was mediated by tumor necrosis factor (TNF) signaling via receptor interacting protein kinase 1 (RIPK1)- and caspase 8-mediated cell death. Mice with myeloid cell-specific autophagy gene deficiency exhibited marked hypersensitivity to fatal systemic TNF administration. This increased mortality in myeloid autophagy gene-deficient mice required the IFNγ receptor, and mortality was completely reversed by pharmacologic inhibition of RIPK1 kinase activity. These findings provide insight into the mechanism of IFNγ-induced cell death via TNF, demonstrate a critical function of autophagy genes in promoting cell viability in the presence of inflammatory cytokines, and implicate this cell survival function in protection against mortality during the systemic inflammatory response.
Collapse
|
|
29
|
Wang F, Lei X, Zhao Y, Yu Q, Li Q, Zhao H, Pei Z. Protective role of thymoquinone in sepsis-induced liver injury in BALB/c mice. Exp Ther Med 2019; 18:1985-1992. [PMID: 31410159 PMCID: PMC6676142 DOI: 10.3892/etm.2019.7779] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2018] [Accepted: 06/06/2019] [Indexed: 02/07/2023] Open
Abstract
Sepsis increases the risk of developing liver injury. Previous studies have demonstrated that thymoquinone (TQ) exhibits hepatoprotective properties in vivo as well as in vitro. The present study aimed to investigate the underlying mechanisms of the protective effects of TQ against liver injury in septic BALB/c mice. Male BALB/c mice (age, 8 weeks) were randomly divided into four groups, namely, the control, TQ (50 mg/kg/day) treatment, cecal ligation and puncture (CLP), and TQ + CLP groups. CLP was performed following gavage of TQ for 2 weeks. At 48 h post-CLP, the histopathological alterations in the liver tissue (LT) and plasma levels of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP) were assessed. The present study evaluated microtubule-associated protein light chain 3 (LC3), sequestosome-1 (p62) and beclin 1 protein expression by western blotting and immunostaining, as well as interleukin (IL)-6, IL-1β, IL-10, monocyte chemoattractant protein-1 (MCP-1) and tumor necrosis factor-α (TNF-α) mRNA expression by RT-qPCR. The results of the present study indicated that administration of TQ to mice reduced the histological alterations caused by CLP in LT. TQ inhibited the plasma levels of ALT, AST and ALP in the CLP group. TQ significantly inhibited the elevation of p62, IL-1β, IL-6, MCP-1 and TNF-α levels as well as increased the LC3, beclin 1 and IL-10 levels in LT. PI3K expression in the TQ + CLP group was significantly decreased compared with that in the CLP group. TQ treatment effectively modulated the expression levels of p62, LC3, beclin 1, PI3K and proinflammatory cytokines, and may be an important agent for the treatment of sepsis-induced liver injury.
Collapse
Affiliation(s)
- Fei Wang
- Department of Gastroenterology, Affiliated Zhongshan Hospital of Dalian University, Dalian, Liaoning 116001, P.R. China
| | - Xiong Lei
- Graduate School of Dalian Medical University, The First Clinical College, Dalian, Liaoning 116044, P.R. China
| | - Yue Zhao
- Graduate School of Dalian Medical University, The First Clinical College, Dalian, Liaoning 116044, P.R. China
| | - Qinggong Yu
- Department of Gastroenterology, Affiliated Zhongshan Hospital of Dalian University, Dalian, Liaoning 116001, P.R. China
| | - Qianwei Li
- Department of Gastroenterology, Affiliated Zhongshan Hospital of Dalian University, Dalian, Liaoning 116001, P.R. China
| | - Hui Zhao
- Department of Vascular Surgery, Affiliated Zhongshan Hospital of Dalian University, Dalian, Liaoning 116001, P.R. China
| | - Zuowei Pei
- Department of Cardiology, Affiliated Zhongshan Hospital of Dalian University, Dalian, Liaoning 116001, P.R. China
| |
Collapse
|
|
30
|
Ilyas G, Cingolani F, Zhao E, Tanaka K, Czaja MJ. Decreased Macrophage Autophagy Promotes Liver Injury and Inflammation from Alcohol. Alcohol Clin Exp Res 2019; 43:1403-1413. [PMID: 30964198 DOI: 10.1111/acer.14041] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2019] [Accepted: 03/27/2019] [Indexed: 12/16/2022]
Abstract
BACKGROUND One mechanism underlying the development of alcoholic liver disease is overactivation of the innate immune response. Recent investigations indicate that the lysosomal pathway of autophagy down-regulates the inflammatory state of hepatic macrophages, suggesting that macrophage autophagy may regulate innate immunity in alcoholic liver disease. The function of macrophage autophagy in the development of alcoholic liver disease was examined in studies employing mice with a myeloid-specific decrease in autophagy. METHODS Littermate control and Atg5Δmye mice lacking Atg5-dependent myeloid autophagy were administered a Lieber-DeCarli control (CD) or ethanol diet (ED) alone or together with lipopolysaccharide (LPS) and examined for the degree of liver injury and inflammation. RESULTS Knockout mice with decreased macrophage autophagy had equivalent steatosis but increased mortality and liver injury from ED alone. Increased liver injury and hepatocyte death also occurred in Atg5Δmye mice administered ED and LPS in association with systemic inflammation as indicated by elevated serum levels of proinflammatory cytokines. Hepatic macrophage and neutrophil infiltration were unaffected by decreased autophagy, but levels of proinflammatory cytokine gene induction were significantly increased in the livers but not adipose tissue of knockout mice treated with ED and LPS. Inflammasome activation was increased in ED/LPS-treated knockout mice resulting in elevated interleukin (IL)-1β production. Increased IL-1β promoted alcoholic liver disease as liver injury was decreased by the administration of an IL-1 receptor antagonist. CONCLUSIONS Macrophage autophagy functions to prevent liver injury from alcohol. This protection is mediated in part by down-regulation of inflammasome-dependent and inflammasome-independent hepatic inflammation. Therapies to increase autophagy may be effective in this disease through anti-inflammatory effects on macrophages.
Collapse
Affiliation(s)
- Ghulam Ilyas
- Department of Medicine , Division of Digestive Diseases, Emory University School of Medicine, Atlanta, Georgia
| | - Francesca Cingolani
- Department of Medicine , Division of Digestive Diseases, Emory University School of Medicine, Atlanta, Georgia
| | - Enpeng Zhao
- Department of Genetics and Genomic Sciences , Icahn School of Medicine at Mount Sinai, New York, New York
| | - Kathryn Tanaka
- Department of Pathology , Albert Einstein College of Medicine, Bronx, New York
| | - Mark J Czaja
- Department of Medicine , Division of Digestive Diseases, Emory University School of Medicine, Atlanta, Georgia
| |
Collapse
|
|
31
|
Feng Y, Liu B, Zheng X, Chen L, Chen W, Fang Z. The protective role of autophagy in sepsis. Microb Pathog 2019; 131:106-111. [PMID: 30935962 DOI: 10.1016/j.micpath.2019.03.039] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2018] [Revised: 03/28/2019] [Accepted: 03/28/2019] [Indexed: 02/06/2023]
Abstract
Sepsis is characterized by life-threatening organ dysfunction caused by a deregulated host response to infection. Autophagy is one of the innate immune defense mechanisms against microbial attack. Previous studies have demonstrated that autophagy is activated initially in sepsis, followed by a subsequent phase of impairment. A number of sepsis-related studies have shown that autophagy plays a protective role in multiple organ injuries partly by clearing pathogens, regulating inflammation and metabolism, inhibiting apoptosis and suppressing immune reactions. In this review, we present a general overview of and recent advances in the role of autophagy in sepsis and consider the therapeutic potential of autophagy activators in treating sepsis.
Collapse
Affiliation(s)
- Ying Feng
- Department of Intensive Care Unit, Taihe Hospital, Hubei University of Medicine, Shiyan, 442000, Hubei Province, China; Institute of Biomedical Research, Taihe Hospital, Hubei University of Medicine, Shiyan, 442000, Hubei Province, China
| | - Boyi Liu
- Department of Intensive Care Unit, Taihe Hospital, Hubei University of Medicine, Shiyan, 442000, Hubei Province, China
| | - Xiang Zheng
- Department of Intensive Care Unit, Taihe Hospital, Hubei University of Medicine, Shiyan, 442000, Hubei Province, China
| | - Li Chen
- Department of Intensive Care Unit, Taihe Hospital, Hubei University of Medicine, Shiyan, 442000, Hubei Province, China
| | - Wei Chen
- Department of Intensive Care Unit, Taihe Hospital, Hubei University of Medicine, Shiyan, 442000, Hubei Province, China
| | - Zhicheng Fang
- Department of Intensive Care Unit, Taihe Hospital, Hubei University of Medicine, Shiyan, 442000, Hubei Province, China.
| |
Collapse
|
|
32
|
Wu Y, Yao YM, Lu ZQ. Mitochondrial quality control mechanisms as potential therapeutic targets in sepsis-induced multiple organ failure. J Mol Med (Berl) 2019; 97:451-462. [PMID: 30788535 DOI: 10.1007/s00109-019-01756-2] [Citation(s) in RCA: 57] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2018] [Revised: 12/24/2018] [Accepted: 02/06/2019] [Indexed: 02/07/2023]
Abstract
Sepsis is a dysregulated response to severe infection characterized by life-threatening organ failure and is the leading cause of mortality worldwide. Multiple organ failure is the central characteristic of sepsis and is associated with poor outcome of septic patients. Ultrastructural damage to the mitochondria and mitochondrial dysfunction are reported in sepsis. Mitochondrial dysfunction with subsequent ATP deficiency, excessive reactive oxygen species (ROS) release, and cytochrome c release are all considered to contribute to organ failure. Consistent mitochondrial dysfunction leads to reduced mitochondrial quality control capacity, which eliminates dysfunctional and superfluous mitochondria to maintain mitochondrial homeostasis. Mitochondrial quality is controlled through a series of processes including mitochondrial biogenesis, mitochondrial dynamics, mitophagy, and transport processes. Several studies have indicated that multiple organ failure is ameliorated by restoring mitochondrial quality control mechanisms and is further amplified by defective quality control mechanisms. This review will focus on advances concerning potential mechanisms in regulating mitochondrial quality control and impacts of mitochondrial quality control on the progression of sepsis.
Collapse
Affiliation(s)
- You Wu
- Emergency Department, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, People's Republic of China.,Wenzhou Municipal Key Laboratory of Emergency, Critical Care and Disaster Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, People's Republic of China
| | - Yong-Ming Yao
- Emergency Department, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, People's Republic of China. .,Trauma Research Center, First Hospital Affiliated to the Chinese PLA General Hospital, Beijing, People's Republic of China.
| | - Zhong-Qiu Lu
- Emergency Department, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, People's Republic of China. .,Wenzhou Municipal Key Laboratory of Emergency, Critical Care and Disaster Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, People's Republic of China. .,College of Nursing, Wenzhou Medical University, Wenzhou, People's Republic of China.
| |
Collapse
|
|
33
|
Liu L, Zhao Y, Lin Y, Zhang R, Luo S, Ye P, Luo M. The antagonistic effect of tamoxifen against d-galactosamine/lipopolysaccharide-induced acute liver failure is associated with reactivation of hepatic nuclear factor-κB. Immunopharmacol Immunotoxicol 2019; 41:192-198. [PMID: 30721100 DOI: 10.1080/08923973.2019.1569044] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
Abstract
Context: Tamoxifen (TAM) ameliorates D-galactosamine/lipopolysaccharide (Gal/LPS)-induced acute liver failure (ALF) through its antioxidative effect; thus, this study was designed to determine whether the effectiveness of TAM is related to nuclear factor-κB (NF-κB) reactivation. Materials and methods: Experimental mice were injected with TAM once daily for 3 consecutive days intraperitoneally (i.p). Twelve hours after pretreatment, Gal/LPS was given to mice (i.p) for ALF induction. In the positive control group, N-acetylcysteine (NAC) was administered immediately after ALF establishment. Except for survival observation, other animals were sacrificed 7 h after Gal/LPS treatment. Survival and hepatic failure were evaluated. For the oxidation assessment, the reduced/oxidized glutathione (GSH/GSSG) ratio and hepatic superoxide dismutase (SOD) activity were analyzed using both colorimetry and Western blotting. Lastly, hepatic NF-κB activation was measured through Western blot analysis of p65 and IκBα. Results: The results indicated that pretreatment with TAM dramatically attenuated Gal/LPS-induced ALF, as demonstrated by improved survival (70%), decreased transaminase levels, and reversed histopathological manifestation. In addition, the hepatic GSH/GSSG ratio and SOD activity were decreased in the ALF model. However, to some degree, TAM and NAC effectively prevented this undesirable phenomenon in contrast to the ALF model. Western blotting revealed that compared with mice in the ALF model group, mice treated with TAM or NAC showed reactivation of hepatic NF-κB. Conclusions: Taking the results together with those of other studies, we conclude that TAM may attenuate Gal/LPS-induced ALF by antagonizing oxidative stress through NF-κB reactivation.
Collapse
Affiliation(s)
- Liping Liu
- a The Affiliated Ganzhou Hospital of Nanchang University , Ganzhou , Jiangxi , China
| | - Yongsheng Zhao
- b The People's Hospital of Xinfeng County , Ganzhou , Jiangxi , China
| | - Yan Lin
- a The Affiliated Ganzhou Hospital of Nanchang University , Ganzhou , Jiangxi , China
| | - Rongshan Zhang
- a The Affiliated Ganzhou Hospital of Nanchang University , Ganzhou , Jiangxi , China
| | - Shi Luo
- a The Affiliated Ganzhou Hospital of Nanchang University , Ganzhou , Jiangxi , China
| | - Ping Ye
- a The Affiliated Ganzhou Hospital of Nanchang University , Ganzhou , Jiangxi , China
| | - Mansheng Luo
- a The Affiliated Ganzhou Hospital of Nanchang University , Ganzhou , Jiangxi , China
| |
Collapse
|
|
34
|
Lin X, Cui M, Xu D, Hong D, Xia Y, Xu C, Li R, Zhang X, Lou Y, He Q, Lv P, Chen Y. Liver-specific deletion of Eva1a/Tmem166 aggravates acute liver injury by impairing autophagy. Cell Death Dis 2018; 9:768. [PMID: 29991758 PMCID: PMC6039435 DOI: 10.1038/s41419-018-0800-x] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2018] [Revised: 06/14/2018] [Accepted: 06/15/2018] [Indexed: 12/15/2022]
Abstract
Acute liver failure (ALF) is an inflammation-mediated hepatocellular injury process associated with cellular autophagy. However, the mechanism by which autophagy regulates ALF remains undefined. Herein, we demonstrated that Eva1a (eva-1 homolog A)/Tmem166 (transmembrane protein 166), an autophagy-related gene, can protect mice from ALF induced by d-galactosamine (D-GalN)/lipopolysaccharide (LPS) via autophagy. Our findings indicate that a hepatocyte-specific deletion of Eva1a aggravated hepatic injury in ALF mice, as evidenced by increased levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), myeloperoxidase (MPO), and inflammatory cytokines (e.g., TNFα and IL-6), which was associated with disordered liver architecture exhibited by Eva1a−/− mouse livers with ALF. Moreover, we found that the decreased autophagy in Eva1a−/− mouse liver resulted in the substantial accumulation of swollen mitochondria in ALF, resulting in a lack of ATP generation, and consequently hepatocyte apoptosis or death. The administration of Adeno-Associated Virus Eva1a (AAV-Eva1a) or antophagy-inducer rapamycin increased autophagy and provided protection against liver injury in Eva1a−/− mice with ALF, suggesting that defective autophagy is a significant mechanism of ALF in mice. Collectively, for the first time, we have demonstrated that Eva1a-mediated autophagy ameliorated liver injury in mice with ALF by attenuating inflammatory responses and apoptosis, indicating a potential therapeutic application for ALF.
Collapse
Affiliation(s)
- Xin Lin
- Department of Immunology, Peking University School of Basic Medical Science; Key Laboratory of Medical Immunology, Ministry of Health, Peking University Health Sciences Center, 100191, Beijing, China
| | - Ming Cui
- Department of Cardiology, Peking University Third Hospital, 100191, Beijing, China
| | - Dong Xu
- Department of Clinical Laboratory, Peking University First Hospital, 100034, Beijing, China
| | - Dubeiqi Hong
- Department of Immunology, Peking University School of Basic Medical Science; Key Laboratory of Medical Immunology, Ministry of Health, Peking University Health Sciences Center, 100191, Beijing, China
| | - Yan Xia
- Department of Immunology, Peking University School of Basic Medical Science; Key Laboratory of Medical Immunology, Ministry of Health, Peking University Health Sciences Center, 100191, Beijing, China
| | - Chentong Xu
- Department of Immunology, Peking University School of Basic Medical Science; Key Laboratory of Medical Immunology, Ministry of Health, Peking University Health Sciences Center, 100191, Beijing, China
| | - Riyong Li
- Department of Immunology, Peking University School of Basic Medical Science; Key Laboratory of Medical Immunology, Ministry of Health, Peking University Health Sciences Center, 100191, Beijing, China
| | - Xuan Zhang
- Department of Immunology, Peking University School of Basic Medical Science; Key Laboratory of Medical Immunology, Ministry of Health, Peking University Health Sciences Center, 100191, Beijing, China
| | - Yaxin Lou
- Medical and Healthy Analytical Center, Peking University, 100191, Beijing, China
| | - Qihua He
- Medical and Healthy Analytical Center, Peking University, 100191, Beijing, China
| | - Ping Lv
- Department of Immunology, Peking University School of Basic Medical Science; Key Laboratory of Medical Immunology, Ministry of Health, Peking University Health Sciences Center, 100191, Beijing, China
| | - Yingyu Chen
- Department of Immunology, Peking University School of Basic Medical Science; Key Laboratory of Medical Immunology, Ministry of Health, Peking University Health Sciences Center, 100191, Beijing, China.
| |
Collapse
|
|
35
|
Xiong X, Ren Y, Cui Y, Li R, Wang C, Zhang Y. Obeticholic acid protects mice against lipopolysaccharide-induced liver injury and inflammation. Biomed Pharmacother 2017; 96:1292-1298. [PMID: 29174575 DOI: 10.1016/j.biopha.2017.11.083] [Citation(s) in RCA: 77] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2017] [Revised: 11/09/2017] [Accepted: 11/16/2017] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Cholestasis, as a main manifestation, induces liver injury during sepsis. The farnesoid X receptor (FXR) plays an important role in regulating bile acid homeostasis. Whether FXR activation by its agonist obeticholic acid (OCA) is contributed to improve sepsis-induced liver injury remains unknown. OBJECTIVE The aim of the present study was to investigate the effect of OCA on lipopolysaccharide (LPS)-induced acute liver injury in mice. RESULTS 8-week old male C57BL/6J mice were randomly divided into control group, LPS group, oral OCA group and LPS plus oral OCA (LPS + OCA) group. The serum and livers were collected for further analysis. Serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bile acid (TBA) and total bilirubin (TBIL) were measured at indicated time after LPS administration. Liver sections were stained with hematoxylin & eosin (H&E). Orally OCA pretreatment stimulated the expression of FXR and BSEP in livers and protected mice from LPS-induced hepatocyte apoptosis and inflammatory infiltration. Consistently, LPS-induced higher serum levels of ALT, AST, TBA and TBIL were significantly reversed by OCA administration. Meanwhile, the mRNA levels of interleukin 1β (IL-1β), tumor necrosis factor α (TNF-α) and IL-6 were decreased in livers of mice in LPS + OCA group compared with LPS group. Further investigation indicated that the higher expression of ATF4 and LC3II/I were associated with the protective effect of OCA on LPS-induced liver injury. CONCLUSION Orally OCA pretreatment protects mice from LPS-induced liver injury possibly contributed by improved bile acid homeostasis, decreased inflammatory factors and ATF4-mediated autophagy activity in hepatocytes.
Collapse
Affiliation(s)
- Xi Xiong
- Department of Critical Care Medicine, Shanghai Children's Hospital, Institute of Pediatric Critical Care, Shanghai Jiao Tong University, No.355 Luding Road, Putuo District, Shanghai, 200062, China
| | - Yuqian Ren
- Department of Critical Care Medicine, Shanghai Children's Hospital, Institute of Pediatric Critical Care, Shanghai Jiao Tong University, No.355 Luding Road, Putuo District, Shanghai, 200062, China
| | - Yun Cui
- Department of Critical Care Medicine, Shanghai Children's Hospital, Institute of Pediatric Critical Care, Shanghai Jiao Tong University, No.355 Luding Road, Putuo District, Shanghai, 200062, China
| | - Rui Li
- Department of Critical Care Medicine, Shanghai Children's Hospital, Institute of Pediatric Critical Care, Shanghai Jiao Tong University, No.355 Luding Road, Putuo District, Shanghai, 200062, China
| | - Chunxia Wang
- Department of Critical Care Medicine, Shanghai Children's Hospital, Institute of Pediatric Critical Care, Shanghai Jiao Tong University, No.355 Luding Road, Putuo District, Shanghai, 200062, China.
| | - Yucai Zhang
- Department of Critical Care Medicine, Shanghai Children's Hospital, Institute of Pediatric Critical Care, Shanghai Jiao Tong University, No.355 Luding Road, Putuo District, Shanghai, 200062, China.
| |
Collapse
|
|
36
|
Thiessen SE, Derese I, Derde S, Dufour T, Pauwels L, Bekhuis Y, Pintelon I, Martinet W, Van den Berghe G, Vanhorebeek I. The Role of Autophagy in Critical Illness-induced Liver Damage. Sci Rep 2017; 7:14150. [PMID: 29074879 PMCID: PMC5658339 DOI: 10.1038/s41598-017-14405-w] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2017] [Accepted: 10/02/2017] [Indexed: 12/14/2022] Open
Abstract
Mitochondrial dysfunction and endoplasmic reticulum (ER) stress, which activates the unfolded protein response (UPR), mediate critical illness-induced organ failure, often affecting the liver. Autophagy is known to alleviate both and suppressed or insufficiently activated autophagy in prolonged illness has shown to associate with organ failure. Whether insufficient autophagy contributes to organ failure during critical illness by affecting these underlying mechanisms is incompletely understood. In this study, we investigated whether the inability to acutely activate hepatic autophagy during critical illness aggravates liver damage by increasing hepatic mitochondrial dysfunction and affecting the UPR. In a mouse model of critical illness, induced by surgery and sepsis, we investigated the impact of inactivating hepatic autophagy on markers of hepatic mitochondrial function, the UPR and liver damage in acute (1 day) and prolonged (3 days) critical illness. Hepatic autophagy inactivation during critical illness acutely worsened mitochondrial dysfunction and time-dependently modulated the hepatic UPR. Furthermore, autophagy inactivation aggravated markers of liver damage on both time points. In conclusion, the inability to acutely activate autophagy in liver during critical illness worsened hepatic mitochondrial damage and dysfunction, partially prohibited acute UPR activation and aggravated liver damage, indicating that autophagy is crucial in alleviating critical illness-induced organ failure.
Collapse
Affiliation(s)
- Steven E Thiessen
- Clinical Division and Laboratory of Intensive Care Medicine, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, 3000, Belgium
| | - Inge Derese
- Clinical Division and Laboratory of Intensive Care Medicine, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, 3000, Belgium
| | - Sarah Derde
- Clinical Division and Laboratory of Intensive Care Medicine, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, 3000, Belgium
| | - Thomas Dufour
- Clinical Division and Laboratory of Intensive Care Medicine, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, 3000, Belgium
| | - Lies Pauwels
- Clinical Division and Laboratory of Intensive Care Medicine, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, 3000, Belgium
| | - Youri Bekhuis
- Clinical Division and Laboratory of Intensive Care Medicine, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, 3000, Belgium
| | - Isabel Pintelon
- Laboratory of Cell Biology and Histology, University of Antwerp, Antwerp, 2610, Belgium
| | - Wim Martinet
- Laboratory of Physiopharmacology, University of Antwerp, Antwerp, 2610, Belgium
| | - Greet Van den Berghe
- Clinical Division and Laboratory of Intensive Care Medicine, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, 3000, Belgium
| | - Ilse Vanhorebeek
- Clinical Division and Laboratory of Intensive Care Medicine, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, 3000, Belgium.
| |
Collapse
|
|
37
|
Abstract
Recent research indicates crucial roles of autophagy during sepsis. In animal models of sepsis induced by cecal ligation and puncture (CLP) or the systemic administration of lipopolysaccharides (LPS), autophagy is implicated in the activation and/or damage of various cells/organs, such as immune cells, heart, lung, kidney, and liver. Since sepsis is associated with an increased production of pro- as well as anti-inflammatory cytokines, it has long been considered that hypercytokinemia is a fetal immune response leading to multiple organ failure (MOF) and mortality of humans during sepsis. However, a recent paradigm illuminates the crucial roles of mitochondrial dysfunction as well as the perturbation of autophagy in the pathogenesis of sepsis. In the livers of animal models of sepsis, autophagy is involved in the elimination of damaged mitochondria to prevent the generation of mitochondrial ROS and the initiation of the mitochondrial apoptotic pathway. In addition, many reports now indicate that the role of autophagy is not restricted to the elimination of hazardous malfunctioning mitochondria within the cells; autophagy has been shown to be involved in the regulation of inflammasome activation and the release of cytokines as well as other inflammatory substances. In this review, we summarize recent literature describing the versatile role of autophagy and its possible implications in the pathogenesis of sepsis in the liver.
Collapse
Affiliation(s)
- Toshihiko Aki
- Department of Forensic Medicine, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan
| | - Kana Unuma
- Department of Forensic Medicine, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan
| | - Koichi Uemura
- Department of Forensic Medicine, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan
| |
Collapse
|
|
38
|
Zhang J, Zhao P, Quan N, Wang L, Chen X, Cates C, Rousselle T, Li J. The endotoxemia cardiac dysfunction is attenuated by AMPK/mTOR signaling pathway regulating autophagy. Biochem Biophys Res Commun 2017; 492:520-527. [PMID: 28807827 DOI: 10.1016/j.bbrc.2017.08.034] [Citation(s) in RCA: 44] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2017] [Accepted: 08/10/2017] [Indexed: 12/11/2022]
Abstract
AMP-activated protein kinase (AMPK), an enzyme that plays a role in cellular energy homeostasis, modulates myocardial signaling in the heart. Myocardial dysfunction is a common complication of sepsis. Autophagy is involved in the aging related cardiac dysfunction. However, the role of AMPK in sepsis-induced cardiotoxicity has yet to be clarified, especially in aging. In this study, we explored the role of AMPK in lipopolysaccharide (LPS)-induced myocardial dysfunction and elucidated the potential mechanisms of AMPK/mTOR pathway regulating autophagy in young and aged mice. We harvested cardiac tissues by intraperitoneal injection of LPS treatment. The results by echocardiography, pathology, contractile and intracellular Ca2+ property as well as western blot analysis revealed that LPS induced remarkable cardiac dysfunction and cardiotoxicity in mice hearts and cardiomyocytes, which were more seriously in the aged mice. Western blot analysis indicated that the underlying mechanisms included inhibition autophagy mediated by AMPK/mTOR activation. LPS overtly promoted the expression of AMPK upstream regulator PP2A and PP2Cα. Pharmacological activation of AMPK improved cardiac function and upregulated cardiac autophagy induced by LPS in the aged mice. Collectively, our findings suggest that upregulation of autophagy by administration of AMPK could attenuate LPS-induced cardiotoxicity, which enhances our knowledge to explore new drugs and strategies for combating cardiac dysfunction induced by sepsis.
Collapse
Affiliation(s)
- Jie Zhang
- Department of Nutrition, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China; Department of Physiology and Biophysics, Mississippi Center for Heart Research, University of Mississippi Medical Center, Jackson, MS, USA
| | - Peng Zhao
- Department of Cardiology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China
| | - Nanhu Quan
- Department of Physiology and Biophysics, Mississippi Center for Heart Research, University of Mississippi Medical Center, Jackson, MS, USA
| | - Lin Wang
- Department of Physiology and Biophysics, Mississippi Center for Heart Research, University of Mississippi Medical Center, Jackson, MS, USA
| | - Xu Chen
- Department of Physiology and Biophysics, Mississippi Center for Heart Research, University of Mississippi Medical Center, Jackson, MS, USA
| | - Courtney Cates
- Department of Physiology and Biophysics, Mississippi Center for Heart Research, University of Mississippi Medical Center, Jackson, MS, USA
| | - Thomas Rousselle
- Department of Physiology and Biophysics, Mississippi Center for Heart Research, University of Mississippi Medical Center, Jackson, MS, USA
| | - Ji Li
- Department of Physiology and Biophysics, Mississippi Center for Heart Research, University of Mississippi Medical Center, Jackson, MS, USA.
| |
Collapse
|
|
39
|
Gunst J. Recovery from critical illness-induced organ failure: the role of autophagy. CRITICAL CARE : THE OFFICIAL JOURNAL OF THE CRITICAL CARE FORUM 2017; 21:209. [PMID: 28784175 PMCID: PMC5547478 DOI: 10.1186/s13054-017-1786-y] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Autophagy is a catabolic process by which cells can dispose of damaged content and intracellular microorganisms. Recent evidence implicates autophagy as a crucial repair process necessary to recover from critical illness-induced organ failure. Withholding parenteral nutrition in the acute phase of critical illness activates autophagy and enhances recovery. Several registered drugs have autophagy-stimulating properties, but all lack specificity and none has been investigated in critically ill patients for this purpose.
Collapse
Affiliation(s)
- Jan Gunst
- Clinical Division and Laboratory of Intensive Care Medicine, Department of Cellular and Molecular Medicine, KU Leuven University and Hospital, Herestraat 49, 3000, Leuven, Belgium.
| |
Collapse
|
|
40
|
Ning Y, Kim JK, Min HK, Ren S. Cholesterol metabolites alleviate injured liver function and decrease mortality in an LPS-induced mouse model. Metabolism 2017; 71:83-93. [PMID: 28521882 DOI: 10.1016/j.metabol.2016.12.007] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2016] [Revised: 12/01/2016] [Accepted: 12/07/2016] [Indexed: 02/06/2023]
Abstract
BACKGROUND Oxysterol sulfation plays a fundamental role in the regulation of many biological events. Its products, 25-hydroxycholesterol 3-sulfate (25HC3S) and 25-hydroxycholesterol 3, 25-disulfate (25HCDS), have been demonstrated to be potent regulators of lipid metabolism, inflammatory response, cell apoptosis, and cell survival. In the present study, we tested these products' potential to treat LPS-induced acute liver failure in a mouse model. METHODS Acute liver failure mouse model was established by intravenous injection with LPS. The injured liver function was treated with intraperitoneal administration of 25HC, 25HC3S or 25HCDS. Serum enzymatic activities were determined in our clinic laboratory. ELISA assays were used to detect pro-inflammatory factor levels in sera. Western blot, Real-time Quantitative PCR and RT2 Profiler PCR Array analysis were used to determine levels of gene expression. RESULTS Administration of 25HC3S/25HCDS decreased serum liver-impaired markers; suppressed secretion of pro-inflammatory factors; alleviated liver, lung, and kidney injury; and subsequently increased the survival rate in the LPS-induced mouse model. These effects resulted from the inhibition of the expression of genes involved in the pro-inflammatory response and apoptosis and the simultaneous induction of the expression of genes involved in cell survival. Compared to 25HC, 25HC3S and 25HCDS exhibited significantly stronger effects in these activities, indicating that the cholesterol metabolites play an important role in the inflammatory response, cell apoptosis, and cell survival in vivo. CONCLUSIONS 25HC3S/25HCDS has potential to serve as novel biomedicines in the therapy of acute liver failure and acute multiple organ failure.
Collapse
Affiliation(s)
- Yanxia Ning
- Department of Internal Medicine, Virginia Commonwealth University/McGuire Veterans Affairs Medical Center, Richmond, VA 23249, United States
| | - Jin Kyung Kim
- Department of Internal Medicine, Virginia Commonwealth University/McGuire Veterans Affairs Medical Center, Richmond, VA 23249, United States
| | - Hae-Ki Min
- Department of Internal Medicine, Virginia Commonwealth University/McGuire Veterans Affairs Medical Center, Richmond, VA 23249, United States
| | - Shunlin Ren
- Department of Internal Medicine, Virginia Commonwealth University/McGuire Veterans Affairs Medical Center, Richmond, VA 23249, United States.
| |
Collapse
|
|
41
|
Yan S, Huda N, Khambu B, Yin XM. Relevance of autophagy to fatty liver diseases and potential therapeutic applications. Amino Acids 2017; 49:1965-1979. [PMID: 28478585 DOI: 10.1007/s00726-017-2429-y] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2017] [Accepted: 04/21/2017] [Indexed: 12/19/2022]
Abstract
Autophagy is an evolutionarily conserved lysosome-mediated cellular degradation program. Accumulating evidence shows that autophagy is important to the maintenance of liver homeostasis. Autophagy involves recycling of cellular nutrients recycling as well as quality control of subcellular organelles. Autophagy deficiency in the liver causes various liver pathologies. Fatty liver disease (FLD) is characterized by the accumulation of lipids in hepatocytes and the dysfunction in energy metabolism. Autophagy is negatively affected by the pathogenesis of FLD and the activation of autophagy could ameliorate steatosis, which suggests a potential therapeutic approach to FLD. In this review, we will discuss autophagy and its relevance to liver diseases, especially FLD. In addition, we will discuss recent findings on potential therapeutic applications of autophagy modulators for FLD.
Collapse
Affiliation(s)
- Shengmin Yan
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, 46202, USA
| | - Nazmul Huda
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, 46202, USA
| | - Bilon Khambu
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, 46202, USA
| | - Xiao-Ming Yin
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, 46202, USA.
| |
Collapse
|
|
42
|
Rah SY, Lee YH, Kim UH. NAADP-mediated Ca 2+ signaling promotes autophagy and protects against LPS-induced liver injury. FASEB J 2017; 31:3126-3137. [PMID: 28386045 PMCID: PMC5471520 DOI: 10.1096/fj.201601290r] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2016] [Accepted: 03/20/2017] [Indexed: 01/12/2023]
Abstract
LPS has been shown to induce hepatocyte autophagy, but little is known about how LPS is able to do this during acute toxic liver injury. Our aim was to determine the existence of any selective Ca2+ signaling coupling to hepatocyte autophagy in response to LPS. LPS increased the autophagic process in hepatocytes, and CD38 knockdown prevented this response. Ned19, a specific inhibitor for nicotinic acid adenine dinucleotide phosphate (NAADP), prevented LPS-mediated Ca2+ signaling and autophagosome formation in hepatocytes. CD38 overexpression protected the liver from LPS/d-galactosamine (GalN)-induced injury, and NAADP administration promoted autophagosome formation and protected hepatocytes from injury induced by LPS/GalN. Autophagy was promoted by the up-regulation of autophagy-related gene expression via NAADP-mediated Ca2+ signaling in response to LPS. However, CD38-knockout mice displayed down-regulation in hepatocyte gene expression. Ned19 also inhibited the NAADP-stimulated induction of gene expression by inhibiting the LPS-induced nuclear translocation of transcription factor EB (TFEB). Hepatocyte autophagy protects against LPS-induced liver injury via the CD38/NAADP/Ca2+/TFEB pathway. The role of NAADP-mediated Ca2+ signaling in the autophagic process will help elucidate the complexities of autophagy regulation, which is essential toward the discovery of new therapeutic tools against acute liver injury.-Rah, S.-Y., Lee, Y.-H., Kim, U.-H. NAADP-mediated Ca2+ signaling promotes autophagy and protects against LPS-induced liver injury.
Collapse
Affiliation(s)
- So-Young Rah
- Department of Biochemistry, Chonbuk National University Medical School.,National Creative Research Laboratory for Ca Signaling Network, Chonbuk National University Medical School
| | - Young-Hoon Lee
- Department of Oral Anatomy, School of Dentistry, Chonbuk National University, Jeonju, South Korea
| | - Uh-Hyun Kim
- Department of Biochemistry, Chonbuk National University Medical School; .,National Creative Research Laboratory for Ca Signaling Network, Chonbuk National University Medical School.,Institute of Cardiovascular Research, Chonbuk National University, Jeonju, South Korea
| |
Collapse
|