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Gao J, Lu W, Xin Y, Ma H, Sheng X, Gao G, Kang X, Jiang S, Zhao Y, Lv Y, Niu Y, Liang Y, Wang H. Liver-specific Bcl3 Knockout Alleviates Acetaminophen-induced Liver Injury by Activating Nrf2 Pathway in Male Mice. Cell Mol Gastroenterol Hepatol 2025; 19:101483. [PMID: 40015625 PMCID: PMC12003009 DOI: 10.1016/j.jcmgh.2025.101483] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2024] [Revised: 02/10/2025] [Accepted: 02/19/2025] [Indexed: 03/01/2025]
Abstract
BACKGROUND & AIMS Acetaminophen (APAP) overdose is the leading cause of acute liver failure, with oxidative stress being a critical factor in this process. Glutathione (GSH) plays a vital defensive role. Activation of nuclear factor erythroid 2 like 2 (Nrf2) pathway mitigates APAP-induced liver damage by promoting GSH biosynthesis and enhancing drug detoxification. Although the role of B cell leukemia/lymphoma 3 (Bcl3) in regulating inflammatory responses, cellular oncogenesis, and immune balance is well-documented, its function in APAP-induced liver injury remains unclear. METHODS We employed liver-specific Bcl3 knockout (Bcl3hep-/-) mice and adeno-associated virus (AAV)-8-mediated Bcl3 overexpression (AAV-Bcl3) mice to model APAP-induced liver injury. Liver damage was assessed through hematoxylin and eosin staining and serum alanine aminotransferase and aspartate aminotransferase measurements. The interaction between Bcl3 and Nrf2 was examined using immunofluorescence and co-immunoprecipitation assays. RESULTS Our study reveals a significant upregulation of Bcl3 expression in the livers of male mice following APAP administration, suggesting Bcl3's potential involvement in this pathological process. In Bcl3hep-/- mice, a reduced severity of liver damage was observed at both 6 and 24 hours post-APAP treatment compared with controls. Notably, Bcl3-deficient mice exhibited accelerated GSH replenishment due to the rapid induction of Gclc and Gclm genes following 6 hours of APAP exposure. Through immunofluorescence and co-immunoprecipitation analyses, we identified an interaction between Bcl3 and Nrf2. The loss of Bcl3 enhanced Nrf2 translocation upon APAP challenge, leading to the upregulation of antioxidant gene expression. These findings suggest that Bcl3 knockout alleviates oxidative stress resulting from APAP overdose. CONCLUSION We uncovered a previously uncharacterized role of Bcl3 in APAP-induced liver injury, emphasizing the role of the Bcl3-Nrf2 axis in oxidative stress-related liver damage.
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Affiliation(s)
- Jingtao Gao
- Department of Immunology, Basic Medical College of Xinjiang Medical University, Urumqi, Xinjiang, China
| | - Wei Lu
- Henan Key Laboratory of Immunology and Targeted Drugs, Xinxiang Medical University, Xinxiang, Henan, China
| | - Yue Xin
- Cardiac Center, Beijing Luhe Hospital Capital Medical University, Tongzhou, Beijing, China
| | - Haowen Ma
- Henan Key Laboratory of Immunology and Targeted Drugs, Xinxiang Medical University, Xinxiang, Henan, China
| | - Xiaohang Sheng
- Henan Key Laboratory of Immunology and Targeted Drugs, Xinxiang Medical University, Xinxiang, Henan, China
| | - Ge Gao
- Henan Key Laboratory of Immunology and Targeted Drugs, Xinxiang Medical University, Xinxiang, Henan, China
| | - Xue Kang
- Henan Key Laboratory of Immunology and Targeted Drugs, Xinxiang Medical University, Xinxiang, Henan, China
| | - Shan Jiang
- Henan Key Laboratory of Immunology and Targeted Drugs, Xinxiang Medical University, Xinxiang, Henan, China
| | - Yuxin Zhao
- Department of Immunology, Basic Medical College of Xinjiang Medical University, Urumqi, Xinjiang, China
| | - Yang Lv
- Henan Key Laboratory of Immunology and Targeted Drugs, Xinxiang Medical University, Xinxiang, Henan, China
| | - Yuna Niu
- Henan Key Laboratory of Immunology and Targeted Drugs, Xinxiang Medical University, Xinxiang, Henan, China
| | - Yinming Liang
- Henan Collaborative Innovation Center of Molecular Diagnosis and Laboratory Medicine, School of Medical Technology, Xinxiang Medical University, Xinxiang, Henan, China; Laboratory of Genetic Regulators in the Immune System, School of Medical Technology, Xinxiang Medical University, Xinxiang, Henan, China
| | - Hui Wang
- Department of Immunology, Basic Medical College of Xinjiang Medical University, Urumqi, Xinjiang, China; Henan Key Laboratory of Immunology and Targeted Drugs, Xinxiang Medical University, Xinxiang, Henan, China; Henan Collaborative Innovation Center of Molecular Diagnosis and Laboratory Medicine, School of Medical Technology, Xinxiang Medical University, Xinxiang, Henan, China.
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Li Q, Xu Q, Shi J, Dong W, Jin J, Zhang C. FAK inhibition delays liver repair after acetaminophen-induced acute liver injury by suppressing hepatocyte proliferation and macrophage recruitment. Hepatol Commun 2024; 8:e0531. [PMID: 39761008 PMCID: PMC11495758 DOI: 10.1097/hc9.0000000000000531] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/18/2024] [Accepted: 08/13/2024] [Indexed: 01/07/2025] Open
Abstract
BACKGROUND Overdose of acetaminophen (APAP), a commonly used antipyretic analgesic, can lead to severe liver injury and failure. Current treatments are only effective in the early stages of APAP-induced acute liver injury (ALI). Therefore, a detailed examination of the mechanisms involved in liver repair following APAP-induced ALI could provide valuable insights for clinical interventions. METHODS 4D-label-free proteomics analysis was used to identify dysregulated proteins in the liver of APAP-treated mice. RNA-Seq, hematoxylin-eosin staining, immunohistochemical staining, immunofluorescence staining, quantitative PCR, western blotting, transwell were used to explore the underlying mechanisms. RESULTS Utilizing high throughput 4D-label-free proteomics analysis, we observed a notable increase in proteins related to the "focal adhesion" pathway in the livers of APAP-treated mice. Inhibiting focal adhesion kinase (FAK) activation with a specific inhibitor, 1,2,4,5-Benzenetetraamine tetrahydrochloride (also called Y15), resulted in reduced macrophage numbers, delayed necrotic cell clearance, and inhibited liver cell proliferation in the necrotic regions of APAP-treated mice. RNA-Seq analysis demonstrated that Y15 downregulated genes associated with "cell cycle" and "phagosome" pathways in the livers of APAP-treated mice. Furthermore, blocking extracellular matrix (ECM)-integrin activation with a competitive peptide inhibitor, Gly-Arg-Gly-Asp-Ser (GRGDS), suppressed FAK activation and liver cell proliferation without affecting macrophage recruitment to necrotic areas. Mechanistically, ECM-induced FAK activation upregulated growth-promoting cell cycle genes, leading to hepatocyte proliferation, while CCL2 enhanced FAK activation and subsequent macrophage recruitment via F-actin rearrangement. CONCLUSIONS Overall, these findings underscore the pivotal role of FAK activation in liver repair post-APAP overdose by promoting liver cell proliferation and macrophage recruitment.
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Affiliation(s)
- Qing Li
- Guangxi Key Laboratory of Molecular Medicine in Liver Injury and Repair, Affiliated Hospital of Guilin Medical University, Guilin, Guangxi, China
- Guangxi Health Commission Key Laboratory of Basic Research in Sphingolipid Metabolism Related Diseases, Affiliated Hospital of Guilin Medical University, Guilin, Guangxi, China
- Laboratory of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Guilin Medical University, Guilin, Guangxi, China
- China-USA Lipids in Health and Disease Research Center, Guilin Medical University, Guilin, Guangxi, China
| | - Qi Xu
- Guangxi Key Laboratory of Molecular Medicine in Liver Injury and Repair, Affiliated Hospital of Guilin Medical University, Guilin, Guangxi, China
| | - Jialin Shi
- Guangxi Key Laboratory of Molecular Medicine in Liver Injury and Repair, Affiliated Hospital of Guilin Medical University, Guilin, Guangxi, China
| | - Wei Dong
- Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Junfei Jin
- Guangxi Key Laboratory of Molecular Medicine in Liver Injury and Repair, Affiliated Hospital of Guilin Medical University, Guilin, Guangxi, China
- Guangxi Health Commission Key Laboratory of Basic Research in Sphingolipid Metabolism Related Diseases, Affiliated Hospital of Guilin Medical University, Guilin, Guangxi, China
- Laboratory of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Guilin Medical University, Guilin, Guangxi, China
- China-USA Lipids in Health and Disease Research Center, Guilin Medical University, Guilin, Guangxi, China
| | - Chong Zhang
- Guangxi Key Laboratory of Molecular Medicine in Liver Injury and Repair, Affiliated Hospital of Guilin Medical University, Guilin, Guangxi, China
- Guangxi Health Commission Key Laboratory of Basic Research in Sphingolipid Metabolism Related Diseases, Affiliated Hospital of Guilin Medical University, Guilin, Guangxi, China
- Laboratory of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Guilin Medical University, Guilin, Guangxi, China
- China-USA Lipids in Health and Disease Research Center, Guilin Medical University, Guilin, Guangxi, China
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Ma T, Huang W, Ding Y, Ji R, Ge S, Liu Q, Liu Y, Chen J, Yan Y, Lu S, Ren Q, Fan Y, Mao R, Lu C. AIBP protects drug-induced liver injury by inhibiting MAPK-mediated NR4A1 expression. iScience 2024; 27:110873. [PMID: 39398235 PMCID: PMC11467680 DOI: 10.1016/j.isci.2024.110873] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2023] [Revised: 04/30/2024] [Accepted: 08/30/2024] [Indexed: 10/15/2024] Open
Abstract
Drug-induced liver injury (DILI) is an important adverse drug reaction that can lead to acute liver failure or even death in severe cases. AIBP is a binding protein of apolipoprotein AI involved in lipid metabolism and maintenance of oxidative respiration in mitochondria, but its role in DILI is unclear. By constructing AIBP knockout mice, overexpressing and knocking down AIBP in cell lines, we established animal and cell models of DILI. Using western blotting and real-time qPCR assay, we explored the influence of AIBP in activation of mitogen-activated protein kinases (MAPK) signal pathways and possible targets. AIBP was downregulated during hepatocyte injury. AIBP deficient mice develop severe liver injury and more sensitive to drug-induced cell death. Overexpression of AIBP protects cells under APAP treatment. Furthermore, AIBP inhibits the activation of MAPK pathways, through which AIBP regulates NR4A1. These results suggest that AIBP is expected to become a valuable biomarker and therapeutic target in liver injury.
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Affiliation(s)
- Tao Ma
- Department of Gastroenterology, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong 226001, China
- Research Center of Clinical Medicine, Nantong University, Affiliated Hospital of Nantong University, Nantong, China
| | - Wei Huang
- Department of Gastroenterology, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong 226001, China
| | - Yihong Ding
- Department of Gastroenterology, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong 226001, China
- Department of Gastroenterology, Rugao People’s Hospital, Nantong, Jiangsu, China
| | - Ran Ji
- Department of Gastroenterology, Nantong First People’s Hospital, Nantong, Jiangsu, China
| | - Sijia Ge
- Department of Gastroenterology, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong 226001, China
- Research Center of Clinical Medicine, Nantong University, Affiliated Hospital of Nantong University, Nantong, China
| | - Qingqing Liu
- Department of Gastroenterology, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong 226001, China
- Research Center of Clinical Medicine, Nantong University, Affiliated Hospital of Nantong University, Nantong, China
| | - Yiheng Liu
- Department of Gastroenterology, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong 226001, China
- Research Center of Clinical Medicine, Nantong University, Affiliated Hospital of Nantong University, Nantong, China
| | - Jing Chen
- Department of Gastroenterology, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong 226001, China
- Research Center of Clinical Medicine, Nantong University, Affiliated Hospital of Nantong University, Nantong, China
| | - Yang Yan
- Department of Gastroenterology, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong 226001, China
- Research Center of Clinical Medicine, Nantong University, Affiliated Hospital of Nantong University, Nantong, China
| | - Shushu Lu
- Department of Gastroenterology, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong 226001, China
- Research Center of Clinical Medicine, Nantong University, Affiliated Hospital of Nantong University, Nantong, China
| | - Qiqi Ren
- Department of Gastroenterology, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong 226001, China
- Research Center of Clinical Medicine, Nantong University, Affiliated Hospital of Nantong University, Nantong, China
| | - Yihui Fan
- Department of Pathogenic Biology, School of Medicine, Nantong University, Nantong, Jiangsu, China
| | - Renfang Mao
- Department of Pathophysiology, School of Medicine, Nantong University, Nantong, Jiangsu, China
| | - Cuihua Lu
- Department of Gastroenterology, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong 226001, China
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Cai L, Xu L, Shen K, Wang Q, Ni R, Xu X, Ma X. Sophorae tonkinensis radix polysaccharide attenuates acetaminophen-induced liver injury by regulating the miR-140-5p-related antioxidant mechanism. J Tradit Complement Med 2024; 14:467-476. [PMID: 39035693 PMCID: PMC11259709 DOI: 10.1016/j.jtcme.2024.01.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2023] [Revised: 12/14/2023] [Accepted: 01/16/2024] [Indexed: 07/23/2024] Open
Abstract
STRP1, a polysaccharide active ingredient isolated from the traditional Chinese medicine Sophorae tonkinensis radix, has demonstrated a protective effect against acetaminophen (APAP)-induced liver injury (AILI). The underlying molecular mechanism was investigated in this study. Here, an acute liver damage mouse model was generated by APAP (400 mg/kg) and used to identify the protective effect of STRP1 (200 mg/kg) on mouse livers. In vitro cell experiments were used to further verify the related signaling pathways. Initially, in our study, STRP1 treatment reduced APAP-induced liver injury by decreasing aminotransferase activity and cell apoptosis and increasing cell proliferation. Furthermore, STRP1 treatment significantly increased Nrf2 expression and alleviated oxidative stress caused by reactive oxygen species in AILI. Based on bioinformatics and experimental studies, miR-140-5p was identified and found to be reduced by STRP1, increasing Nrf2 expression. Additionally, Nrf2 played an important role in the protective impact of STRP1-suppressed miR-140-5p expression. Generally, these results showed that STRP1-mediated suppression of miR-140-5p expression mitigates AILI by activating the Nrf2-mediated Nrf2-Keap1 pathway. This study revealed that STRP1 might be a potential treatment agent for AILI.
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Affiliation(s)
- Liangliang Cai
- Department of Pharmacy, Affiliated Hospital of Nantong University, Nantong, 226001, PR China
| | - Lixing Xu
- School of Pharmacy, Jiangsu Key Laboratory of Inflammation and Molecular Drug Targets, Nantong University, Nantong, 226001, PR China
| | - Kai Shen
- Department of Pharmacy, Affiliated Hospital of Nantong University, Nantong, 226001, PR China
| | - Qin Wang
- Department of Pharmacy, Affiliated Hospital of Nantong University, Nantong, 226001, PR China
| | - Ronghua Ni
- Department of Pharmacy, Affiliated Hospital of Nantong University, Nantong, 226001, PR China
| | - Xin Xu
- Department of Pharmacy, Affiliated Hospital of Nantong University, Nantong, 226001, PR China
| | - Xiaofei Ma
- Department of Pharmacy, Affiliated Hospital of Nantong University, Nantong, 226001, PR China
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Zou Z, Liu X, Yu J, Ban T, Zhang Z, Wang P, Huang R, Zheng F, Chang Y, Peng W, Tang Y, Feng X, Zhao Z, Lv X, Huang S, Guo J, Tuo Y, Zhou Z, Liang S. Nuclear miR-204-3p mitigates metabolic dysfunction-associated steatotic liver disease in mice. J Hepatol 2024; 80:834-845. [PMID: 38331323 DOI: 10.1016/j.jhep.2024.01.029] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2023] [Revised: 01/16/2024] [Accepted: 01/29/2024] [Indexed: 02/10/2024]
Abstract
BACKGROUND & AIMS Accumulating evidence has indicated the presence of mature microRNAs (miR) in the nucleus, but their effects on steatohepatitis remain elusive. We have previously demonstrated that the intranuclear miR-204-3p in macrophages protects against atherosclerosis, which shares multiple risk factors with metabolic dysfunction-associated steatotic liver disease (MASLD). Herein, we aimed to explore the functional significance of miR-204-3p in steatohepatitis. METHODS miR-204-3p levels and subcellular localization were assessed in the livers and peripheral blood mononuclear cells of patients with MASLD. Wild-type mice fed high-fat or methionine- and choline-deficient diets were injected with an adeno-associated virus system containing miR-204-3p to determine the effect of miR-204-3p on steatohepatitis. Co-culture systems were applied to investigate the crosstalk between macrophages and hepatocytes or hepatic stellate cells (HSCs). Multiple high-throughput epigenomic sequencings were performed to explore miR-204-3p targets. RESULTS miR-204-3p expression decreased in livers and macrophages in mice and patients with fatty liver. In patients with MASLD, miR-204-3p levels in peripheral blood mononuclear cells were inversely related to the severity of hepatic inflammation and damage. Macrophage-specific miR-204-3p overexpression reduced steatohepatitis in high-fat or methionine- and choline-deficient diet-fed mice. miR-204-3p-overexpressing macrophages inhibited TLR4/JNK signaling and pro-inflammatory cytokine release, thereby limiting fat deposition and inflammation in hepatocytes and fibrogenic activation in HSCs. Epigenomic profiling identified miR-204-3p as a specific regulator of ULK1 expression. ULK1 transcription and VPS34 complex activation by intranuclear miR-204-3p improved autophagic flux, promoting the anti-inflammatory effects of miR-204-3p in macrophages. CONCLUSIONS miR-204-3p inhibits macrophage inflammation, coordinating macrophage actions on hepatocytes and HSCs to ameliorate steatohepatitis. Macrophage miR-204-3p may be a therapeutic target for MASLD. IMPACT AND IMPLICATIONS Metabolic dysfunction-associated steatotic liver disease (MASLD) is a chronic inflammatory disease ranging from simple steatosis to steatohepatitis. However, the molecular mechanisms underlying the progression of MASLD remain incompletely understood. Here, we demonstrate that miR-204-3p levels in circulating peripheral blood mononuclear cells are negatively correlated with disease severity in patients with MASLD. Nuclear miR-204-3p activates ULK1 transcription and improves autophagic flux, limiting macrophage activation and hepatic steatosis. Our study provides a novel understanding of the mechanism of macrophage autophagy and inflammation in steatohepatitis and suggests that miR-204-3p may act as a potential therapeutic target for MASLD.
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Affiliation(s)
- Zhaowei Zou
- Department of General Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, China
| | - Xiu Liu
- Department of Cardiovascular Surgery, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Jie Yu
- Department of General Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, China; Department of Gastrointestinal Surgery, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510080, China
| | - Tao Ban
- Department of General Surgery, The Fourth Affiliated Hospital of Harbin Medical University, Harbin 150081, China; Department of Pharmacology (State Key Laboratory of Frigid Zone Cardiovascular Diseases, Ministry of Science and Technology; The Key Laboratory of Cardiovascular Research, Ministry of Education) at College of Pharmacy, Harbin Medical University, Harbin 150081, China; Heilongjiang Academy of Medical Sciences, Harbin 150081, China
| | - Ziyi Zhang
- Department of Pharmacology, Cardiac and Cerebral Vascular Research Center, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou 510080, China
| | - Peiqi Wang
- Department of General Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, China
| | - Renli Huang
- Department of General Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, China
| | - Fuxin Zheng
- Department of General Surgery, Beihai Hospital, Guangxi University of Chinese Medicine, Beihai 536000, China
| | - Yafei Chang
- Faculty of Forensic Medicine, Guangdong Province Translational Forensic Medicine Engineering Technology Research Center, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou 510080, China
| | - Wanli Peng
- Department of Pharmacology, Cardiac and Cerebral Vascular Research Center, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou 510080, China
| | - Yubo Tang
- Department of Pharmacy, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China
| | - Xiaoqing Feng
- Department of Pharmacy, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China
| | - Ziying Zhao
- Department of Pharmacy, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China
| | - Xiaofei Lv
- Department of Pharmacology, Cardiac and Cerebral Vascular Research Center, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou 510080, China
| | - Shuai Huang
- Department of Orthopaedic Surgery, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou 510260, China
| | - Jiawei Guo
- Department of Pharmacology, School of Medicine, Yangtze University, Jingzhou 434023, China
| | - Yonghua Tuo
- Department of Neurosurgery, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou 510260, China
| | - Zhijun Zhou
- Department of Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, United States
| | - Sijia Liang
- Department of Pharmacology, Cardiac and Cerebral Vascular Research Center, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou 510080, China; Advanced Medical Technology Center, The First Affiliated Hospital, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou 510080, China.
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Cui Q, Jiang T, Xie X, Wang H, Qian L, Cheng Y, Li Q, Lu T, Yao Q, Liu J, Lai B, Chen C, Xiao L, Wang N. S-nitrosylation attenuates pregnane X receptor hyperactivity and acetaminophen-induced liver injury. JCI Insight 2024; 9:e172632. [PMID: 38032737 PMCID: PMC10906221 DOI: 10.1172/jci.insight.172632] [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: 05/31/2023] [Accepted: 11/28/2023] [Indexed: 12/02/2023] Open
Abstract
Drug-induced liver injury (DILI), especially acetaminophen overdose, is the leading cause of acute liver failure. Pregnane X receptor (PXR) is a nuclear receptor and the master regulator of drug metabolism. Aberrant activation of PXR plays a pathogenic role in the acetaminophen hepatotoxicity. Here, we aimed to examine the S-nitrosylation of PXR (SNO-PXR) in response to acetaminophen. We found that PXR was S-nitrosylated in hepatocytes and the mouse livers after exposure to acetaminophen or S-nitrosoglutathione (GSNO). Mass spectrometry and site-directed mutagenesis identified the cysteine 307 as the primary residue for S-nitrosylation (SNO) modification. In hepatocytes, SNO suppressed both agonist-induced (rifampicin and SR12813) and constitutively active PXR (VP-PXR, a human PXR fused to the minimal transactivator domain of the herpes virus transcription factor VP16) activations. Furthermore, in acetaminophen-overdosed mouse livers, PXR protein was decreased at the centrilobular regions overlapping with increased SNO. In PXR-/- mice, replenishing the livers with the SNO-deficient PXR significantly aggravated hepatic necrosis, increased HMGB1 release, and exacerbated liver injury and inflammation. Particularly, we demonstrated that S-nitrosoglutathione reductase (GSNOR) inhibitor N6022 promoted hepatoprotection by increasing the levels of SNO-PXR. In conclusion, PXR is posttranslationally modified by SNO in hepatocytes in response to acetaminophen. This modification mitigated the acetaminophen-induced PXR hyperactivity. It may serve as a target for therapeutical intervention.
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Affiliation(s)
- Qi Cui
- Advanced Institute for Medical Sciences, Dalian Medical University, Dalian, China
- School of Basic Medical Sciences, Xi’an Jiaotong University, Xi’an, China
| | - Tingting Jiang
- Advanced Institute for Medical Sciences, Dalian Medical University, Dalian, China
- School of Basic Medical Sciences, Xi’an Jiaotong University, Xi’an, China
| | - Xinya Xie
- School of Basic Medical Sciences, Xi’an Jiaotong University, Xi’an, China
| | - Haodong Wang
- East China Normal University Health Science Center, Shanghai, China
| | - Lei Qian
- Advanced Institute for Medical Sciences, Dalian Medical University, Dalian, China
| | - Yanyan Cheng
- Advanced Institute for Medical Sciences, Dalian Medical University, Dalian, China
| | - Qiang Li
- School of Public Health, Xi’an Jiaotong University, Xi’an, China
| | - Tingxu Lu
- School of Basic Medical Sciences, Xi’an Jiaotong University, Xi’an, China
| | - Qinyu Yao
- School of Basic Medical Sciences, Xi’an Jiaotong University, Xi’an, China
| | - Jia Liu
- School of Basic Medical Sciences, Xi’an Jiaotong University, Xi’an, China
| | - Baochang Lai
- School of Basic Medical Sciences, Xi’an Jiaotong University, Xi’an, China
| | - Chang Chen
- National Laboratory of Biomacromolecules, Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
| | - Lei Xiao
- School of Basic Medical Sciences, Xi’an Jiaotong University, Xi’an, China
| | - Nanping Wang
- East China Normal University Health Science Center, Shanghai, China
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Cai C, Ma H, Peng J, Shen X, Zhen X, Yu C, Zhang P, Ji F, Wang J. USP25 regulates KEAP1-NRF2 anti-oxidation axis and its inactivation protects acetaminophen-induced liver injury in male mice. Nat Commun 2023; 14:3648. [PMID: 37339955 PMCID: PMC10282087 DOI: 10.1038/s41467-023-39412-6] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2022] [Accepted: 06/13/2023] [Indexed: 06/22/2023] Open
Abstract
Nuclear factor erythroid 2-related factor 2 (NRF2) is a transcription factor responsible for mounting an anti-oxidation gene expression program to counter oxidative stress. Under unstressed conditions, Kelch-like ECH-associated protein 1 (KEAP1), an adaptor protein for CUL3 E3 ubiquitin ligase, mediates NRF2 ubiquitination and degradation. We show here that the deubiquitinase USP25 directly binds to KEAP1 and prevents KEAP1's own ubiquitination and degradation. In the absence of Usp25 or if the DUB is inhibited, KEAP1 is downregulated and NRF2 is stabilized, allowing the cells to respond to oxidative stress more readily. In acetaminophen (APAP) overdose-induced oxidative liver damage in male mice, the inactivation of Usp25, either genetically or pharmacologically, greatly attenuates liver injury and reduces the mortality rates resulted from lethal doses of APAP.
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Affiliation(s)
- Changzhou Cai
- Department of Gastroenterology, The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310003, China
| | - Huailu Ma
- Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310058, China
| | - Jin Peng
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310003, China
| | - Xiang Shen
- Chaser Therapeutics, Inc., Hangzhou, Zhejiang, 310018, China
| | - Xinghua Zhen
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310003, China
| | - Chaohui Yu
- Department of Gastroenterology, The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310003, China
| | - Pumin Zhang
- Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310058, China.
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310003, China.
- Cancer Center, Zhejiang University, Hangzhou, Zhejiang, 310058, China.
| | - Feng Ji
- Department of Gastroenterology, The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310003, China.
| | - Jiewei Wang
- Department of Gastroenterology, The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310003, China.
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8
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Luo G, Huang L, Zhang Z. The molecular mechanisms of acetaminophen-induced hepatotoxicity and its potential therapeutic targets. Exp Biol Med (Maywood) 2023; 248:412-424. [PMID: 36670547 DOI: 10.1177/15353702221147563] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023] Open
Abstract
Acetaminophen (APAP), a widely used antipyretic and analgesic drug in clinics, is relatively safe at therapeutic doses; however, APAP overdose may lead to fatal acute liver injury. Currently, N-acetylcysteine (NAC) is clinically used as the main antidote for APAP poisoning, but its therapeutic effect remains limited owing to rapid disease progression and the general diagnosis of advanced poisoning. As is well known, APAP-induced hepatotoxicity (AIH) is mainly caused by the toxic metabolite N-acetyl-p-benzoquinone imine (NAPQI), and the toxic mechanisms of AIH are complicated. Several cellular processes are involved in the pathogenesis of AIH, including liver metabolism, mitochondrial oxidative stress and dysfunction, sterile inflammation, endoplasmic reticulum stress, autophagy, and microcirculation dysfunction. Mitochondrial oxidative stress and dysfunction are the major cellular events associated with APAP-induced liver injury. Many biomolecules involved in these biological processes are potential therapeutic targets for AIH. Therefore, there is an urgent need to comprehensively clarify the molecular mechanisms underlying AIH and to explore novel therapeutic strategies. This review summarizes the various cellular events involved in AIH and discusses their potential therapeutic targets, with the aim of providing new ideas for the treatment of AIH.
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Affiliation(s)
- Guangwen Luo
- Jinhua Municipal Central Hospital, Jinhua 321000, China
| | - Lili Huang
- Ningbo Medical Center Lihuili Hospital, Ningbo 315040, China
| | - Zhaowei Zhang
- Jinhua Municipal Central Hospital, Jinhua 321000, China
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9
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Wang L, Dong W, Gao H, Chen C, Liang S, Ye X, Liu Y, Hou Y, Fan L, Pan T, Wang Z, Chen Y, Luo Y, Song L. A non-mitogenic FGF4 analog alleviates non-alcoholic steatohepatitis through an AMPK-dependent pathway. Biochim Biophys Acta Mol Basis Dis 2022; 1868:166560. [PMID: 36167161 DOI: 10.1016/j.bbadis.2022.166560] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2022] [Revised: 09/16/2022] [Accepted: 09/22/2022] [Indexed: 10/14/2022]
Abstract
BACKGROUND & AIMS Non-alcoholic fatty liver disease (NAFLD) has emerged as a major liver disease increasingly in association with non-alcoholic steatohepatitis (NASH), cirrhosis and hepatocellular carcinoma (HCC). However, there are currently no approved therapies for treating NAFLD and NASH. Fibroblast growth factor 4 (FGF4) has recently been shown as a promising drug candidate for several metabolic diseases. METHODS Mice fed a high-fat diet with high fructose/glucose drinking water (HF/HFG, Western-like diet) for 21 weeks were intraperitoneally injected with non-mitogenic recombinant FGF4△NT (rFGF4△NT, 1.0 mg/kg body weight) every other day for 8 weeks. Primary mouse hepatocytes cultured in medium containing high glucose/palmitic acid (HG/PA) or TNFα/cyclohexane (TNFα/CHX) were treated with 1.0 μg/ml rFGF4△NT. Changes in parameters for histopathology, lipid metabolism, inflammation, hepatocellular apoptosis and fibrosis were determined. The Caspase6 activity and AMPK pathway were assessed. RESULTS Administration of rFGF4△NT significantly attenuated the Western-like diet-induced hepatic steatosis, inflammation, liver injury and fibrosis in mice. rFGF4△NT treatment reduced fatty acid-induced lipid accumulation and lipotoxicity-induced hepatocyte apoptosis, which were associated with inhibition of Caspase6 cleavage and activation. Inhibition of AMP-activated protein kinase (AMPK) by Compound C or deficiency of Ampk abrogated rFGF4△NT-induced hepatoprotection in primary hepatocytes and in mice with NASH. CONCLUSION rFGF4△NT exerts significant protective effects on NASH via an AMPK-dependent signaling pathway. Our study indicates that FGF4 analogs may have therapeutic potential for the Western-like diet induced NASH.
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Affiliation(s)
- Luyao Wang
- The First Affiliated Hospital and School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Wenliya Dong
- The First Affiliated Hospital and School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Huan Gao
- The First Affiliated Hospital and School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Chuchu Chen
- The First Affiliated Hospital and School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Siyu Liang
- The 2nd Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Xianxi Ye
- The First Affiliated Hospital and School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Yi Liu
- The First Affiliated Hospital and School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Yushu Hou
- The First Affiliated Hospital and School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Lei Fan
- The First Affiliated Hospital and School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China; Clinical Pharmacy Research Center, Jinhua Hospital of Zhejiang University and Jinhua Municipal Central Hospital, Jinhua, Zhejiang 321000, China
| | - Tongtong Pan
- The First Affiliated Hospital and School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Zengshou Wang
- The 2nd Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
| | - Yongping Chen
- The First Affiliated Hospital and School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
| | - Yongde Luo
- The First Affiliated Hospital and School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
| | - Lintao Song
- Institute of Aging, Key Laboratory of Alzheimer's Disease of Zhejiang Province, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
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10
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Morishita H, Komatsu M. Role of autophagy in liver diseases. CURRENT OPINION IN PHYSIOLOGY 2022. [DOI: 10.1016/j.cophys.2022.100594] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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11
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Min RWM, Aung FWM, Liu B, Arya A, Win S. Mechanism and Therapeutic Targets of c-Jun-N-Terminal Kinases Activation in Nonalcoholic Fatty Liver Disease. Biomedicines 2022; 10:biomedicines10082035. [PMID: 36009582 PMCID: PMC9406172 DOI: 10.3390/biomedicines10082035] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2022] [Revised: 08/15/2022] [Accepted: 08/18/2022] [Indexed: 11/16/2022] Open
Abstract
Non-alcoholic fatty liver (NAFL) is the most common chronic liver disease. Activation of mitogen-activated kinases (MAPK) cascade, which leads to c-Jun N-terminal kinase (JNK) activation occurs in the liver in response to the nutritional and metabolic stress. The aberrant activation of MAPKs, especially c-Jun-N-terminal kinases (JNKs), leads to unwanted genetic and epi-genetic modifications in addition to the metabolic stress adaptation in hepatocytes. A mechanism of sustained P-JNK activation was identified in acute and chronic liver diseases, suggesting an important role of aberrant JNK activation in NASH. Therefore, modulation of JNK activation, rather than targeting JNK protein levels, is a plausible therapeutic application for the treatment of chronic liver disease.
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Affiliation(s)
| | | | - Bryant Liu
- Division of Gastrointestinal and Liver Disease, Department of Medicine, Keck School of Medicine, University of Southern California, 2011 Zonal Ave., HMR 612, Los Angeles, CA 90089, USA
| | - Aliza Arya
- Division of Gastrointestinal and Liver Disease, Department of Medicine, Keck School of Medicine, University of Southern California, 2011 Zonal Ave., HMR 612, Los Angeles, CA 90089, USA
| | - Sanda Win
- Division of Gastrointestinal and Liver Disease, Department of Medicine, Keck School of Medicine, University of Southern California, 2011 Zonal Ave., HMR 612, Los Angeles, CA 90089, USA
- Correspondence:
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12
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Function and regulation of ULK1: From physiology to pathology. Gene 2022; 840:146772. [PMID: 35905845 DOI: 10.1016/j.gene.2022.146772] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Revised: 07/03/2022] [Accepted: 07/24/2022] [Indexed: 11/21/2022]
Abstract
The expression of ULK1, a core protein of autophagy, is closely related to autophagic activity. Numerous studies have shown that pathological abnormal expression of ULK1 is associated with various human diseases such as neurological disorders, infections, cardiovascular diseases, liver diseases and cancers. In addition, new advances in the regulation of ULK1 have been identified. Furthermore, targeting ULK1 as a therapeutic strategy for diseases is gaining attention as new corresponding activators or inhibitors are being developed. In this review, we describe the structure and regulation of ULK1 as well as the current targeted activators and inhibitors. Moreover, we highlight the pathological disorders of ULK1 expression and its critical role in human diseases.
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13
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Zou L, Liao M, Zhen Y, Zhu S, Chen X, Zhang J, Hao Y, Liu B. Autophagy and beyond: Unraveling the complexity of UNC-51-like kinase 1 (ULK1) from biological functions to therapeutic implications. Acta Pharm Sin B 2022; 12:3743-3782. [PMID: 36213540 PMCID: PMC9532564 DOI: 10.1016/j.apsb.2022.06.004] [Citation(s) in RCA: 38] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2022] [Revised: 05/27/2022] [Accepted: 06/02/2022] [Indexed: 12/13/2022] Open
Abstract
UNC-51-like kinase 1 (ULK1), as a serine/threonine kinase, is an autophagic initiator in mammals and a homologous protein of autophagy related protein (Atg) 1 in yeast and of UNC-51 in Caenorhabditis elegans. ULK1 is well-known for autophagy activation, which is evolutionarily conserved in protein transport and indispensable to maintain cell homeostasis. As the direct target of energy and nutrition-sensing kinase, ULK1 may contribute to the distribution and utilization of cellular resources in response to metabolism and is closely associated with multiple pathophysiological processes. Moreover, ULK1 has been widely reported to play a crucial role in human diseases, including cancer, neurodegenerative diseases, cardiovascular disease, and infections, and subsequently targeted small-molecule inhibitors or activators are also demonstrated. Interestingly, the non-autophagy function of ULK1 has been emerging, indicating that non-autophagy-relevant ULK1 signaling network is also linked with diseases under some specific contexts. Therefore, in this review, we summarized the structure and functions of ULK1 as an autophagic initiator, with a focus on some new approaches, and further elucidated the key roles of ULK1 in autophagy and non-autophagy. Additionally, we also discussed the relationships between ULK1 and human diseases, as well as illustrated a rapid progress for better understanding of the discovery of more candidate small-molecule drugs targeting ULK1, which will provide a clue on novel ULK1-targeted therapeutics in the future.
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Affiliation(s)
- Ling Zou
- School of Pharmaceutical Sciences, Health Science Center, Shenzhen University, Shenzhen 518060, China
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Minru Liao
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Yongqi Zhen
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Shiou Zhu
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Xiya Chen
- School of Pharmaceutical Sciences, Health Science Center, Shenzhen University, Shenzhen 518060, China
| | - Jin Zhang
- School of Pharmaceutical Sciences, Health Science Center, Shenzhen University, Shenzhen 518060, China
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China
- Corresponding authors. Tel./fax: +86 28 85503817.
| | - Yue Hao
- School of Pharmaceutical Sciences, Health Science Center, Shenzhen University, Shenzhen 518060, China
- Corresponding authors. Tel./fax: +86 28 85503817.
| | - Bo Liu
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China
- Corresponding authors. Tel./fax: +86 28 85503817.
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14
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Cai X, Cai H, Wang J, Yang Q, Guan J, Deng J, Chen Z. Molecular pathogenesis of acetaminophen-induced liver injury and its treatment options. J Zhejiang Univ Sci B 2022; 23:265-285. [PMID: 35403383 DOI: 10.1631/jzus.b2100977] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Acetaminophen, also known as N-acetyl-p-aminophenol (APAP), is commonly used as an antipyretic and analgesic agent. APAP overdose can induce hepatic toxicity, known as acetaminophen-induced liver injury (AILI). However, therapeutic doses of APAP can also induce AILI in patients with excessive alcohol intake or who are fasting. Hence, there is a need to understand the potential pathological mechanisms underlying AILI. In this review, we summarize three main mechanisms involved in the pathogenesis of AILI: hepatocyte necrosis, sterile inflammation, and hepatocyte regeneration. The relevant factors are elucidated and discussed. For instance, N-acetyl-p-benzoquinone imine (NAPQI) protein adducts trigger mitochondrial oxidative/nitrosative stress during hepatocyte necrosis, danger-associated molecular patterns (DAMPs) are released to elicit sterile inflammation, and certain growth factors contribute to liver regeneration. Finally, we describe the current potential treatment options for AILI patients and promising novel strategies available to researchers and pharmacists. This review provides a clearer understanding of AILI-related mechanisms to guide drug screening and selection for the clinical treatment of AILI patients in the future.
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Affiliation(s)
- Xiaopeng Cai
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Huiqiang Cai
- Department of Clinical Medicine, University of Aarhus, Palle Juul-Jensens Boulevard 82, 8200 Aarhus N, Denmark
| | - Jing Wang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Qin Yang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Jun Guan
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Jingwen Deng
- Department of Pathology, Key Laboratory of Disease Proteomics of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou 310058, China. , .,Department of Pathology, Women's Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China. ,
| | - Zhi Chen
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China.
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15
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Zhou K, Yin F, Li Y, Ma C, Liu P, Xin Z, Ren R, Wei S, Khan M, Wang H, Zhang H. MicroRNA-29b ameliorates hepatic inflammation via suppression of STAT3 in alcohol-associated liver disease. Alcohol 2022; 99:9-22. [PMID: 34688828 DOI: 10.1016/j.alcohol.2021.10.003] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2021] [Revised: 09/11/2021] [Accepted: 10/18/2021] [Indexed: 02/08/2023]
Abstract
Alcohol-associated liver disease (ALD) is induced by chronic excessive alcohol consumption resulting in the clinical manifestations of steatosis, inflammation, and cirrhosis. MicroRNA-29b (miR-29b) is mainly expressed in hepatic nonparenchymal cells, and its expression level varies in different diseases. In this study, we aimed to determine the role of miR-29b in a mouse model of alcohol-associated liver disease. Wild-type (WT) and miR-29b knockout (miR-29b-/-) mice were fed a Lieber-DeCarli liquid diet containing 5% alcohol for 10 days, followed by gavage of a single dose of ethanol (5 g/kg body weight). Histology, immunoblotting, and biochemical analyses were then conducted for comparison. miR-29b expression was decreased in the livers of chronic-plus-binge ethanol-fed mice. Further analysis revealed that alcohol exposure exacerbated hepatic injury by significantly increasing serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, with decreased survival rates for miR-29b-/- mice. Results from the luciferase assay indicated that miR-29b negatively regulated the signal transducer and activator of transcription 3 (STAT3). Depletion of miR-29b led to an increase in STAT3 and more noticeable inflammation in the liver, whereas overexpression of miR-29b downregulated STAT3 and proinflammatory cytokine expression in primary mouse peritoneal macrophages. Taken together, these results demonstrate a novel association between miR-29b and ALD. miR-29b plays a hepatoprotective role in alcohol-induced inflammation and liver injury by targeting STAT3.
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16
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Rajak S, Raza S, Sinha RA. ULK1 Signaling in the Liver: Autophagy Dependent and Independent Actions. Front Cell Dev Biol 2022; 10:836021. [PMID: 35252196 PMCID: PMC8894804 DOI: 10.3389/fcell.2022.836021] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Accepted: 02/04/2022] [Indexed: 12/18/2022] Open
Abstract
Liver is the primary organ for energy metabolism and detoxification in the human body. Not surprisingly, a derangement in liver function leads to several metabolic diseases. Autophagy is a cellular process, which primarily deals with providing molecules for energy production, and maintains cellular health. Autophagy in the liver has been implicated in several hepatic metabolic processes, such as, lipolysis, glycogenolysis, and gluconeogenesis. Autophagy also provides protection against drugs and pathogens. Deregulation of autophagy is associated with the development of non-alcoholic fatty liver disease (NAFLD) acute-liver injury, and cancer. The process of autophagy is synchronized by the action of autophagy family genes or autophagy (Atg) genes that perform key functions at different steps. The uncoordinated-51-like kinases 1 (ULK1) is a proximal kinase member of the Atg family that plays a crucial role in autophagy. Interestingly, ULK1 actions on hepatic cells may also involve some autophagy-independent signaling. In this review, we provide a comprehensive update of ULK1 mediated hepatic action involving lipotoxicity, acute liver injury, cholesterol synthesis, and hepatocellular carcinoma, including both its autophagic and non-autophagic functions.
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Affiliation(s)
| | | | - Rohit Anthony Sinha
- Department of Endocrinology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
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17
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Klionsky DJ, Petroni G, Amaravadi RK, Baehrecke EH, Ballabio A, Boya P, Bravo‐San Pedro JM, Cadwell K, Cecconi F, Choi AMK, Choi ME, Chu CT, Codogno P, Colombo M, Cuervo AM, Deretic V, Dikic I, Elazar Z, Eskelinen E, Fimia GM, Gewirtz DA, Green DR, Hansen M, Jäättelä M, Johansen T, Juhász G, Karantza V, Kraft C, Kroemer G, Ktistakis NT, Kumar S, Lopez‐Otin C, Macleod KF, Madeo F, Martinez J, Meléndez A, Mizushima N, Münz C, Penninger JM, Perera R, Piacentini M, Reggiori F, Rubinsztein DC, Ryan K, Sadoshima J, Santambrogio L, Scorrano L, Simon H, Simon AK, Simonsen A, Stolz A, Tavernarakis N, Tooze SA, Yoshimori T, Yuan J, Yue Z, Zhong Q, Galluzzi L, Pietrocola F. Autophagy in major human diseases. EMBO J 2021; 40:e108863. [PMID: 34459017 PMCID: PMC8488577 DOI: 10.15252/embj.2021108863] [Citation(s) in RCA: 943] [Impact Index Per Article: 235.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2021] [Revised: 07/07/2021] [Accepted: 07/12/2021] [Indexed: 02/06/2023] Open
Abstract
Autophagy is a core molecular pathway for the preservation of cellular and organismal homeostasis. Pharmacological and genetic interventions impairing autophagy responses promote or aggravate disease in a plethora of experimental models. Consistently, mutations in autophagy-related processes cause severe human pathologies. Here, we review and discuss preclinical data linking autophagy dysfunction to the pathogenesis of major human disorders including cancer as well as cardiovascular, neurodegenerative, metabolic, pulmonary, renal, infectious, musculoskeletal, and ocular disorders.
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Affiliation(s)
| | - Giulia Petroni
- Department of Radiation OncologyWeill Cornell Medical CollegeNew YorkNYUSA
| | - Ravi K Amaravadi
- Department of MedicineUniversity of PennsylvaniaPhiladelphiaPAUSA
- Abramson Cancer CenterUniversity of PennsylvaniaPhiladelphiaPAUSA
| | - Eric H Baehrecke
- Department of Molecular, Cell and Cancer BiologyUniversity of Massachusetts Medical SchoolWorcesterMAUSA
| | - Andrea Ballabio
- Telethon Institute of Genetics and MedicinePozzuoliItaly
- Department of Translational Medical SciencesSection of PediatricsFederico II UniversityNaplesItaly
- Department of Molecular and Human GeneticsBaylor College of Medicine, and Jan and Dan Duncan Neurological Research InstituteTexas Children HospitalHoustonTXUSA
| | - Patricia Boya
- Margarita Salas Center for Biological ResearchSpanish National Research CouncilMadridSpain
| | - José Manuel Bravo‐San Pedro
- Faculty of MedicineDepartment Section of PhysiologyComplutense University of MadridMadridSpain
- Center for Networked Biomedical Research in Neurodegenerative Diseases (CIBERNED)MadridSpain
| | - Ken Cadwell
- Kimmel Center for Biology and Medicine at the Skirball InstituteNew York University Grossman School of MedicineNew YorkNYUSA
- Department of MicrobiologyNew York University Grossman School of MedicineNew YorkNYUSA
- Division of Gastroenterology and HepatologyDepartment of MedicineNew York University Langone HealthNew YorkNYUSA
| | - Francesco Cecconi
- Cell Stress and Survival UnitCenter for Autophagy, Recycling and Disease (CARD)Danish Cancer Society Research CenterCopenhagenDenmark
- Department of Pediatric Onco‐Hematology and Cell and Gene TherapyIRCCS Bambino Gesù Children's HospitalRomeItaly
- Department of BiologyUniversity of Rome ‘Tor Vergata’RomeItaly
| | - Augustine M K Choi
- Division of Pulmonary and Critical Care MedicineJoan and Sanford I. Weill Department of MedicineWeill Cornell MedicineNew YorkNYUSA
- New York‐Presbyterian HospitalWeill Cornell MedicineNew YorkNYUSA
| | - Mary E Choi
- New York‐Presbyterian HospitalWeill Cornell MedicineNew YorkNYUSA
- Division of Nephrology and HypertensionJoan and Sanford I. Weill Department of MedicineWeill Cornell MedicineNew YorkNYUSA
| | - Charleen T Chu
- Department of PathologyUniversity of Pittsburgh School of MedicinePittsburghPAUSA
| | - Patrice Codogno
- Institut Necker‐Enfants MaladesINSERM U1151‐CNRS UMR 8253ParisFrance
- Université de ParisParisFrance
| | - Maria Isabel Colombo
- Laboratorio de Mecanismos Moleculares Implicados en el Tráfico Vesicular y la Autofagia‐Instituto de Histología y Embriología (IHEM)‐Universidad Nacional de CuyoCONICET‐ Facultad de Ciencias MédicasMendozaArgentina
| | - Ana Maria Cuervo
- Department of Developmental and Molecular BiologyAlbert Einstein College of MedicineBronxNYUSA
- Institute for Aging StudiesAlbert Einstein College of MedicineBronxNYUSA
| | - Vojo Deretic
- Autophagy Inflammation and Metabolism (AIMCenter of Biomedical Research ExcellenceUniversity of New Mexico Health Sciences CenterAlbuquerqueNMUSA
- Department of Molecular Genetics and MicrobiologyUniversity of New Mexico Health Sciences CenterAlbuquerqueNMUSA
| | - Ivan Dikic
- Institute of Biochemistry IISchool of MedicineGoethe UniversityFrankfurt, Frankfurt am MainGermany
- Buchmann Institute for Molecular Life SciencesGoethe UniversityFrankfurt, Frankfurt am MainGermany
| | - Zvulun Elazar
- Department of Biomolecular SciencesThe Weizmann Institute of ScienceRehovotIsrael
| | | | - Gian Maria Fimia
- Department of Molecular MedicineSapienza University of RomeRomeItaly
- Department of EpidemiologyPreclinical Research, and Advanced DiagnosticsNational Institute for Infectious Diseases ‘L. Spallanzani’ IRCCSRomeItaly
| | - David A Gewirtz
- Department of Pharmacology and ToxicologySchool of MedicineVirginia Commonwealth UniversityRichmondVAUSA
| | - Douglas R Green
- Department of ImmunologySt. Jude Children's Research HospitalMemphisTNUSA
| | - Malene Hansen
- Sanford Burnham Prebys Medical Discovery InstituteProgram of DevelopmentAging, and RegenerationLa JollaCAUSA
| | - Marja Jäättelä
- Cell Death and MetabolismCenter for Autophagy, Recycling & DiseaseDanish Cancer Society Research CenterCopenhagenDenmark
- Department of Cellular and Molecular MedicineFaculty of Health SciencesUniversity of CopenhagenCopenhagenDenmark
| | - Terje Johansen
- Department of Medical BiologyMolecular Cancer Research GroupUniversity of Tromsø—The Arctic University of NorwayTromsøNorway
| | - Gábor Juhász
- Institute of GeneticsBiological Research CenterSzegedHungary
- Department of Anatomy, Cell and Developmental BiologyEötvös Loránd UniversityBudapestHungary
| | | | - Claudine Kraft
- Institute of Biochemistry and Molecular BiologyZBMZFaculty of MedicineUniversity of FreiburgFreiburgGermany
- CIBSS ‐ Centre for Integrative Biological Signalling StudiesUniversity of FreiburgFreiburgGermany
| | - Guido Kroemer
- Centre de Recherche des CordeliersEquipe Labellisée par la Ligue Contre le CancerUniversité de ParisSorbonne UniversitéInserm U1138Institut Universitaire de FranceParisFrance
- Metabolomics and Cell Biology PlatformsInstitut Gustave RoussyVillejuifFrance
- Pôle de BiologieHôpital Européen Georges PompidouAP‐HPParisFrance
- Suzhou Institute for Systems MedicineChinese Academy of Medical SciencesSuzhouChina
- Karolinska InstituteDepartment of Women's and Children's HealthKarolinska University HospitalStockholmSweden
| | | | - Sharad Kumar
- Centre for Cancer BiologyUniversity of South AustraliaAdelaideSAAustralia
- Faculty of Health and Medical SciencesUniversity of AdelaideAdelaideSAAustralia
| | - Carlos Lopez‐Otin
- Departamento de Bioquímica y Biología MolecularFacultad de MedicinaInstituto Universitario de Oncología del Principado de Asturias (IUOPA)Universidad de OviedoOviedoSpain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC)MadridSpain
| | - Kay F Macleod
- The Ben May Department for Cancer ResearchThe Gordon Center for Integrative SciencesW‐338The University of ChicagoChicagoILUSA
- The University of ChicagoChicagoILUSA
| | - Frank Madeo
- Institute of Molecular BiosciencesNAWI GrazUniversity of GrazGrazAustria
- BioTechMed‐GrazGrazAustria
- Field of Excellence BioHealth – University of GrazGrazAustria
| | - Jennifer Martinez
- Immunity, Inflammation and Disease LaboratoryNational Institute of Environmental Health SciencesNIHResearch Triangle ParkNCUSA
| | - Alicia Meléndez
- Biology Department, Queens CollegeCity University of New YorkFlushingNYUSA
- The Graduate Center Biology and Biochemistry PhD Programs of the City University of New YorkNew YorkNYUSA
| | - Noboru Mizushima
- Department of Biochemistry and Molecular BiologyGraduate School of MedicineThe University of TokyoTokyoJapan
| | - Christian Münz
- Viral ImmunobiologyInstitute of Experimental ImmunologyUniversity of ZurichZurichSwitzerland
| | - Josef M Penninger
- Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA)Vienna BioCenter (VBC)ViennaAustria
- Department of Medical GeneticsLife Sciences InstituteUniversity of British ColumbiaVancouverBCCanada
| | - Rushika M Perera
- Department of AnatomyUniversity of California, San FranciscoSan FranciscoCAUSA
- Department of PathologyUniversity of California, San FranciscoSan FranciscoCAUSA
- Helen Diller Family Comprehensive Cancer CenterUniversity of California, San FranciscoSan FranciscoCAUSA
| | - Mauro Piacentini
- Department of BiologyUniversity of Rome “Tor Vergata”RomeItaly
- Laboratory of Molecular MedicineInstitute of Cytology Russian Academy of ScienceSaint PetersburgRussia
| | - Fulvio Reggiori
- Department of Biomedical Sciences of Cells & SystemsMolecular Cell Biology SectionUniversity of GroningenUniversity Medical Center GroningenGroningenThe Netherlands
| | - David C Rubinsztein
- Department of Medical GeneticsCambridge Institute for Medical ResearchUniversity of CambridgeCambridgeUK
- UK Dementia Research InstituteUniversity of CambridgeCambridgeUK
| | - Kevin M Ryan
- Cancer Research UK Beatson InstituteGlasgowUK
- Institute of Cancer SciencesUniversity of GlasgowGlasgowUK
| | - Junichi Sadoshima
- Department of Cell Biology and Molecular MedicineCardiovascular Research InstituteRutgers New Jersey Medical SchoolNewarkNJUSA
| | - Laura Santambrogio
- Department of Radiation OncologyWeill Cornell Medical CollegeNew YorkNYUSA
- Sandra and Edward Meyer Cancer CenterNew YorkNYUSA
- Caryl and Israel Englander Institute for Precision MedicineNew YorkNYUSA
| | - Luca Scorrano
- Istituto Veneto di Medicina MolecolarePadovaItaly
- Department of BiologyUniversity of PadovaPadovaItaly
| | - Hans‐Uwe Simon
- Institute of PharmacologyUniversity of BernBernSwitzerland
- Department of Clinical Immunology and AllergologySechenov UniversityMoscowRussia
- Laboratory of Molecular ImmunologyInstitute of Fundamental Medicine and BiologyKazan Federal UniversityKazanRussia
| | | | - Anne Simonsen
- Department of Molecular MedicineInstitute of Basic Medical SciencesUniversity of OsloOsloNorway
- Centre for Cancer Cell ReprogrammingInstitute of Clinical MedicineUniversity of OsloOsloNorway
- Department of Molecular Cell BiologyInstitute for Cancer ResearchOslo University Hospital MontebelloOsloNorway
| | - Alexandra Stolz
- Institute of Biochemistry IISchool of MedicineGoethe UniversityFrankfurt, Frankfurt am MainGermany
- Buchmann Institute for Molecular Life SciencesGoethe UniversityFrankfurt, Frankfurt am MainGermany
| | - Nektarios Tavernarakis
- Institute of Molecular Biology and BiotechnologyFoundation for Research and Technology‐HellasHeraklion, CreteGreece
- Department of Basic SciencesSchool of MedicineUniversity of CreteHeraklion, CreteGreece
| | - Sharon A Tooze
- Molecular Cell Biology of AutophagyThe Francis Crick InstituteLondonUK
| | - Tamotsu Yoshimori
- Department of GeneticsGraduate School of MedicineOsaka UniversitySuitaJapan
- Department of Intracellular Membrane DynamicsGraduate School of Frontier BiosciencesOsaka UniversitySuitaJapan
- Integrated Frontier Research for Medical Science DivisionInstitute for Open and Transdisciplinary Research Initiatives (OTRI)Osaka UniversitySuitaJapan
| | - Junying Yuan
- Interdisciplinary Research Center on Biology and ChemistryShanghai Institute of Organic ChemistryChinese Academy of SciencesShanghaiChina
- Department of Cell BiologyHarvard Medical SchoolBostonMAUSA
| | - Zhenyu Yue
- Department of NeurologyFriedman Brain InstituteIcahn School of Medicine at Mount SinaiNew YorkNYUSA
| | - Qing Zhong
- Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of EducationDepartment of PathophysiologyShanghai Jiao Tong University School of Medicine (SJTU‐SM)ShanghaiChina
| | - Lorenzo Galluzzi
- Department of Radiation OncologyWeill Cornell Medical CollegeNew YorkNYUSA
- Sandra and Edward Meyer Cancer CenterNew YorkNYUSA
- Caryl and Israel Englander Institute for Precision MedicineNew YorkNYUSA
- Department of DermatologyYale School of MedicineNew HavenCTUSA
- Université de ParisParisFrance
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18
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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: 44] [Impact Index Per Article: 11.0] [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.
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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.
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19
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Comparison of effects of high and low dose paracetamol treatment and toxicity on brain and liver in rats. North Clin Istanb 2020; 7:541-550. [PMID: 33381692 PMCID: PMC7754870 DOI: 10.14744/nci.2020.54926] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2020] [Accepted: 06/08/2020] [Indexed: 12/24/2022] Open
Abstract
OBJECTIVE Paracetamol is thought that it acts by inhibiting the central cyclooxygenase (COX) enzyme; its mechanism of action is still not fully explained. Although its most important side effect is hepatoxicity, it is thought to cause toxicity on the brain in recent years. The present study aims to investigate the treatment and toxic effects of low and high doses of paracetamol on the liver and brain. METHODS Wistar-albino rats were used in this study. At doses of 20-500 mg/kg, paracetamol was administered intraperitoneally once a day for one and three days. The brain and liver were used for immunohistochemical evaluation using COX-3, prostaglandin E2 (PGE2) and caspase 3 antibodies and for total antioxidant (TAS), total oxidant (TOS) and oxidative stress index (OSI) measurements. Results were evaluated using the Kruskal Wallis test (SPSS ver.24). RESULTS The liver COX-3 levels were significantly lower in both groups with higher doses (p<0.05). In the brain, there was no statistically significant difference in COX-3 levels between the groups. There was no statistically significant difference in PGE2 levels in the liver and brain between the groups (p>0.05). The caspase 3 level in the liver was statistically significantly higher in the low dose group compared to the other groups (p<0.05). In both liver and brain, OSI values were significantly higher in the 3-day high-dose group compared to others (p<0.05). There was no statistically significant difference between the groups in ALT and AST values (p>0.05). CONCLUSION The results of our study show that paracetamol inhibits the COX-3 enzyme in the liver but has no effect in the brain, and COX-3 does not have an effect on PGE2. Paracetamol causes apoptosis in the liver only in low doses; higher doses may cause toxicity by increasing oxidative stress, especially in the brain.
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20
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Current etiological comprehension and therapeutic targets of acetaminophen-induced hepatotoxicity. Pharmacol Res 2020; 161:105102. [DOI: 10.1016/j.phrs.2020.105102] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2020] [Revised: 07/03/2020] [Accepted: 07/21/2020] [Indexed: 02/07/2023]
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21
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Lee DH, Park SH, Ahn J, Hong SP, Lee E, Jang YJ, Ha TY, Huh YH, Ha SY, Jeon TI, Jung CH. Mir214-3p and Hnf4a/Hnf4α reciprocally regulate Ulk1 expression and autophagy in nonalcoholic hepatic steatosis. Autophagy 2020; 17:2415-2431. [PMID: 33078654 PMCID: PMC8496708 DOI: 10.1080/15548627.2020.1827779] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Macroautophagy/autophagy, a self-degradative process, regulates metabolic homeostasis in response to various stress conditions and is a therapeutic target for nonalcoholic fatty liver disease. We found that autophagic activity was inhibited as a result of a significant reduction in the expression of autophagy-related genes such as Ulk1 in a mouse model and patients with fatty liver. This downregulation was caused by increased Mir214-3p levels and decreased Hnf4a/Hnf4α mRNA levels in hepatocytes. Mir214-3p suppressed Ulk1 expression through direct binding at a 3' untranslated region sequence. Hnf4a directly activated transcription of Ulk1. We investigated lipid accumulation and the expression of autophagy-related genes in the livers of mice treated with anti-Mir214-3p. Hepatic steatosis was alleviated, and Ulk1 mRNA levels were significantly increased by locked nucleic acid-mediated Mir214-3p silencing. Additionally, autophagosome formation and MAP1LC3/LC3-II protein levels were increased, indicating an increase in autophagic activity. Interestingly, suppression of Mir214-3p did not ameliorate fatty liver under Ulk1 suppression, suggesting that reduced Mir214-3p levels mitigate hepatic steatosis through upregulation of Ulk1. These results demonstrate that inhibition of Mir214-3p expression ameliorated fatty liver disease through increased autophagic activity by increasing the expression of Ulk1. Thus, Mir214-3p is a potential therapeutic target for nonalcoholic fatty disease.Abbreviations: AMPK: adenosine monophosphate-activated protein kinase; ATG: autophagy-related; ChIP: chromatin immunoprecipitation; CTSB: cathepsin B; CTSL: cathepsin L; CQ: chloroquine; HFD: high-fat diet; HNF4A: hepatocyte nuclear factor 4, alpha; IF: immunofluorescence; IHC: immunohistochemistry; LDs: lipid droplets; Leup: leupeptin; LFD: low-fat diet; LNA: locked nucleic acid; MAP1LC3B/LC3B: microtubule-associated protein 1 light chain 3 beta; miRNA: microRNA; MTOR: mechanistic target of rapamycin kinase; NAFLD: non-alcoholic fatty liver disease; NASH: non-alcoholic steatohepatitis; PCR: polymerase chain reaction; TEM: transmission electron microscopy; TF: transcription factor; TLDA: TaqMan low-density array; ULK1: unc-51 like kinase 1; UTR: untranslated region.
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Affiliation(s)
- Da-Hye Lee
- Research Division of Food Functionality, Korea Food Research Institute, Wanju-gun, Republic of Korea.,Department of Food Biotechnology, Korea University of Science and Technology, Daejeon, Republic of Korea
| | - So-Hyun Park
- Research Division of Food Functionality, Korea Food Research Institute, Wanju-gun, Republic of Korea.,Department of Food Biotechnology, Korea University of Science and Technology, Daejeon, Republic of Korea
| | - Jiyun Ahn
- Research Division of Food Functionality, Korea Food Research Institute, Wanju-gun, Republic of Korea.,Department of Food Biotechnology, Korea University of Science and Technology, Daejeon, Republic of Korea
| | - Seung Pyo Hong
- Research Division of Food Functionality, Korea Food Research Institute, Wanju-gun, Republic of Korea
| | - Eunyoung Lee
- Research Division of Food Functionality, Korea Food Research Institute, Wanju-gun, Republic of Korea
| | - Young-Jin Jang
- Research Division of Food Functionality, Korea Food Research Institute, Wanju-gun, Republic of Korea
| | - Tae-Youl Ha
- Research Division of Food Functionality, Korea Food Research Institute, Wanju-gun, Republic of Korea.,Department of Food Biotechnology, Korea University of Science and Technology, Daejeon, Republic of Korea
| | - Yang Hoon Huh
- Center for Electron Microscopy Research, Korea Basic Science Institute, Cheongju, Republic of Korea
| | - Seung-Yeon Ha
- Department of Pathology, Gil Medical Center, Gachon University College of Medicine, Incheon, Republic of Korea
| | - Tae-Il Jeon
- Department of Animal Science, Chonnam National University, Gwangju, Republic of Korea
| | - Chang Hwa Jung
- Research Division of Food Functionality, Korea Food Research Institute, Wanju-gun, Republic of Korea.,Department of Food Biotechnology, Korea University of Science and Technology, Daejeon, Republic of Korea
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22
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Hu C, Zhao L, Shen M, Wu Z, Li L. Autophagy regulation is an effective strategy to improve the prognosis of chemically induced acute liver injury based on experimental studies. J Cell Mol Med 2020; 24:8315-8325. [PMID: 32627386 PMCID: PMC7412417 DOI: 10.1111/jcmm.15565] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2020] [Revised: 05/25/2020] [Accepted: 06/16/2020] [Indexed: 12/12/2022] Open
Abstract
Acute liver injury (ALI) induced by chemicals in current experimental studies is characterized by inflammation, oxidative stress and necrosis, which can greatly influence the long-term outcome and lead to liver failure. In liver cells, different autophagy forms envelop cytoplasm components, including proteins, endoplasmic reticulum (ER), mitochondria and lipids, and they effectively participate in breaking down the cargo enclosed inside lysosomes to replenish cellular energy and contents. In general, autophagy serves as a cell survival mechanism in stressful microenvironments, but it also serves as a destructive mechanism that results in cell death in vitro and in vivo. In experimental animals, multiple chemicals are used to mimic ALI in patients to clarify the potential pathological mechanisms and develop effective strategies in the clinic. In this review, we summarize related publications about autophagy modulation to attenuate chemically induced ALI in vitro and in vivo. We also analysed the underlying mechanisms of autophagy regulators and genetic modifications to clarify how to control autophagy to protect against chemically induced ALI in animal models. We anticipate that selectively controlling the dual effects of hepatic autophagy will help to protect against ALI in various animals, but the detailed mechanisms and effects should be determined further in future studies. In this way, we are more confident that modulating autophagy in liver regeneration can improve the prognosis of ALI.
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Affiliation(s)
- Chenxia Hu
- Collaborative Innovation Center for the Diagnosis and Treatment of Infectious DiseasesState Key Laboratory for the Diagnosis and Treatment of Infectious DiseasesThe First Affiliated HospitalSchool of MedicineZhejiang UniversityHangzhouPR China
- National Clinical Research Center for Infectious DiseasesThe First Affiliated HospitalSchool of MedicineZhejiang UniversityHangzhouPR China
| | - Lingfei Zhao
- Key Laboratory of Kidney Disease Prevention and Control TechnologyKidney Disease CenterInstitute of NephrologyFirst Affiliated HospitalCollege of MedicineZhejiang UniversityHangzhouPR China
| | - Miaoda Shen
- Department of OrthopedicsThe First Affiliated HospitalSchool of MedicineZhejiang UniversityHangzhouPR China
| | - Zhongwen Wu
- Collaborative Innovation Center for the Diagnosis and Treatment of Infectious DiseasesState Key Laboratory for the Diagnosis and Treatment of Infectious DiseasesThe First Affiliated HospitalSchool of MedicineZhejiang UniversityHangzhouPR China
- National Clinical Research Center for Infectious DiseasesThe First Affiliated HospitalSchool of MedicineZhejiang UniversityHangzhouPR China
| | - Lanjuan Li
- Collaborative Innovation Center for the Diagnosis and Treatment of Infectious DiseasesState Key Laboratory for the Diagnosis and Treatment of Infectious DiseasesThe First Affiliated HospitalSchool of MedicineZhejiang UniversityHangzhouPR China
- National Clinical Research Center for Infectious DiseasesThe First Affiliated HospitalSchool of MedicineZhejiang UniversityHangzhouPR China
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23
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COX-2 in liver fibrosis. Clin Chim Acta 2020; 506:196-203. [PMID: 32184095 DOI: 10.1016/j.cca.2020.03.024] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2020] [Revised: 03/13/2020] [Accepted: 03/13/2020] [Indexed: 02/07/2023]
Abstract
As a vital inducible sensor, cyclooxygenase-2 (COX-2) plays an important role in the progress of hepatic fibrogenesis. Activation of hepatic stellate cells (HSCs) in the liver can significantly accelerate the onset and development of liver fibrosis. COX-2 overexpression triggers inflammation that is an important inducer in hepatic fibrosis. Increasing evidence indicates that COX-2 is involved in the main pathogenesis of liver fibrosis, such as inflammation, apoptosis, and cell senescence. Moreover, COX-2 expression is altered in patients and animal models with non-alcoholic fatty liver disease or cirrhosis. These findings suggest that COX-2 has a broad and critical role in the development of liver fibrosis. In this review, we summarize the latest advances in the regulation and signal transduction of COX-2 and its impact on liver fibrosis.
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24
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Fan L, Ding L, Lan J, Niu J, He Y, Song L. Fibroblast Growth Factor-1 Improves Insulin Resistance via Repression of JNK-Mediated Inflammation. Front Pharmacol 2019; 10:1478. [PMID: 31866871 PMCID: PMC6906192 DOI: 10.3389/fphar.2019.01478] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2019] [Accepted: 11/13/2019] [Indexed: 12/21/2022] Open
Abstract
Insulin resistance is associated with a greatly increased risk of type 2 diabetes. Administration of fibroblast growth factor-1 (FGF-1) resulted in a marked improvement in insulin sensitivity. However, the underlying molecular mechanism whereby FGF-1 represses insulin resistance remains largely unknown. Here, we sought to delineate the role of FGF-1 in insulin resistance with respect to its anti-inflammatory capability. In this study, we found that FGF-1 had positive effects on glucose intolerance, hepatic lipid accumulation, and insulin resistance, while it markedly repressed cytokine secretion (TNF-α and IL-6) in serum and reduced liver inflammation in diet-induced obesity (DIO) mice. Further, FGF-1 treatment significantly represses TNF-α-induced insulin resistance in vitro and in vivo. These results indicate that FGF-1 likely ameliorates insulin resistance via a mechanism that is independent of its glucose-lowering activity. Subsequent experiments demonstrated that FGF-1 ameliorated insulin resistance, and inflammation was accompanied by decreased c-Jun N-terminal kinase (JNK) signaling. In addition, it is likely that FGF-1 impedes JNK phosphorylation via blocking the transforming growth factor-β activated kinase 1 (TAK1) and TAK1 binding protein 1 (TAB1) interaction. These findings reveal that FGF-1 regulates insulin sensitivity and may represent an attractive therapeutic target for preventing the development of insulin resistance.
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Affiliation(s)
- Lei Fan
- Jinhua Hospital of Zhejiang University and Jinhua Municipal Central Hospital, Jinhua, China
| | - Linchao Ding
- Jinhua Hospital of Zhejiang University and Jinhua Municipal Central Hospital, Jinhua, China
| | - Junjie Lan
- School of Pharmacy, Wenzhou Medical University, Wenzhou, China
| | - Jianlou Niu
- School of Pharmacy, Wenzhou Medical University, Wenzhou, China
| | - Yiling He
- Jinhua Hospital of Zhejiang University and Jinhua Municipal Central Hospital, Jinhua, China
| | - Lintao Song
- School of Pharmacy, Wenzhou Medical University, Wenzhou, China
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25
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Meng J, Wang DM, Luo LL. CTRP3 acts as a novel regulator in depressive-like behavior associated inflammation and apoptosis by meditating p38 and JNK MAPK signaling. Biomed Pharmacother 2019; 120:109489. [PMID: 31629950 DOI: 10.1016/j.biopha.2019.109489] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2019] [Revised: 09/18/2019] [Accepted: 09/22/2019] [Indexed: 10/25/2022] Open
Abstract
Depression is a complicated etiological pattern, and its pathology and effective treatments are highly limited.C1q-tumor necrosis factor-related protein-3 (CTRP3) is an adipokine, playing crucial roles in metabolic regulatory properties. However, the effects of CTRP3 on depression are largely unknown. In the present study, we found that CTRP3 expression levels were markedly reduced in hippocampus of mice with depression induced by chronic unpredictable mild stress (CUMS). In mouse model with depression, CTRP3-deficient mice aggravated depression-associated behaviors, as evidenced by the reduced locomotor activity and sucrose consumption, while the elevated immobility time in the tail suspension test (TST) and forced swimming test (FST). Moreover, CUMS-induced neuron death and increased expression of cleaved Caspase-3 were significantly accelerated by CTRP3 knockout. Furthermore, CTRP3 deletion intensified pro-inflammatory response in CUMS-exposed mice, which was associated with the activation of nuclear factor-κB(NF-κB) signaling. The activity of mitogen-activated protein kinases (MAPKs), including p38 and JNK, was further promoted in hippocampus of CTRP3-knockout mice with CUMS exposure. In contrast,CTRP3 over-expression showed anti-apoptotic and anti-inflammatory effects in lipopolysaccharide (LPS)-treated microglial cells. Importantly, the in vitro experiments demonstrated that CTRP3 knockdown-exacerbated apoptosis and inflammatory responsewere remarkably abrogated by the blockage of p38 and JNK signaling pathways in microglia stimulated by LPS. Next, in CUMS-exposed mice with CTRP3 deficiency, suppressing p38 and JNK markedly alleviated depressive-like behavior,hippocampal neuron death, apoptosis and inflammation. Therefore, CTRP3 may be an innovative therapeutic target for treating patients with depression through regulating p38 and JNK signaling.
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Affiliation(s)
- Jing Meng
- Department of Geriatrics, Wuhan Mental Health Center, Wuhan, 430022, China
| | - Dong-Ming Wang
- Department of Geriatric Psychiatry, Qingdao Mental Heath Center, Qingdao, 266034, China
| | - Li-Ling Luo
- Department of Psychosomatic, The Fourth People's Hospital of Shaanxi, Xi'an, 710043, China.
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26
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Wang B, Maxwell BA, Joo JH, Gwon Y, Messing J, Mishra A, Shaw TI, Ward AL, Quan H, Sakurada SM, Pruett-Miller SM, Bertorini T, Vogel P, Kim HJ, Peng J, Taylor JP, Kundu M. ULK1 and ULK2 Regulate Stress Granule Disassembly Through Phosphorylation and Activation of VCP/p97. Mol Cell 2019; 74:742-757.e8. [PMID: 30979586 PMCID: PMC6859904 DOI: 10.1016/j.molcel.2019.03.027] [Citation(s) in RCA: 130] [Impact Index Per Article: 21.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2018] [Revised: 02/08/2019] [Accepted: 03/22/2019] [Indexed: 12/22/2022]
Abstract
Disturbances in autophagy and stress granule dynamics have been implicated as potential mechanisms underlying inclusion body myopathy (IBM) and related disorders. Yet the roles of core autophagy proteins in IBM and stress granule dynamics remain poorly characterized. Here, we demonstrate that disrupted expression of the core autophagy proteins ULK1 and ULK2 in mice causes a vacuolar myopathy with ubiquitin and TDP-43-positive inclusions; this myopathy is similar to that caused by VCP/p97 mutations, the most common cause of familial IBM. Mechanistically, we show that ULK1/2 localize to stress granules and phosphorylate VCP, thereby increasing VCP's activity and ability to disassemble stress granules. These data suggest that VCP dysregulation and defective stress granule disassembly contribute to IBM-like disease in Ulk1/2-deficient mice. In addition, stress granule disassembly is accelerated by an ULK1/2 agonist, suggesting ULK1/2 as targets for exploiting the higher-order regulation of stress granules for therapeutic intervention of IBM and related disorders.
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Affiliation(s)
- Bo Wang
- Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA; Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
| | - Brian A Maxwell
- Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
| | - Joung Hyuck Joo
- Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA; Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
| | - Youngdae Gwon
- Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
| | - James Messing
- Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA
| | - Ashutosh Mishra
- Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA; St. Jude Proteomics Facility, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
| | - Timothy I Shaw
- Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA; St. Jude Proteomics Facility, St. Jude Children's Research Hospital, Memphis, TN 38105, USA; Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
| | - Amber L Ward
- Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA; Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
| | - Honghu Quan
- Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA; Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
| | - Sadie Miki Sakurada
- Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA; Center for Advanced Genome Engineering, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
| | - Shondra M Pruett-Miller
- Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA; Center for Advanced Genome Engineering, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
| | - Tulio Bertorini
- Department of Neurology, University of Tennessee Heath Science Center, Memphis, TN 38163, USA
| | - Peter Vogel
- Veterinary Pathology Core, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
| | - Hong Joo Kim
- Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
| | - Junmin Peng
- Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA; Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
| | - J Paul Taylor
- Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA
| | - Mondira Kundu
- Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA; Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
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Abstract
Acetaminophen (APAP) is one of the most popular and safe pain medications worldwide. However, due to its wide availability, it is frequently implicated in intentional or unintentional overdoses where it can cause severe liver injury and even acute liver failure (ALF). In fact, APAP toxicity is responsible for 46% of all ALF cases in the United States. Early mechanistic studies in mice demonstrated the formation of a reactive metabolite, which is responsible for hepatic glutathione depletion and initiation of the toxicity. This insight led to the rapid introduction of N-acetylcysteine as a clinical antidote. However, more recently, substantial progress was made in further elucidating the detailed mechanisms of APAP-induced cell death. Mitochondrial protein adducts trigger a mitochondrial oxidant stress, which requires amplification through a MAPK cascade that ultimately results in activation of c-jun N-terminal kinase (JNK) in the cytosol and translocation of phospho-JNK to the mitochondria. The enhanced oxidant stress is responsible for the membrane permeability transition pore opening and the membrane potential breakdown. The ensuing matrix swelling causes the release of intermembrane proteins such as endonuclease G, which translocate to the nucleus and induce DNA fragmentation. These pathophysiological signaling mechanisms can be additionally modulated by removing damaged mitochondria by autophagy and replacing them by mitochondrial biogenesis. Importantly, most of the mechanisms have been confirmed in human hepatocytes and indirectly through biomarkers in plasma of APAP overdose patients. The extensive necrosis caused by APAP overdose leads to a sterile inflammatory response. Although recruitment of inflammatory cells is necessary for removal of cell debris in preparation for regeneration, these cells have the potential to aggravate the injury. This review touches on the newest insight into the intracellular mechanisms of APAP-induced cells death and the resulting inflammatory response. Furthermore, it discusses the translation of these findings to humans and the emergence of new therapeutic interventions.
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Affiliation(s)
- Anup Ramachandran
- Department of Pharmacology, Toxicology & Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA
| | - Hartmut Jaeschke
- Department of Pharmacology, Toxicology & Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA
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28
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Win S, Than TA, Kaplowitz N. The Regulation of JNK Signaling Pathways in Cell Death through the Interplay with Mitochondrial SAB and Upstream Post-Translational Effects. Int J Mol Sci 2018; 19:ijms19113657. [PMID: 30463289 PMCID: PMC6274687 DOI: 10.3390/ijms19113657] [Citation(s) in RCA: 57] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2018] [Revised: 11/17/2018] [Accepted: 11/17/2018] [Indexed: 02/08/2023] Open
Abstract
c-Jun-N-terminal kinase (JNK) activity plays a critical role in modulating cell death, which depends on the level and duration of JNK activation. The kinase cascade from MAPkinase kinase kinase (MAP3K) to MAPkinase kinase (MAP2K) to MAPKinase (MAPK) can be regulated by a number of direct and indirect post-transcriptional modifications, including acetylation, ubiquitination, phosphorylation, and their reversals. Recently, a JNK-mitochondrial SH3-domain binding protein 5 (SH3BP5/SAB)-ROS activation loop has been elucidated, which is required to sustain JNK activity. Importantly, the level of SAB expression in the outer membrane of mitochondria is a major determinant of the set-point for sustained JNK activation. SAB is a docking protein and substrate for JNK, leading to an intramitochondrial signal transduction pathway, which impairs electron transport and promotes reactive oxygen species (ROS) release to sustain the MAPK cascade.
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Affiliation(s)
- Sanda Win
- Division of Gastrointestinal and Liver Disease, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
| | - Tin Aung Than
- Division of Gastrointestinal and Liver Disease, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
| | - Neil Kaplowitz
- Division of Gastrointestinal and Liver Disease, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
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Autophagy and acetaminophen-induced hepatotoxicity. Arch Toxicol 2018; 92:2153-2161. [PMID: 29876591 DOI: 10.1007/s00204-018-2237-5] [Citation(s) in RCA: 55] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2018] [Accepted: 06/04/2018] [Indexed: 12/15/2022]
Abstract
Acetaminophen (APAP) is a widely used analgesic and antipyretic drug. APAP overdose can induce acute liver injury in humans, which is responsible for approximately 50% of total cases of acute liver failure in the United States and some European countries. Currently, the metabolism of APAP in the body has been extensively investigated; however, the exact mechanisms for APAP hepatotoxicity are not well understood. Recent studies have shown that mitochondrial dysfunction, oxidative stress and inflammatory responses play a critical role in the pathogenesis of APAP hepatotoxicity. Autophagy is a catabolic machinery aimed at recycling cellular components and damaged organelles in response to a variety of stimuli, such as nutrient deprivation and toxic stress. Increasing evidence supports that autophagy is involved in the pathophysiological process of APAP-induced liver injury. In this review, we summarized the changes of autophagy in the liver following APAP intoxication and discussed the role and its possible mechanisms of autophagy in APAP hepatotoxicity. Furthermore, this review highlights the crosstalk between mitophagy, oxidative stress and inflammation in APAP-induced liver injury and presents some possible molecular mechanisms by which activated autophagy protects against APAP-induced liver injury.
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30
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Zhang C, Song F. Knockout of ULK1/2 protects against acetaminophen-induced acute liver injury independent of autophagy? Hepatology 2018; 67:2476-2477. [PMID: 29394464 DOI: 10.1002/hep.29824] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2018] [Accepted: 01/26/2018] [Indexed: 12/07/2022]
Affiliation(s)
- Cuiqin Zhang
- Institute of Toxicology, Shandong University, Jinan, Shandong, P. R. China
| | - Fuyong Song
- Institute of Toxicology, Shandong University, Jinan, Shandong, P. R. China
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