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Hajian H, Shahaboddin ME, Akhavan Taheri M, Kheiripour N, Kabiri-Arani S, Aghadavod E, Motallebi M. Therapeutic potential of heat-killed Lactobacillus reuteri against bile acid-induced male reproductive toxicity. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2025:10.1007/s00210-025-04092-0. [PMID: 40232374 DOI: 10.1007/s00210-025-04092-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/03/2025] [Accepted: 03/21/2025] [Indexed: 04/16/2025]
Abstract
Exposure of testicular tissue to supraphysiological concentrations of bile acids can lead to infertility. This study aimed to investigate the protective effects of heat-killed Lactobacillus reuteri (L. reuteri) against male reproductive toxicity induced by bile duct ligation (BDL). Thirty-two male Wistar rats were randomly assigned to four groups (N = 8): control normal (CN), sham-control (SC), BDL-control (underwent BDL surgery), and BDL + heat-killed L. reuteri (received probiotic supplementation for 7 days before and 21 days after BDL). At the end of the study, reproductive parameters, including sex hormones, sperm characteristics, oxidative stress markers, antioxidant status, and inflammatory gene expression in testicular tissue, were analyzed. Additionally, histological assessments of the testis and epididymis were performed. The administration of heat-killed L. reuteri significantly improved sperm viability (p ≤ 0.05) and luteinizing hormone levels (p ≤ 0.05) while reducing total oxidative status, carbonyl protein, and oxidative stress index (p ≤ 0.05) compared to the BDL-control group. Moreover, nitric oxide levels were significantly increased (p ≤ 0.05) in the probiotic-treated group. The expression levels of TNF-α and IL-6 were notably downregulated (p ≤ 0.05), indicating reduced testicular inflammation. Histological analysis demonstrated significant improvements in epithelial height, spermatogenic epithelial area ratio, lumen diameter, and lumen area (p ≤ 0.05) in the probiotic-treated group. These findings suggest that heat-killed L. reuteri alleviates cholestasis-related male reproductive toxicity through its antioxidant and anti-inflammatory effects.
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Affiliation(s)
- Hajar Hajian
- Department of Clinical Biochemistry, Faculty of Medicine, Kashan University of Medical Sciences, Kashan, Iran
| | - Mohammad Esmaeil Shahaboddin
- Department of Clinical Biochemistry, Faculty of Medicine, Kashan University of Medical Sciences, Kashan, Iran
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran
| | - Maryam Akhavan Taheri
- Anatomical Sciences Research Center, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran
- Gametogenesis Research Center, Kashan University of Medical Sciences, Kashan, Iran
| | - Nejat Kheiripour
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran
| | - Shima Kabiri-Arani
- Department of Clinical Biochemistry, Faculty of Medicine, Kashan University of Medical Sciences, Kashan, Iran
| | - Esmat Aghadavod
- Department of Clinical Biochemistry, Faculty of Medicine, Kashan University of Medical Sciences, Kashan, Iran
| | - Mitra Motallebi
- Department of Microbiology, Faculty of Medicine, Kashan University of Medical Sciences, Pezeshk Blvd, Qotbe Ravandi Blvd, Kashan, Iran.
- Infectious Diseases Research Center, Kashan University of Medical Sciences, Kashan, Iran.
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Wang Y, Zhou X, Chen H, Li Z. Molecular mechanisms of alcohol-associated liver disease-ferroptosis and autophagy crosstalk. Mol Biol Rep 2025; 52:361. [PMID: 40183835 DOI: 10.1007/s11033-025-10443-0] [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: 12/28/2024] [Accepted: 03/17/2025] [Indexed: 04/05/2025]
Abstract
Alcohol-associated liver disease (ALD) is a chronic liver injury caused by prolonged heavy drinking and its pathogenesis is extremely complex. According to current researches, ethanol metabolism and the generation of some of its related metabolites, including acetaldehyde and reactive oxygen species, are significant contributors to hepatocyte toxicity. These substances-induced lipid metabolism disorders, inflammatory response, mitochondrial damage, and cellular oxidative stress are important factors that lead to liver injury. Ethanol has been shown in numerous studies to exacerbate ALD by disrupting autophagy via a variety of mechanisms. ALD can be somewhat alleviated by activating autophagy, which plays a significant role in the development of ALD by removing accumulated protein polymers, damaged mitochondria, and excess lipid droplets from hepatocytes. Furthermore, persistent alcohol use raises serum iron levels, which in turn causes hepatocytes to absorb more iron. This, in turn, encourages iron loading in the liver's and other organs' parenchymal and nonparenchymal cells, finally resulting in ferroptosis. Both ferroptosis and autophagy are significant types of controlled cell death, and new research has revealed that cellular autophagy and a variety of signaling pathways play a key role in the initiation and progression of ferroptosis. Alcohol and iron both have the ability to cause oxidative stress on their own, thus their combined effects hasten liver damage. Iron loading, on the other hand, accelerates the development of ALD by triggering mitochondrial oxidative stress and activating signaling pathways and proteins linked to Ferritinophagy. Thus, we think that a new approach to treating ALD in the future will involve examining the interaction between ferroptosis and mitochondrial autophagy based on iron overload.
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Affiliation(s)
- Yangyang Wang
- Department of Spleen and Stomach Diseases, The Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, Sichuan Province, China
- The Key Laboratory of Integrated Traditional Chinese and Western Medicine for Prevention and Treatment of Digestive System Diseases of Luzhou City, The Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, Sichuan Province, China
| | - Xin Zhou
- Department of Spleen and Stomach Diseases, The Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, Sichuan Province, China
- The Key Laboratory of Integrated Traditional Chinese and Western Medicine for Prevention and Treatment of Digestive System Diseases of Luzhou City, The Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, Sichuan Province, China
| | - Hui Chen
- Department of Spleen and Stomach Diseases, The Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, Sichuan Province, China.
| | - Zhi Li
- Department of Spleen and Stomach Diseases, The Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, Sichuan Province, China.
- School of Integrated Traditional Chinese and Western Clinical Medicine, North Sichuan Medical College, Nanchong, Sichuan, China.
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Kang J, Park SH, Khanam M, Park SB, Shin S, Seo W. Impact of binge drinking on alcoholic liver disease. Arch Pharm Res 2025; 48:212-223. [PMID: 40035998 DOI: 10.1007/s12272-025-01537-1] [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: 05/30/2024] [Accepted: 02/13/2025] [Indexed: 03/06/2025]
Abstract
Numerous studies have examined the pathophysiological changes induced by chronic alcohol (ethanol) consumption and the underlying mechanisms, while much less attention has been devoted to understanding the health impacts of binge drinking. Binge drinking is defined as the excessive consumption of alcohol within a single drinking episode, and is the typical consumption pattern among young people in Western countries. While most young binge drinkers are not clinically alcohol dependent, binge drinking has emerged as a significant social and public health concern. The circulating alcohol consumed during binge episodes permeates cellular membranes throughout the body, exerting profound effects on multiple organs, and signaling pathways. Regular binge drinking eventually induces hepatic steatosis (fatty liver), initiates acute inflammation, and accelerates neutrophil infiltration, de novo lipogenesis, adipocyte death/lipolysis, and the production of nonoxidative alcohol metabolites, processes that synergize to damage liver tissue and impair liver function. Metabolic abnormalities such as diabetes and obesity can also exacerbate the progression of alcohol-related liver disease among binge drinkers. Several animal models have been developed to evaluate the pathophysiological changes resulting from binge drinking; however, the pathogenesis of binge drinking is not fully understood due to differences in alcohol metabolism between animal models and humans. Thus, given the high prevalence and severe health implications of binge drinking, there is an urgent need for comprehensive experimental and clinical investigations to unravel the associated pathophysiological changes. This review summarizes recent research findings on the impact of binge drinking, specifically focusing on its contributions to alcoholic liver injury.
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Affiliation(s)
- Jisoo Kang
- College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul, 03760, Republic of Korea
| | - Seol Hee Park
- Department of Companion Animal Health, Hanyang Women's University, Seoul, 04763, Republic of Korea
| | - Mushira Khanam
- College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul, 03760, Republic of Korea
| | - Seo Bhin Park
- College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul, 03760, Republic of Korea
| | - Sumin Shin
- College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul, 03760, Republic of Korea
| | - Wonhyo Seo
- College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul, 03760, Republic of Korea.
- Graduate Program in Innovative Biomaterials Convergence, Ewha Womans University, Seoul, 03760, Republic of Korea.
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Yu Z, Lin S, Gong X, Zou Z, Yang X, Ruan Y, Qian L, Liu Y, Si Z. The role of macroautophagy in substance use disorders. Ann N Y Acad Sci 2025; 1543:68-78. [PMID: 39714908 DOI: 10.1111/nyas.15272] [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] [Indexed: 12/24/2024]
Abstract
Macroautophagy, a universal cellular process, sends cellular material to lysosomes for breakdown and is often activated by stressors like hypoxia or drug exposure. It is vital for protein balance, neurotransmitter release, synaptic function, and neuron survival. The role of macroautophagy in substance use disorders is dual. On one hand, substances like cocaine, methamphetamine, opiates, and alcohol can activate macroautophagy pathways to degrade various neuroinflammatory factors in neuronal cells, providing a protective function. On the other hand, long-term and excessive use of addictive substances can inhibit macroautophagy pathways, obstructing the fusion of autophagosomes with lysosomes and losing the original protective function. This review first summarizes the key proteins and signaling pathways involved in macroautophagy, including mTORC1, AMPK, and endoplasmic reticulum stress, and suggests that the regulation of macroautophagy plays a central role in drug-rewarding behavior and addiction. Second, we focus on the interactions between macroautophagy and neuroinflammation induced by drugs, evaluating the potential of macroautophagy modulators as therapeutic strategies for substance use disorder (SUD), and identifying autophagy-related biomarkers that can be used for early diagnosis and monitoring of treatment response. Our review summarizes the important scientific basis involved in macroautophagy pathways for the development of new therapies for SUD.
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Affiliation(s)
- Zhaoying Yu
- Department of Psychology, College of Teacher Education, Ningbo University, Ningbo, China
| | - Shujun Lin
- Department of Psychology, College of Teacher Education, Ningbo University, Ningbo, China
| | - Xinshuang Gong
- Department of Medicine, School of Public Health, Ningbo University, Ningbo, China
| | - Zhiting Zou
- Department of Psychology, College of Teacher Education, Ningbo University, Ningbo, China
| | - Xiangdong Yang
- Department of Psychology, College of Teacher Education, Ningbo University, Ningbo, China
| | - Yuer Ruan
- Department of Psychology, College of Teacher Education, Ningbo University, Ningbo, China
| | - Liyin Qian
- Department of Medicine, School of Public Health, Ningbo University, Ningbo, China
| | - Yu Liu
- Department of Medicine, School of Basic Medicine, Ningbo University, Ningbo, China
| | - Zizhen Si
- Department of Medicine, School of Basic Medicine, Ningbo University, Ningbo, China
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Jarocki M, Turek K, Saczko J, Tarek M, Kulbacka J. Lipids associated with autophagy: mechanisms and therapeutic targets. Cell Death Discov 2024; 10:460. [PMID: 39477959 PMCID: PMC11525783 DOI: 10.1038/s41420-024-02224-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2024] [Revised: 10/18/2024] [Accepted: 10/22/2024] [Indexed: 11/02/2024] Open
Abstract
Autophagy is a molecular process essential for maintaining cellular homeostasis, with its impairment or dysregulation linked to the progression of various diseases in mammals. Specific lipids, including phosphoinositides, sphingolipids, and oxysterols, play pivotal roles in inducing and regulating autophagy, highlighting their significance in this intricate process. This review focuses on the critical involvement of these lipids in autophagy and lipophagy, providing a comprehensive overview of the current understanding of their functions. Moreover, we delve into how abnormalities in autophagy, influenced by these lipids, contribute to the pathogenesis of various diseases. These include age-related conditions such as cardiovascular diseases, neurodegenerative disorders, type 2 diabetes, and certain cancers, as well as inflammatory and liver diseases, skeletal muscle pathologies and age-related macular degeneration (AMD). This review aims to highlight function of lipids and their potential as therapeutic targets in treating diverse human pathologies by elucidating the specific roles of phosphoinositides, sphingolipids, and oxysterols in autophagy.
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Affiliation(s)
- Michał Jarocki
- University Clinical Hospital, Wroclaw Medical University, Wroclaw, Poland
| | | | - Jolanta Saczko
- Department of Molecular and Cellular Biology, Faculty of Pharmacy, Wroclaw Medical University, Wroclaw, Poland
| | - Mounir Tarek
- Université de Lorraine, CNRS, LPCT, Nancy, France
| | - Julita Kulbacka
- Department of Molecular and Cellular Biology, Faculty of Pharmacy, Wroclaw Medical University, Wroclaw, Poland.
- Department of Immunology and Bioelectrochemistry, State Research Institute Centre for Innovative Medicine, Vilnius, Lithuania.
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Hajian H, Motallebi M, Akhavan Taheri M, Kheiripour N, Aghadavod E, Shahaboddin ME. The preventive effect of heat-killed Lactobacillus plantarum on male reproductive toxicity induced by cholestasis in rats. Food Chem Toxicol 2024:114571. [PMID: 38452966 DOI: 10.1016/j.fct.2024.114571] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2023] [Revised: 02/23/2024] [Accepted: 03/04/2024] [Indexed: 03/09/2024]
Abstract
This study investigated the preventive effect of heat-killed Lactobacillus plantarum (L. plantarum) on cholestasis-induced male reproductive toxicity in rats. Rats were divided into control normal, sham control, bile duct ligation (BDL) control, and BDL with heat-killed L. plantarum supplementation groups. The effects on sexual hormones, testicular and epididymal histology, sperm parameters, oxidative stress markers, and inflammatory gene expression were evaluated. Compared to the BDL control group, the BDL + heat-killed L. plantarum group showed higher levels of normal sperm, luteinizing hormone, testosterone, total antioxidant capacity, and catalase activity, indicating improved reproductive function. Conversely, markers of oxidative stress, such as total oxidative status, oxidative stress index, and carbonyl protein, were lower in the BDL + heat-killed L. plantarum group. The expression levels of inflammatory genes tumor necrosis factor-alpha and interleukin-6 were reduced, while interleukin-10 gene expression was increased in the BDL + heat-killed L. plantarum group. Histological evaluation confirmed the positive effects of heat-killed L. plantarum intervention on testicular parameters. In conclusion, heat-killed L. plantarum supplementation protects against cholestasis-induced male reproductive dysfunction in rats, as evidenced by improvements in hormonal balance, sperm quality, oxidative stress, and inflammation.
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Affiliation(s)
- Hajar Hajian
- Department of Clinical Biochemistry, Faculty of Medicine, Kashan University of Medical Sciences, Kashan, Iran
| | - Mitra Motallebi
- Department of Immunology and Microbiology, Faculty of Medicine, Kashan University of Medical Sciences, Kashan, Iran
| | - Maryam Akhavan Taheri
- Institute for Basic Sciences, Anatomical Sciences Research Center, Kashan University of Medical Sciences, Kashan, Iran
| | - Nejat Kheiripour
- Institute for Basic Sciences, Research Center for Biochemistry and Nutrition in Metabolic Diseases, Kashan University of Medical Sciences, Kashan, Iran
| | - Esmat Aghadavod
- Department of Clinical Biochemistry, Faculty of Medicine, Kashan University of Medical Sciences, Kashan, Iran
| | - Mohammad Esmaeil Shahaboddin
- Department of Clinical Biochemistry, Faculty of Medicine, Kashan University of Medical Sciences, Kashan, Iran; Institute for Basic Sciences, Research Center for Biochemistry and Nutrition in Metabolic Diseases, Kashan University of Medical Sciences, Kashan, Iran.
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7
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Nguyen TH, Nguyen TM, Ngoc DTM, You T, Park MK, Lee CH. Unraveling the Janus-Faced Role of Autophagy in Hepatocellular Carcinoma: Implications for Therapeutic Interventions. Int J Mol Sci 2023; 24:16255. [PMID: 38003445 PMCID: PMC10671265 DOI: 10.3390/ijms242216255] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2023] [Revised: 11/02/2023] [Accepted: 11/08/2023] [Indexed: 11/26/2023] Open
Abstract
This review aims to provide a comprehensive understanding of the molecular mechanisms underlying autophagy and mitophagy in hepatocellular carcinoma (HCC). Autophagy is an essential cellular process in maintaining cell homeostasis. Still, its dysregulation is associated with the development of liver diseases, including HCC, which is one of leading causes of cancer-related death worldwide. We focus on elucidating the dual role of autophagy in HCC, both in tumor initiation and progression, and highlighting the complex nature involved in the disease. In addition, we present a detailed analysis of a small subset of autophagy- and mitophagy-related molecules, revealing their specific functions during tumorigenesis and the progression of HCC cells. By understanding these mechanisms, we aim to provide valuable insights into potential therapeutic strategies to manipulate autophagy effectively. The goal is to improve the therapeutic response of liver cancer cells and overcome drug resistance, providing new avenues for improved treatment options for HCC patients. Overall, this review serves as a valuable resource for researchers and clinicians interested in the complex role of autophagy in HCC and its potential as a target for innovative therapies aimed to combat this devastating disease.
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Affiliation(s)
- Thi Ha Nguyen
- College of Pharmacy, Dongguk University, Seoul 04620, Republic of Korea
| | - Tuan Minh Nguyen
- College of Pharmacy, Dongguk University, Seoul 04620, Republic of Korea
| | | | - Taesik You
- College of Pharmacy, Dongguk University, Seoul 04620, Republic of Korea
| | - Mi Kyung Park
- Department of Cancer Biomedical Science, Graduate School of Cancer Science and Policy National Cance Center, Goyang 10408, Republic of Korea
- Department of Bio-Healthcare, Hwasung Medi-Science University, Hwaseong-si 18274, Republic of Korea
| | - Chang Hoon Lee
- College of Pharmacy, Dongguk University, Seoul 04620, Republic of Korea
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Qian H, Ding WX. SQSTM1/p62 and Hepatic Mallory-Denk Body Formation in Alcohol-Associated Liver Disease. THE AMERICAN JOURNAL OF PATHOLOGY 2023; 193:1415-1426. [PMID: 36906265 PMCID: PMC10642158 DOI: 10.1016/j.ajpath.2023.02.015] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/15/2022] [Revised: 02/14/2023] [Accepted: 02/24/2023] [Indexed: 03/12/2023]
Abstract
Sequestosome 1 (SQSTM1/p62; hereafter p62) is an autophagy receptor protein for selective autophagy primarily due to its direct interaction with the microtubule light chain 3 protein that specifically localizes on autophagosome membranes. As a result, impaired autophagy leads to the accumulation of p62. p62 is also a common component of many human liver disease-related cellular inclusion bodies, such as Mallory-Denk bodies, intracytoplasmic hyaline bodies, α1-antitrypsin aggregates, as well as p62 bodies and condensates. p62 also acts as an intracellular signaling hub, and it involves multiple signaling pathways, including nuclear factor erythroid 2-related factor 2, NF-κB, and the mechanistic target of rapamycin, which are critical for oxidative stress, inflammation, cell survival, metabolism, and liver tumorigenesis. This review discusses the recent insights of p62 in protein quality control, including the role of p62 in the formation and degradation of p62 stress granules and protein aggregates as well as regulation of multiple signaling pathways in the pathogenesis of alcohol-associated liver disease.
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Affiliation(s)
- Hui Qian
- Department of Pharmacology, Toxicology, and Therapeutics, The University of Kansas Medical Center, Kansas City, Kansas
| | - Wen-Xing Ding
- Department of Pharmacology, Toxicology, and Therapeutics, The University of Kansas Medical Center, Kansas City, Kansas; Department of Internal Medicine, The University of Kansas Medical Center, Kansas City, Kansas.
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Han W, Li H, Jiang H, Xu H, Lin Y, Chen J, Bi C, Liu Z. Progress in the mechanism of autophagy and traditional Chinese medicine herb involved in alcohol-related liver disease. PeerJ 2023; 11:e15977. [PMID: 37727691 PMCID: PMC10506582 DOI: 10.7717/peerj.15977] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2023] [Accepted: 08/07/2023] [Indexed: 09/21/2023] Open
Abstract
Alcohol-related liver disease (ALD) is chronic liver damage caused by long-term heavy drinking with, extremely complicated pathogenesis. The current studies speculated that excessive alcohol and its metabolites are the major causes of liver cell toxicity. Autophagy is evolutionarily conserved in eukaryotes and aggravates alcoholic liver damage, through various mechanisms, such as cellular oxidative stress, inflammation, mitochondrial damage and lipid metabolism disorders. Therefore, autophagy plays an critical role in the occurrence and development of ALD. Some studies have shown that traditional Chinese medicine extracts improve the histological characteristics of ALD, as reflected in the improvement of oxidative stress and lipid droplet clearance, which might be achieved by inducing autophagy. This article reviews the mechanisms of quercetin, baicalin, glycycoumarin, salvianolic acid A, resveratrol, ginsenoside rg1, and dihydromyricetin inducing autophagy and their participation in the inhibition of ALD. The regulation of autophagy in ALD by these traditional Chinese medicine extracts provides novel ideas for the treatment of the disease; however, its molecular mechanism needs to be elucidated further.
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Affiliation(s)
- Wenwen Han
- Department of Medical Laboratory, School of Medicine, Shaoxing University, Shaoxing, Zhejiang Province, China
- Department of Clinical Medicine, School of Medicine, Shaoxing University, Shaoxing, Zhejiang Province, China
| | - Haiyu Li
- Department of Medical Laboratory, School of Medicine, Shaoxing University, Shaoxing, Zhejiang Province, China
- Department of Clinical Medicine, School of Medicine, Shaoxing University, Shaoxing, Zhejiang Province, China
| | - Hanqi Jiang
- Department of Clinical Medicine, School of Medicine, Shaoxing University, Shaoxing, Zhejiang Province, China
| | - Hang Xu
- Department of Clinical Medicine, School of Medicine, Shaoxing University, Shaoxing, Zhejiang Province, China
| | - Yifeng Lin
- Department of Clinical Medicine, School of Medicine, Shaoxing University, Shaoxing, Zhejiang Province, China
| | - Jiahuan Chen
- Department of Medical Laboratory, School of Medicine, Shaoxing University, Shaoxing, Zhejiang Province, China
| | - Chenchen Bi
- Department of Clinical Medicine, School of Medicine, Shaoxing University, Shaoxing, Zhejiang Province, China
| | - Zheng Liu
- Department of Pharmacology, School of Medicine, Shaoxing University, Shaoxing, Zhejiang Province, China
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Li Y, Kong MW, Jiang N, Ye C, Yao XW, Zou XJ, Hu HM, Liu HT. Vine tea extract ameliorated acute liver injury by inhibiting hepatic autophagy and reversing abnormal bile acid metabolism. Heliyon 2023; 9:e20145. [PMID: 37809393 PMCID: PMC10559920 DOI: 10.1016/j.heliyon.2023.e20145] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2023] [Revised: 09/08/2023] [Accepted: 09/13/2023] [Indexed: 10/10/2023] Open
Abstract
Gut microbiota disturbance, autophagy dysregulation, and accumulation of hepatic bile acids (BAs) are essential features of liver injury. Therefore, regulating autophagy and BA metabolism are potential strategies for treating liver diseases. Vine tea has been seen beyond a pleasant tea in food science. Our previous study found that vine tea extract (VTE) intervention alleviated acute liver injury (ALI) by restoring gut microbiota dysbiosis. In this study, we aim to investigate the effect of VTE on carbon tetrachloride (CCl4)-induced hepatic autophagy and BA metabolism disorder in mice. The results showed that VTE effectively suppressed CCl4-induced liver fibrosis and hepatic autophagy. LC-MS/MS assay suggested that VTE affected fecal BA production by reducing the fecal BA levels and improving cholestasis in ALI mice. Besides, VTE inhibited BA synthesis, promoted BA transport in the liver, and enhanced BA reabsorption in the ileum through the farnesoid X receptor (FXR)-related signaling pathway. The hepatic expressions of Fxr and Abca1 were elevated by VTE. Finally, the depletion of gut microbiota in ALI mice had a negative impact on abnormal autophagy and BA metabolism. It was also noted that the administration of VTE did not provide any additional improvement in this regard. Overall, VTE ameliorated ALI by reversing hepatic autophagy and abnormal BA metabolism, and the beneficial effects of VTE on liver injury depended on the existence of gut microbiota.
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Affiliation(s)
- Ying Li
- College of Basic Medical Sciences, Hubei University of Chinese Medicine, Huangjiahu West Road 16, Wuhan 430065, PR China
| | - Ming-Wang Kong
- College of Basic Medical Sciences, Hubei University of Chinese Medicine, Huangjiahu West Road 16, Wuhan 430065, PR China
| | - Nan Jiang
- Hubei Provincial Hospital of Traditional Chinese Medicine, Wuhan 430061, PR China
- Hubei Province Academy of Traditional Chinese Medicine, Wuhan 430074, PR China
| | - Chen Ye
- Wuhan Customs Technology Center, Qintai Avenue 588, Wuhan 430050, PR China
| | - Xiao-Wei Yao
- College of Basic Medical Sciences, Hubei University of Chinese Medicine, Huangjiahu West Road 16, Wuhan 430065, PR China
| | - Xiao-Juan Zou
- College of Basic Medical Sciences, Hubei University of Chinese Medicine, Huangjiahu West Road 16, Wuhan 430065, PR China
| | - Hai-Ming Hu
- School of Laboratory Medicine, Hubei University of Chinese Medicine, Huangjiahu West Road 16, Wuhan 430065, PR China
| | - Hong-Tao Liu
- College of Basic Medical Sciences, Hubei University of Chinese Medicine, Huangjiahu West Road 16, Wuhan 430065, PR China
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Salete-Granado D, Carbonell C, Puertas-Miranda D, Vega-Rodríguez VJ, García-Macia M, Herrero AB, Marcos M. Autophagy, Oxidative Stress, and Alcoholic Liver Disease: A Systematic Review and Potential Clinical Applications. Antioxidants (Basel) 2023; 12:1425. [PMID: 37507963 PMCID: PMC10376811 DOI: 10.3390/antiox12071425] [Citation(s) in RCA: 28] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2023] [Revised: 07/06/2023] [Accepted: 07/12/2023] [Indexed: 07/30/2023] Open
Abstract
Ethanol consumption triggers oxidative stress by generating reactive oxygen species (ROS) through its metabolites. This process leads to steatosis and liver inflammation, which are critical for the development of alcoholic liver disease (ALD). Autophagy is a regulated dynamic process that sequesters damaged and excess cytoplasmic organelles for lysosomal degradation and may counteract the harmful effects of ROS-induced oxidative stress. These effects include hepatotoxicity, mitochondrial damage, steatosis, endoplasmic reticulum stress, inflammation, and iron overload. In liver diseases, particularly ALD, macroautophagy has been implicated as a protective mechanism in hepatocytes, although it does not appear to play the same role in stellate cells. Beyond the liver, autophagy may also mitigate the harmful effects of alcohol on other organs, thereby providing an additional layer of protection against ALD. This protective potential is further supported by studies showing that drugs that interact with autophagy, such as rapamycin, can prevent ALD development in animal models. This systematic review presents a comprehensive analysis of the literature, focusing on the role of autophagy in oxidative stress regulation, its involvement in organ-organ crosstalk relevant to ALD, and the potential of autophagy-targeting therapeutic strategies.
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Affiliation(s)
- Daniel Salete-Granado
- Instituto de Investigación Biomédica de Salamanca (IBSAL), 37007 Salamanca, Spain; (D.S.-G.); (C.C.); (D.P.-M.); (V.-J.V.-R.); (M.G.-M.); (A.B.H.)
| | - Cristina Carbonell
- Instituto de Investigación Biomédica de Salamanca (IBSAL), 37007 Salamanca, Spain; (D.S.-G.); (C.C.); (D.P.-M.); (V.-J.V.-R.); (M.G.-M.); (A.B.H.)
- Hospital Universitario de Salamanca, 37007 Salamanca, Spain
- Unidad de Medicina Molecular, Departamento de Medicina, Universidad de Salamanca, 37007 Salamanca, Spain
| | - David Puertas-Miranda
- Instituto de Investigación Biomédica de Salamanca (IBSAL), 37007 Salamanca, Spain; (D.S.-G.); (C.C.); (D.P.-M.); (V.-J.V.-R.); (M.G.-M.); (A.B.H.)
- Hospital Universitario de Salamanca, 37007 Salamanca, Spain
| | - Víctor-José Vega-Rodríguez
- Instituto de Investigación Biomédica de Salamanca (IBSAL), 37007 Salamanca, Spain; (D.S.-G.); (C.C.); (D.P.-M.); (V.-J.V.-R.); (M.G.-M.); (A.B.H.)
- Hospital Universitario de Salamanca, 37007 Salamanca, Spain
| | - Marina García-Macia
- Instituto de Investigación Biomédica de Salamanca (IBSAL), 37007 Salamanca, Spain; (D.S.-G.); (C.C.); (D.P.-M.); (V.-J.V.-R.); (M.G.-M.); (A.B.H.)
- Instituto de Biología Funcional y Genómica (IBFG), Universidad de Salamanca, 37007 Salamanca, Spain
| | - Ana Belén Herrero
- Instituto de Investigación Biomédica de Salamanca (IBSAL), 37007 Salamanca, Spain; (D.S.-G.); (C.C.); (D.P.-M.); (V.-J.V.-R.); (M.G.-M.); (A.B.H.)
- Unidad de Medicina Molecular, Departamento de Medicina, Universidad de Salamanca, 37007 Salamanca, Spain
| | - Miguel Marcos
- Instituto de Investigación Biomédica de Salamanca (IBSAL), 37007 Salamanca, Spain; (D.S.-G.); (C.C.); (D.P.-M.); (V.-J.V.-R.); (M.G.-M.); (A.B.H.)
- Hospital Universitario de Salamanca, 37007 Salamanca, Spain
- Unidad de Medicina Molecular, Departamento de Medicina, Universidad de Salamanca, 37007 Salamanca, Spain
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12
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Wang Y, Li J, Wang S, Pang Y, Liu P, Xie B, Dou S, Yang T, Liu X, Shi Y, Chen D. The hepatitis B virus promotes the progression of non-alcoholic fatty liver disease through incomplete autophagy. Free Radic Biol Med 2023:S0891-5849(23)00436-7. [PMID: 37244371 DOI: 10.1016/j.freeradbiomed.2023.05.020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2023] [Revised: 05/09/2023] [Accepted: 05/18/2023] [Indexed: 05/29/2023]
Abstract
Hepatitis B virus (HBV) infection is still a serious public health problem. In recent years, with the increasing incidence of chronic hepatitis B (CHB) combined with nonalcoholic fatty liver disease (NAFLD), a more in-depth exploration of the pathogenesis of CHB combined with NAFLD is required. HBV can induce autophagy and use to increase replication. The removal of fat by autophagy, also known as lipophagy, is also currently considered an alternative pathway for lipid metabolism in liver cells. This degradation of autophagy prevents hepatotoxicity and steatosis. However, it is not known whether there is a correlation between HBV-related autophagy and the progression of NAFLD. We explored how HBV affects disease progression in NAFLD should be " and determined whether it is associated with HBV-associated autophagy. In this study, we constructed HBV-TG mouse high-fat diet (HFD) models and controls, and the results showed that the presence of HBV promoted the occurrence of NAFLD. We also demonstrated that HBV promotes lipid droplet accumulation in hepatocytes using HBV-stable expression cell lines HepG2.2.15 and AML12-HBV. In addition, this study also found that exogenous OA supplementation reduced HBV replication. We further studied the mechanism and found that HBV-related autophagy can promote the absorption of liver cells to lipid droplets. It can reduce the decomposition of lipid droplets by inhibiting the function of autophagolysosome, and eventually lead to the accumulation of lipid droplets in hepatocytes. In a word, HBV promotes the progression of NAFLD by increasing lipid accumulation in hepatocytes through incomplete autophagy.
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Affiliation(s)
- Yang Wang
- Beijing Institute of Hepatology, Beijing YouAn Hospital, Capital Medical University, Beijing, China
| | - Jiaxi Li
- Beijing Institute of Hepatology, Beijing YouAn Hospital, Capital Medical University, Beijing, China
| | - Shanshan Wang
- Beijing Institute of Hepatology, Beijing YouAn Hospital, Capital Medical University, Beijing, China
| | - Yuheng Pang
- Beijing Institute of Hepatology, Beijing YouAn Hospital, Capital Medical University, Beijing, China; Harbin Medical University Cancer Hospital, Harbin, China
| | - Pengxiang Liu
- Beijing Institute of Hepatology, Beijing YouAn Hospital, Capital Medical University, Beijing, China
| | - Bangxiang Xie
- Beijing Institute of Hepatology, Beijing YouAn Hospital, Capital Medical University, Beijing, China
| | - Shuangshuang Dou
- Beijing Institute of Hepatology, Beijing YouAn Hospital, Capital Medical University, Beijing, China
| | - Tongwang Yang
- Academician Workstation, Changsha Medical University, Changsha, China; Hunan Key Laboratory of the Research and Development of Novel Pharmaceutical Preparations, Changsha Medical University, Changsha, China
| | - Xiaoni Liu
- Beijing Institute of Hepatology, Beijing YouAn Hospital, Capital Medical University, Beijing, China
| | - Ying Shi
- Beijing Institute of Hepatology, Beijing YouAn Hospital, Capital Medical University, Beijing, China.
| | - Dexi Chen
- Beijing Institute of Hepatology, Beijing YouAn Hospital, Capital Medical University, Beijing, China.
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13
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Aryapour E, Kietzmann T. Mitochondria, mitophagy, and the role of deubiquitinases as novel therapeutic targets in liver pathology. J Cell Biochem 2022; 123:1634-1646. [PMID: 35924961 PMCID: PMC9804494 DOI: 10.1002/jcb.30312] [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: 06/28/2022] [Revised: 07/15/2022] [Accepted: 07/21/2022] [Indexed: 01/05/2023]
Abstract
Liver diseases such as nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), fibrosis, and hepatocellular carcinoma (HCC) have increased over the past few decades due to the absence or ineffective therapeutics. Recently, it has been shown that inappropriate regulation of hepatic mitophagy is linked to the pathogenesis of the above-mentioned liver diseases. As mitophagy maintains cellular homeostasis by removing damaged and nonfunctional mitochondria from the cell, the proper function of the molecules involved are of utmost importance. Thereby, mitochondrial E3 ubiquitin ligases as well as several deubiquitinases (DUBs) appear to play a unique role for the degradation of mitochondrial proteins and for proper execution of the mitophagy process by either adding or removing ubiquitin chains from target proteins. Therefore, these enzymes could be considered as valuable liver disease biomarkers and also as novel targets for therapy. In this review, we focus on the role of different DUBs on mitophagy and their contribution to NAFLD, NASH, alcohol-related liver disease, and especially HCC.
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Affiliation(s)
- Elham Aryapour
- Faculty of Biochemistry and Molecular Medicine, and Biocenter OuluUniversity of OuluOuluFinland
| | - Thomas Kietzmann
- Faculty of Biochemistry and Molecular Medicine, and Biocenter OuluUniversity of OuluOuluFinland
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14
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Chao X, Williams SN, Ding WX. Role of mechanistic target of rapamycin in autophagy and alcohol-associated liver disease. Am J Physiol Cell Physiol 2022; 323:C1100-C1111. [PMID: 36062877 PMCID: PMC9550572 DOI: 10.1152/ajpcell.00281.2022] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Revised: 08/26/2022] [Accepted: 08/26/2022] [Indexed: 11/22/2022]
Abstract
Mechanistic target of rapamycin (mTOR) is a serine-threonine kinase and a cellular sensor for nutrient and energy status, which is critical in regulating cell metabolism and growth by governing the anabolic (protein and lipid synthesis) and catabolic process (autophagy). Alcohol-associated liver disease (ALD) is a major chronic liver disease worldwide that carries a huge financial burden. The spectrum of the pathogenesis of ALD includes steatosis, fibrosis, inflammation, ductular reaction, and eventual hepatocellular carcinoma, which is closely associated with metabolic changes that are regulated by mTOR. In this review, we summarized recent progress of alcohol consumption on the changes of mTORC1 and mTORC2 activity, the potential mechanisms and possible impact of the mTORC1 changes on autophagy in ALD. We also discussed the potential beneficial effects and limitations of targeting mTORC1 against ALD.
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Affiliation(s)
- Xiaojuan Chao
- Department of Pharmacology, Toxicology and Therapeutics, The University of Kansas Medical Center, Kansas City, Kansas
| | - Sha Neisha Williams
- Department of Pharmacology, Toxicology and Therapeutics, The University of Kansas Medical Center, Kansas City, Kansas
| | - Wen-Xing Ding
- Department of Pharmacology, Toxicology and Therapeutics, The University of Kansas Medical Center, Kansas City, Kansas
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15
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Jie L, Hong RT, Zhang YJ, Sha LL, Chen W, Ren XF. Melatonin Alleviates Liver Fibrosis by Inhibiting Autophagy. Curr Med Sci 2022; 42:498-504. [PMID: 35583587 DOI: 10.1007/s11596-022-2530-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2020] [Accepted: 06/18/2021] [Indexed: 11/09/2022]
Abstract
OBJECTIVE Melatonin has been reported to suppress inflammation and alleviate liver fibrosis, but its effect on autophagy in liver fibrosis has not been studied. This study investigated the effect of melatonin on autophagy in an animal model of liver fibrosis and the hepatic stellate cell (HSC)-T6 cell line. METHODS The model was established in rats through carbon tetrachloride treatment, and melatonin was administered at three doses (2.5, 5.0, and 10.0 mg/kg). Haematoxylin and eosin staining and Van Gieson's staining were performed to examine the pathological changes of liver. The expression of alpha-smooth muscle actin (α-SMA) and Beclin1 in liver tissues was detected by immunohistochemical staining. The protein levels of α-SMA, Beclin1 and LC3 in the animal model were detected by Western blot analysis, and gene levels of Beclin1 and LC3 were detected by quantitative real-time PCR (qRT-PCR) in the animal model. HSC-T6 cells were activated by platelet-derived growth factor-BB (PDGF-BB). The expression of α-SMA, Beclin1 and collagen I was detected by Western blot analysis, and the gene expression of Beclin1 and LC3 was detected by qRT-PCR. RESULTS Melatonin reduced the expression of α-SMA, Beclin1 and LC3 in liver tissues. In addition, melatonin inhibited the activation of HSC-T6 cells and the expression of α-SMA, Beclin1 and LC3 in these cells. These results revealed that melatonin could inhibit autophagy and HSC activation. CONCLUSION Melatonin might ameliorate liver fibrosis by regulating autophagy, suggesting that melatonin is a potential therapeutic agent for liver fibrosis.
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Affiliation(s)
- Lei Jie
- Department of Gastroenterology, First Affiliated Hospital of Anhui Medical University, Key Laboratory of Digestive Disease of Anhui Province, Hefei, 230022, China
| | - Ru-Tao Hong
- Department of Gastroenterology, First Affiliated Hospital of Anhui Medical University, Key Laboratory of Digestive Disease of Anhui Province, Hefei, 230022, China.
| | - Yu-Jie Zhang
- Department of Gastroenterology, First Affiliated Hospital of Anhui Medical University, Key Laboratory of Digestive Disease of Anhui Province, Hefei, 230022, China
| | - Lu-Lin Sha
- Department of Critical Care Medicine of Cardiothoracic Surgery, First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China
| | - Wei Chen
- Department of Gastroenterology, First Affiliated Hospital of Anhui Medical University, Key Laboratory of Digestive Disease of Anhui Province, Hefei, 230022, China
| | - Xiao-Fei Ren
- Department of Gastroenterology, First Affiliated Hospital of Anhui Medical University, Key Laboratory of Digestive Disease of Anhui Province, Hefei, 230022, China
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16
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Zhang S, Peng X, Yang S, Li X, Huang M, Wei S, Liu J, He G, Zheng H, Yang L, Li H, Fan Q. The regulation, function, and role of lipophagy, a form of selective autophagy, in metabolic disorders. Cell Death Dis 2022; 13:132. [PMID: 35136038 PMCID: PMC8825858 DOI: 10.1038/s41419-022-04593-3] [Citation(s) in RCA: 131] [Impact Index Per Article: 43.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2021] [Revised: 01/07/2022] [Accepted: 01/27/2022] [Indexed: 12/15/2022]
Abstract
Autophagy is a conserved method of quality control in which cytoplasmic contents are degraded via lysosomes. Lipophagy, a form of selective autophagy and a novel type of lipid metabolism, has recently received much attention. Lipophagy is defined as the autophagic degradation of intracellular lipid droplets (LDs). Although much remains unknown, lipophagy appears to play a significant role in many organisms, cell types, metabolic states, and diseases. It participates in the regulation of intracellular lipid storage, intracellular free lipid levels (e.g., fatty acids), and energy balance. However, it remains unclear how intracellular lipids regulate autophagy. Impaired lipophagy can cause cells to become sensitive to death stimuli and may be responsible for the onset of a variety of diseases, including nonalcoholic fatty liver disease and metabolic syndrome. Like autophagy, the role of lipophagy in cancer is poorly understood, although analysis of specific autophagy receptors has helped to expand the diversity of chemotherapeutic targets. These studies have stimulated increasing interest in the role of lipophagy in the pathogenesis and treatment of cancer and other human diseases.
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Affiliation(s)
- Sheng Zhang
- Department of General Surgery, The Fourth Affiliated Hospital, China Medical University, Shenyang, 110032, China
| | - Xueqiang Peng
- Department of General Surgery, The Fourth Affiliated Hospital, China Medical University, Shenyang, 110032, China
| | - Shuo Yang
- Department of General Surgery, The Fourth Affiliated Hospital, China Medical University, Shenyang, 110032, China
| | - Xinyu Li
- Department of General Surgery, The Fourth Affiliated Hospital, China Medical University, Shenyang, 110032, China
| | - Mingyao Huang
- Department of General Surgery, The Fourth Affiliated Hospital, China Medical University, Shenyang, 110032, China
| | - Shibo Wei
- Department of General Surgery, The Fourth Affiliated Hospital, China Medical University, Shenyang, 110032, China
| | - Jiaxing Liu
- Department of General Surgery, The Fourth Affiliated Hospital, China Medical University, Shenyang, 110032, China
| | - Guangpeng He
- Department of General Surgery, The Fourth Affiliated Hospital, China Medical University, Shenyang, 110032, China
| | - Hongyu Zheng
- Department of General Surgery, The Fourth Affiliated Hospital, China Medical University, Shenyang, 110032, China
| | - Liang Yang
- Department of General Surgery, The Fourth Affiliated Hospital, China Medical University, Shenyang, 110032, China
| | - Hangyu Li
- Department of General Surgery, The Fourth Affiliated Hospital, China Medical University, Shenyang, 110032, China
| | - Qing Fan
- Department of General Surgery, The Fourth Affiliated Hospital, China Medical University, Shenyang, 110032, China.
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17
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Nieto-Torres JL, Hansen M. Macroautophagy and aging: The impact of cellular recycling on health and longevity. Mol Aspects Med 2021; 82:101020. [PMID: 34507801 PMCID: PMC8671213 DOI: 10.1016/j.mam.2021.101020] [Citation(s) in RCA: 51] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2021] [Revised: 08/11/2021] [Accepted: 08/31/2021] [Indexed: 02/08/2023]
Abstract
Aging is associated with many deleterious changes at the cellular level, including the accumulation of potentially toxic components that can have devastating effects on health. A key protective mechanism to this end is the cellular recycling process called autophagy. During autophagy, damaged or surplus cellular components are delivered to acidic vesicles called lysosomes, that secure degradation and recycling of the components. Numerous links between autophagy and aging exist. Autophagy declines with age, and increasing evidence suggests that this reduction plays important roles in both physiological aging and the development of age-associated disorders. Studies in pharmacologically and genetically manipulated model organisms indicate that defects in autophagy promote age-related diseases, and conversely, that enhancement of autophagy has beneficial effects on both healthspan and lifespan. Here, we review our current understanding of the role of autophagy in different physiological processes and their molecular links with aging and age-related diseases. We also highlight some recent advances in the field that could accelerate the development of autophagy-based therapeutic interventions.
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Affiliation(s)
- Jose L Nieto-Torres
- Sanford Burnham Prebys Medical Discovery Institute. Program of Development, Aging, and Regeneration, La Jolla, CA, USA
| | - Malene Hansen
- Sanford Burnham Prebys Medical Discovery Institute. Program of Development, Aging, and Regeneration, La Jolla, CA, USA.
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18
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Obydah WO, Shaker GA, Samir SM, El Bassiony SF, Abd El Moneim HA. Effect of vanillic acid and exercise training on fatty liver and insulin resistance in rats: Possible role of fibroblast growth factor 21 and autophagy. Physiol Int 2021; 108:412-426. [PMID: 34813496 DOI: 10.1556/2060.2021.00188] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2021] [Accepted: 10/22/2021] [Indexed: 01/01/2023]
Abstract
BACKGROUND AND AIMS The prevalence of non-alcoholic fatty liver disease has been alarmingly increased with no lines of effective treatment. Vanillic acid is a naturally occurring polyphenol with promising therapeutic effects. Exercise is well known to be an effective tool against obesity and its consequences. Thus, we aim to study the effect of vanillic acid alone and along with exercise on fatty liver induced by a high-fat diet in a rat model and to investigate possible novel mechanisms involved in their action. METHODS In this study, 40 male rats were divided equally into five groups: control (standard chow diet), HFD (high-fat diet), HFD+VA (HFD+ vanillic acid (50 mg/kg/day orally), HFD+EX (HFD+ swimming exercise 5 days/week), HFD+VA+EX (HFD+ vanillic acid+ swimming exercise) for eight weeks. RESULTS Body mass, liver weight, liver enzymes, cholesterol, and triglycerides were significantly decreased in the combined VA+EX group, with marked improvement in hyperglycemia, hyperinsulinemia, and consequently HOMA-IR index compared to the HFD group. These improvements were also reflected in the pathological view. VA and swimming, either solely or in combination, markedly increased hepatic and circulating fibroblast growth factor 21. Additionally, VA and swimming increased the immunohistochemical expression of the autophagosomal marker LC3 and decreased the expression of P62, which is selectively degraded during autophagy. CONCLUSIONS These results suggest the hepatoprotective effect of VA and swimming exercise against fatty liver and the involvement of FGF21 and autophagy in their effect.
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Affiliation(s)
- Walaa O Obydah
- Department of Medical Physiology, Faculty of Medicine, Mansoura University, Egypt
| | - Gehan A Shaker
- Department of Medical Physiology, Faculty of Medicine, Mansoura University, Egypt
| | - Shereen M Samir
- Department of Medical Physiology, Faculty of Medicine, Mansoura University, Egypt
| | - Soheir F El Bassiony
- Department of Medical Physiology, Faculty of Medicine, Mansoura University, Egypt
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19
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Wu LX, Xu YC, Hogstrand C, Zhao T, Wu K, Xu YH, Liu W, Luo Z. Lipophagy mediated glucose-induced changes of lipid deposition and metabolism via ROS dependent AKT-Beclin1 activation. J Nutr Biochem 2021; 100:108882. [PMID: 34655756 DOI: 10.1016/j.jnutbio.2021.108882] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2020] [Revised: 07/29/2021] [Accepted: 09/20/2021] [Indexed: 12/12/2022]
Abstract
High dietary carbohydrate intake leads to lipid accumulation in the intestinal tract, but the molecular mechanism remains unknown. In the present study, using yellow catfish (Pelteobagrus fulvidraco) as a model, we found that (1) high carbohydrate diets (HCD) and high glucose (HG) increased lipid deposition, up-regulated lipogenesis and fatty acid β-oxidation, activated autophagy and induced oxidative stress in the intestinal tissues and intestinal epithelial cells (IECs); (2) lipophagy alleviated HG-induced lipid accumulation via the up-regulation of fatty acid β-oxidation; (3) Akt interacted directly with Beclin1; (4) HG suppressed Akt1 phosphorylation, downregulated Akt1-mediated phosphorylation of Beclin1, activated lipophagy and alleviated the increment of TG deposition induced by HG with S87 and S292 being the key phosphorylation residues of Beclin1 in response to HG; (5) ROS generation mediated HG-induced activation of lipophagy and HG-induced suppression of AKT phosphorylation, activated AMPK and alleviated HG-induced increase of TG deposition. Our study provides mechanistic evidence that high carbohydrate- and glucose-induced lipophagy in intestine and IECs is associated with ROS-AKT-Beclin1-dependent activation of autophagy, which alleviates glucose-induced lipid accumulation. Our findings are important since the regulation of autophagy can be used as potential molecular targets for the prevention and treatment of lipotoxicity in the intestine of vertebrates, including humans.
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Affiliation(s)
- Li-Xiang Wu
- Key Laboratory of Freshwater Animal Breeding, Ministry of Agriculture, Fishery College, Huazhong Agricultural University, Wuhan, China
| | - Yi-Chuang Xu
- Key Laboratory of Freshwater Animal Breeding, Ministry of Agriculture, Fishery College, Huazhong Agricultural University, Wuhan, China
| | - Christer Hogstrand
- Diabetes and Nutritional Sciences Division, School of Medicine, King's College London, London, United Kingdom
| | - Tao Zhao
- Key Laboratory of Freshwater Animal Breeding, Ministry of Agriculture, Fishery College, Huazhong Agricultural University, Wuhan, China
| | - Kun Wu
- Key Laboratory of Freshwater Animal Breeding, Ministry of Agriculture, Fishery College, Huazhong Agricultural University, Wuhan, China
| | - Yi-Huan Xu
- Key Laboratory of Freshwater Animal Breeding, Ministry of Agriculture, Fishery College, Huazhong Agricultural University, Wuhan, China
| | - Wei Liu
- Laboratory of Fish Nutrition, Yangtze River Fisheries Research Institute, Chinese Academy of Fishery Sciences, Wuhan, China
| | - Zhi Luo
- Key Laboratory of Freshwater Animal Breeding, Ministry of Agriculture, Fishery College, Huazhong Agricultural University, Wuhan, China.
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20
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Chen C, Wang S, Yu L, Mueller J, Fortunato F, Rausch V, Mueller S. H 2O 2-mediated autophagy during ethanol metabolism. Redox Biol 2021; 46:102081. [PMID: 34343907 PMCID: PMC8350071 DOI: 10.1016/j.redox.2021.102081] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2021] [Revised: 07/15/2021] [Accepted: 07/22/2021] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Alcoholic liver disease (ALD) is the most common liver disease worldwide and its underlying molecular mechanisms are still poorly understood. Moreover, conflicting data have been reported on potentially protective autophagy, the exact role of ethanol-metabolizing enzymes and ROS. METHODS Expression of LC3B, CYP2E1, and NOX4 was studied in a mouse model of acute ethanol exposure by immunoblotting and immunohistochemistry. Autophagy was further studied in primary mouse hepatocytes and huh7 cells in response to ethanol and its major intermediator acetaldehyde. Experiments were carried out in cells overexpressing CYP2E1 and knock down of NOX4 using siRNA. The response to external H2O2 was studied by using the GOX/CAT system. Autophagic flux was monitored using the mRFP-GFP-LC3 plasmid, while rapamycin and chloroquine served as positive and negative controls. RESULTS Acute ethanol exposure of mice over 24 h significantly induced autophagy as measured by LC3B expression but also induced the ROS-generating CYP2E1 and NOX4 enzymes. Notably, ethanol but not its downstream metabolite acetaldehyde induced autophagy in primary mouse hepatocytes. In contrast, autophagy could only be induced in huh7 cells in the presence of overexpressed CYP2E1. In addition, overexpression of NOX4 also significantly increased autophagy, which could be blocked by siRNA mediated knock down. The antioxidant N-acetylcysteine (NAC) also efficiently blocked CYP2E1-and NOX4-mediated induction of autophagy. Finally, specific and non-toxic production of H2O2 by the GOX/CAT system as evidenced by elevated peroxiredoxin (Prx-2) also induced LC3B which was efficiently blocked by NAC. H2O2 strongly increased the autophagic flux as measured by mRFP-GFP-LC3 plasmid. CONCLUSION We here provide evidence that short-term ethanol exposure induces autophagy in hepatocytes both in vivo and in vitro through the generation of ROS. These data suggest that suppression of autophagy by ethanol is most likely due to longer alcohol exposure during chronic alcohol consumption with the accumulation of e.g. misfolded proteins.
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Affiliation(s)
- Cheng Chen
- Center for Alcohol Research and Salem Medical Center, University of Heidelberg, Heidelberg, Germany
| | - Shijin Wang
- Center for Alcohol Research and Salem Medical Center, University of Heidelberg, Heidelberg, Germany
| | - Linna Yu
- Center for Alcohol Research and Salem Medical Center, University of Heidelberg, Heidelberg, Germany
| | - Johannes Mueller
- Center for Alcohol Research and Salem Medical Center, University of Heidelberg, Heidelberg, Germany
| | - Franco Fortunato
- Department of Surgery, University of Heidelberg, Heidelberg, Germany
| | - Vanessa Rausch
- Center for Alcohol Research and Salem Medical Center, University of Heidelberg, Heidelberg, Germany
| | - Sebastian Mueller
- Center for Alcohol Research and Salem Medical Center, University of Heidelberg, Heidelberg, Germany.
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21
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Aman Y, Schmauck-Medina T, Hansen M, Morimoto RI, Simon AK, Bjedov I, Palikaras K, Simonsen A, Johansen T, Tavernarakis N, Rubinsztein DC, Partridge L, Kroemer G, Labbadia J, Fang EF. Autophagy in healthy aging and disease. NATURE AGING 2021; 1:634-650. [PMID: 34901876 PMCID: PMC8659158 DOI: 10.1038/s43587-021-00098-4] [Citation(s) in RCA: 723] [Impact Index Per Article: 180.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/16/2021] [Accepted: 07/07/2021] [Indexed: 12/12/2022]
Abstract
Autophagy is a fundamental cellular process that eliminates molecules and subcellular elements, including nucleic acids, proteins, lipids and organelles, via lysosome-mediated degradation to promote homeostasis, differentiation, development and survival. While autophagy is intimately linked to health, the intricate relationship among autophagy, aging and disease remains unclear. This Review examines several emerging features of autophagy and postulates how they may be linked to aging as well as to the development and progression of disease. In addition, we discuss current preclinical evidence arguing for the use of autophagy modulators as suppressors of age-related pathologies such as neurodegenerative diseases. Finally, we highlight key questions and propose novel research avenues that will likely reveal new links between autophagy and the hallmarks of aging. Understanding the precise interplay between autophagy and the risk of age-related pathologies across organisms will eventually facilitate the development of clinical applications that promote long-term health.
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Affiliation(s)
- Yahyah Aman
- Department of Clinical Molecular Biology, University of Oslo and Akershus University Hospital, Lørenskog, Norway
- Institute of Healthy Ageing, Department of Genetics, Evolution and Environment, University College London, London, UK
- These authors contributed equally: Yahyah Aman, Tomas Schmauck-Medina
| | - Tomas Schmauck-Medina
- Department of Clinical Molecular Biology, University of Oslo and Akershus University Hospital, Lørenskog, Norway
- These authors contributed equally: Yahyah Aman, Tomas Schmauck-Medina
| | - Malene Hansen
- Development, Aging and Regeneration Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA
| | - Richard I. Morimoto
- Department of Molecular Biosciences, Rice Institute for Biomedical Research, Northwestern University, Evanston, IL, USA
| | | | - Ivana Bjedov
- Institute of Healthy Ageing, Department of Genetics, Evolution and Environment, University College London, London, UK
- UCL Cancer Institute, University College London, London, UK
| | - Konstantinos Palikaras
- Department of Physiology, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - Anne Simonsen
- Department of Molecular Medicine, Institute of Basic Medical Sciences and Centre for Cancer Cell Reprogramming, Institute of Clinical Medicine, Faculty of Medicine, The University of Oslo, Oslo, Norway
- Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, Montebello, Oslo, Norway
| | - Terje Johansen
- Molecular Cancer Research Group, Institute of Medical Biology, University of Tromsø–The Arctic University of Norway, Tromsø, Norway
| | - Nektarios Tavernarakis
- Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology–Hellas, Heraklion, Greece
- Department of Basic Sciences, School of Medicine, University of Crete, Heraklion, Greece
| | - David C. Rubinsztein
- Department of Medical Genetics, Cambridge Institute for Medical Research, Cambridge, UK
- UK Dementia Research Institute, University of Cambridge, Cambridge, UK
| | - Linda Partridge
- Institute of Healthy Ageing, Department of Genetics, Evolution and Environment, University College London, London, UK
- Department of Biological Mechanisms of Ageing, Max Planck Institute for Biology of Ageing, Cologne, Germany
| | - Guido Kroemer
- Centre de Recherche des Cordeliers, Equipe Labellisée par la Ligue contre le Cancer, Université de Paris, Sorbonne Université, INSERM U1138, Institut Universitaire de France, Paris, France
- Metabolomics and Cell Biology Platforms, Gustave Roussy, Villejuif, France
- Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, Paris, France
- Suzhou Institute for Systems Medicine, Chinese Academy of Medical Sciences, Suzhou, China
- Karolinska Institute, Department of Women’s and Children’s Health, Karolinska University Hospital, Stockholm, Sweden
| | - John Labbadia
- Institute of Healthy Ageing, Department of Genetics, Evolution and Environment, University College London, London, UK
| | - Evandro F. Fang
- Department of Clinical Molecular Biology, University of Oslo and Akershus University Hospital, Lørenskog, Norway
- The Norwegian Centre on Healthy Ageing (NO-Age), Oslo, Norway
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22
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Qian H, Chao X, Williams J, Fulte S, Li T, Yang L, Ding WX. Autophagy in liver diseases: A review. Mol Aspects Med 2021; 82:100973. [PMID: 34120768 DOI: 10.1016/j.mam.2021.100973] [Citation(s) in RCA: 215] [Impact Index Per Article: 53.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2021] [Revised: 05/29/2021] [Accepted: 05/30/2021] [Indexed: 02/07/2023]
Abstract
The liver is a highly dynamic metabolic organ that plays critical roles in plasma protein synthesis, gluconeogenesis and glycogen storage, cholesterol metabolism and bile acid synthesis as well as drug/xenobiotic metabolism and detoxification. Research from the past decades indicate that autophagy, the cellular catabolic process mediated by lysosomes, plays an important role in maintaining cellular and metabolic homeostasis in the liver. Hepatic autophagy fluctuates with hormonal cues and the availability of nutrients that respond to fed and fasting states as well as circadian activities. Dysfunction of autophagy in liver parenchymal and non-parenchymal cells can lead to various liver diseases including non-alcoholic fatty liver diseases, alcohol associated liver disease, drug-induced liver injury, cholestasis, viral hepatitis and hepatocellular carcinoma. Therefore, targeting autophagy may be a potential strategy for treating these various liver diseases. In this review, we will discuss the current progress on the understanding of autophagy in liver physiology. We will also discuss several forms of selective autophagy in the liver and the molecular signaling pathways in regulating autophagy of different cell types and their implications in various liver diseases.
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Affiliation(s)
- Hui Qian
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Blvd., Kansas City, KS, 66160, USA
| | - Xiaojuan Chao
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Blvd., Kansas City, KS, 66160, USA
| | - Jessica Williams
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Blvd., Kansas City, KS, 66160, USA
| | - Sam Fulte
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Blvd., Kansas City, KS, 66160, USA
| | - Tiangang Li
- Harold Hamm Diabetes Center, Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA
| | - Ling Yang
- Department of Anatomy and Cell Biology, Fraternal Order of Eagles Diabetes Research Center, Pappajohn Biomedical Institute, University of Iowa Carver College of Medicine, Iowa City, IA, USA
| | - Wen-Xing Ding
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Blvd., Kansas City, KS, 66160, USA.
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23
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Ji W, Wan T, Zhang F, Zhu X, Guo S, Mei X. Aldehyde Dehydrogenase 2 Protects Against Lipopolysaccharide-Induced Myocardial Injury by Suppressing Mitophagy. Front Pharmacol 2021; 12:641058. [PMID: 34025411 PMCID: PMC8139555 DOI: 10.3389/fphar.2021.641058] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2020] [Accepted: 04/19/2021] [Indexed: 01/18/2023] Open
Abstract
Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. Sepsis-induced circulatory and cardiac dysfunction is associated with high mortality rates. Mitophagy, a specific form of autophagy, is excessively activated in lipopolysaccharide-induced myocardial injury. The present study investigated whether aldehyde dehydrogenase 2 (ALDH2) regulates mitophagy in sepsis-induced myocardial dysfunction. After lipopolysaccharide administration, cardiac dysfunction, inflammatory cell infiltration, biochemical indicators of myocardial cell injury, and cardiomyocyte apoptosis were ameliorated in mice by ALDH2 activation or overexpression. In contrast, cardiac dysfunction and cardiomyocyte apoptosis were exacerbated in mice followed ALDH2 inhibition. Moreover, ALDH2 activation or overexpression regulated mitophagy by suppressing the expression of phosphatase and tensin homolog-induced putative kinase 1 (PINK1)/Parkin, by preventing the accumulation of 4-hydroxy-trans-nonenal. Conversely, ALDH2 inhibition promoted the expression of LC3B by increasing 4-hydroxy-trans-2-nonenal accumulation. Consequently, ALDH2 may protect the heart from lipopolysaccharide-induced injury by suppressing PINK1/Parkin-dependent mitophagy.
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Affiliation(s)
- Wenqing Ji
- Emergency Medicine Clinical Research Center, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China.,Beijing Key Laboratory of Cardiopulmonary Cerebral Resuscitation, Beijing, China
| | - Tiantian Wan
- Emergency Medicine Clinical Research Center, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China.,Beijing Key Laboratory of Cardiopulmonary Cerebral Resuscitation, Beijing, China
| | - Fang Zhang
- Emergency Medicine Clinical Research Center, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China.,Beijing Key Laboratory of Cardiopulmonary Cerebral Resuscitation, Beijing, China
| | - Xiaomei Zhu
- Emergency Medicine Clinical Research Center, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China.,Beijing Key Laboratory of Cardiopulmonary Cerebral Resuscitation, Beijing, China
| | - Shubin Guo
- Emergency Medicine Clinical Research Center, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China.,Beijing Key Laboratory of Cardiopulmonary Cerebral Resuscitation, Beijing, China
| | - Xue Mei
- Emergency Medicine Clinical Research Center, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China.,Beijing Key Laboratory of Cardiopulmonary Cerebral Resuscitation, Beijing, China
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24
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Onishi M, Yamano K, Sato M, Matsuda N, Okamoto K. Molecular mechanisms and physiological functions of mitophagy. EMBO J 2021; 40:e104705. [PMID: 33438778 PMCID: PMC7849173 DOI: 10.15252/embj.2020104705] [Citation(s) in RCA: 813] [Impact Index Per Article: 203.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2020] [Revised: 08/03/2020] [Accepted: 10/02/2020] [Indexed: 12/12/2022] Open
Abstract
Degradation of mitochondria via a selective form of autophagy, named mitophagy, is a fundamental mechanism conserved from yeast to humans that regulates mitochondrial quality and quantity control. Mitophagy is promoted via specific mitochondrial outer membrane receptors, or ubiquitin molecules conjugated to proteins on the mitochondrial surface leading to the formation of autophagosomes surrounding mitochondria. Mitophagy-mediated elimination of mitochondria plays an important role in many processes including early embryonic development, cell differentiation, inflammation, and apoptosis. Recent advances in analyzing mitophagy in vivo also reveal high rates of steady-state mitochondrial turnover in diverse cell types, highlighting the intracellular housekeeping role of mitophagy. Defects in mitophagy are associated with various pathological conditions such as neurodegeneration, heart failure, cancer, and aging, further underscoring the biological relevance. Here, we review our current molecular understanding of mitophagy, and its physiological implications, and discuss how multiple mitophagy pathways coordinately modulate mitochondrial fitness and populations.
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Affiliation(s)
- Mashun Onishi
- Laboratory of Mitochondrial DynamicsGraduate School of Frontier BiosciencesOsaka UniversitySuitaJapan
| | - Koji Yamano
- The Ubiquitin ProjectTokyo Metropolitan Institute of Medical ScienceTokyoJapan
| | - Miyuki Sato
- Laboratory of Molecular Membrane BiologyInstitute for Molecular and Cellular RegulationGunma UniversityMaebashiJapan
| | - Noriyuki Matsuda
- The Ubiquitin ProjectTokyo Metropolitan Institute of Medical ScienceTokyoJapan
| | - Koji Okamoto
- Laboratory of Mitochondrial DynamicsGraduate School of Frontier BiosciencesOsaka UniversitySuitaJapan
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25
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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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26
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Li W, He P, Huang Y, Li YF, Lu J, Li M, Kurihara H, Luo Z, Meng T, Onishi M, Ma C, Jiang L, Hu Y, Gong Q, Zhu D, Xu Y, Liu R, Liu L, Yi C, Zhu Y, Ma N, Okamoto K, Xie Z, Liu J, He RR, Feng D. Selective autophagy of intracellular organelles: recent research advances. Theranostics 2021; 11:222-256. [PMID: 33391472 PMCID: PMC7681076 DOI: 10.7150/thno.49860] [Citation(s) in RCA: 292] [Impact Index Per Article: 73.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2020] [Accepted: 09/04/2020] [Indexed: 12/11/2022] Open
Abstract
Macroautophagy (hereafter called autophagy) is a highly conserved physiological process that degrades over-abundant or damaged organelles, large protein aggregates and invading pathogens via the lysosomal system (the vacuole in plants and yeast). Autophagy is generally induced by stress, such as oxygen-, energy- or amino acid-deprivation, irradiation, drugs, etc. In addition to non-selective bulk degradation, autophagy also occurs in a selective manner, recycling specific organelles, such as mitochondria, peroxisomes, ribosomes, endoplasmic reticulum (ER), lysosomes, nuclei, proteasomes and lipid droplets (LDs). This capability makes selective autophagy a major process in maintaining cellular homeostasis. The dysfunction of selective autophagy is implicated in neurodegenerative diseases (NDDs), tumorigenesis, metabolic disorders, heart failure, etc. Considering the importance of selective autophagy in cell biology, we systemically review the recent advances in our understanding of this process and its regulatory mechanisms. We emphasize the 'cargo-ligand-receptor' model in selective autophagy for specific organelles or cellular components in yeast and mammals, with a focus on mitophagy and ER-phagy, which are finely described as types of selective autophagy. Additionally, we highlight unanswered questions in the field, helping readers focus on the research blind spots that need to be broken.
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27
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Yuan F, Xu Y, You K, Zhang J, Yang F, Li YX. Calcitriol alleviates ethanol-induced hepatotoxicity via AMPK/mTOR-mediated autophagy. Arch Biochem Biophys 2020; 697:108694. [PMID: 33232716 DOI: 10.1016/j.abb.2020.108694] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2020] [Revised: 11/04/2020] [Accepted: 11/17/2020] [Indexed: 12/28/2022]
Abstract
Excessive ethanol consumption causes cellular damage, leading to fetal alcohol syndrome and alcohol liver diseases, which are frequently seen with vitamin D (VD) deficiency. A great deal of progress has been achieved in the mechanisms of ethanol-induced hepatocyte damage. However, there are limited intervention means to reduce or rescue hepatocytes damage caused by ethanol. On the basis of our preliminary limited screen process, calcitriol showed a positive effect on protecting hepatocyte viability. Therefore, the molecular basis is worth elucidating. We found that calcitriol pretreatment markedly improved the cell viability, decreased cell apoptosis and oxidative stress and alleviated the abnormal mitochondrial morphology and membrane potential of hepatocytes induced by ethanol. Notably, autophagy was significantly enhanced by calcitriol, as evident by the increasing number of autophagosomes and autolysosomes, upregulated LC3B-Ⅱ and ATG5 levels, and promotion of p62 degradation. Furthermore, calcitriol pretreatment increased the colocalization of GFP-LC3-labeled autophagosomes with mitochondria, suggesting that calcitriol effectively promoted ethanol-induced mitophagy in hepatocytes. In addition, the inhibition of autophagy attenuated the protective and preventive effect of calcitriol. Furthermore, the effect of calcitriol on autophagy was regulated by AMPK/mTOR signaling, and signaling transduction was dependent on the Vitamin D receptor (VDR). In conclusion, calcitriol ameliorates ethanol-induced hepatocyte damage by enhancing autophagy. It may offer a convenient preventive and hepatoprotective mean for people on occasional social drink.
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Affiliation(s)
- Fang Yuan
- School of Life Sciences, University of Science and Technology of China, 230027, Hefei, China; Institute of Public Health, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 510530, Guangzhou, China; Key Laboratory of Regenerative Biology, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 510530, Guangzhou, China; Guangdong Provincial Key Laboratory of Biocomputing, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 510530, Guangzhou, China
| | - Yingying Xu
- Institute of Public Health, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 510530, Guangzhou, China; Key Laboratory of Regenerative Biology, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 510530, Guangzhou, China; Guangdong Provincial Key Laboratory of Biocomputing, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 510530, Guangzhou, China
| | - Kai You
- Institute of Public Health, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 510530, Guangzhou, China; Key Laboratory of Regenerative Biology, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 510530, Guangzhou, China; Guangdong Provincial Key Laboratory of Biocomputing, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 510530, Guangzhou, China
| | - Jiaye Zhang
- Institute of Public Health, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 510530, Guangzhou, China; Key Laboratory of Regenerative Biology, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 510530, Guangzhou, China; Guangdong Provincial Key Laboratory of Biocomputing, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 510530, Guangzhou, China
| | - Fan Yang
- Institute of Public Health, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 510530, Guangzhou, China; Key Laboratory of Regenerative Biology, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 510530, Guangzhou, China; Guangdong Provincial Key Laboratory of Biocomputing, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 510530, Guangzhou, China
| | - Yin-Xiong Li
- Institute of Public Health, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 510530, Guangzhou, China; Key Laboratory of Regenerative Biology, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 510530, Guangzhou, China; Guangdong Provincial Key Laboratory of Biocomputing, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 510530, Guangzhou, China.
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28
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Ma X, McKeen T, Zhang J, Ding WX. Role and Mechanisms of Mitophagy in Liver Diseases. Cells 2020; 9:cells9040837. [PMID: 32244304 PMCID: PMC7226762 DOI: 10.3390/cells9040837] [Citation(s) in RCA: 169] [Impact Index Per Article: 33.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2020] [Revised: 03/23/2020] [Accepted: 03/28/2020] [Indexed: 12/12/2022] Open
Abstract
The mitochondrion is an organelle that plays a vital role in the regulation of hepatic cellular redox, lipid metabolism, and cell death. Mitochondrial dysfunction is associated with both acute and chronic liver diseases with emerging evidence indicating that mitophagy, a selective form of autophagy for damaged/excessive mitochondria, plays a key role in the liver’s physiology and pathophysiology. This review will focus on mitochondrial dynamics, mitophagy regulation, and their roles in various liver diseases (alcoholic liver disease, non-alcoholic fatty liver disease, drug-induced liver injury, hepatic ischemia-reperfusion injury, viral hepatitis, and cancer) with the hope that a better understanding of the molecular events and signaling pathways in mitophagy regulation will help identify promising targets for the future treatment of liver diseases.
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Affiliation(s)
- Xiaowen Ma
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Blvd., Kansas City, KS 66160, USA; (X.M.); (T.M.)
| | - Tara McKeen
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Blvd., Kansas City, KS 66160, USA; (X.M.); (T.M.)
| | - Jianhua Zhang
- Department of Pathology, Division of Molecular Cellular Pathology, University of Alabama at Birmingham, 901 19th street South, Birmingham, AL 35294, USA;
| | - Wen-Xing Ding
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Blvd., Kansas City, KS 66160, USA; (X.M.); (T.M.)
- Correspondence: ; Tel.: +1-913-588-9813
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29
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Ke PY. Mitophagy in the Pathogenesis of Liver Diseases. Cells 2020; 9:cells9040831. [PMID: 32235615 PMCID: PMC7226805 DOI: 10.3390/cells9040831] [Citation(s) in RCA: 63] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2020] [Revised: 03/25/2020] [Accepted: 03/27/2020] [Indexed: 02/07/2023] Open
Abstract
Autophagy is a catabolic process involving vacuolar sequestration of intracellular components and their targeting to lysosomes for degradation, thus supporting nutrient recycling and energy regeneration. Accumulating evidence indicates that in addition to being a bulk, nonselective degradation mechanism, autophagy may selectively eliminate damaged mitochondria to promote mitochondrial turnover, a process termed “mitophagy”. Mitophagy sequesters dysfunctional mitochondria via ubiquitination and cargo receptor recognition and has emerged as an important event in the regulation of liver physiology. Recent studies have shown that mitophagy may participate in the pathogenesis of various liver diseases, such as liver injury, liver steatosis/fatty liver disease, hepatocellular carcinoma, viral hepatitis, and hepatic fibrosis. This review summarizes the current knowledge on the molecular regulations and functions of mitophagy in liver physiology and the roles of mitophagy in the development of liver-related diseases. Furthermore, the therapeutic implications of targeting hepatic mitophagy to design a new strategy to cure liver diseases are discussed.
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Affiliation(s)
- Po-Yuan Ke
- Department of Biochemistry & Molecular Biology and Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan; ; Tel.: +886-3-211-8800 (ext. 5115); Fax: +886-3-211-8700
- Liver Research Center, Chang Gung Memorial Hospital, Taoyuan 33305, Taiwan
- Division of Allergy, Immunology, and Rheumatology, Chang Gung Memorial Hospital, Taoyuan 33305, Taiwan
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30
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Role of autophagy in alcohol and drug-induced liver injury. Food Chem Toxicol 2019; 136:111075. [PMID: 31877367 DOI: 10.1016/j.fct.2019.111075] [Citation(s) in RCA: 42] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2019] [Revised: 12/16/2019] [Accepted: 12/20/2019] [Indexed: 02/07/2023]
Abstract
Alcohol-related liver disease (ALD) and drug-induced liver injury (DILI) are common causes of severe liver disease, and successful treatments are lacking. Autophagy plays a protective role in both ALD and DILI by selectively removing damaged mitochondria (mitophagy), lipid droplets (lipophagy), protein aggregates and adducts in hepatocytes. Autophagy also protects against ALD by degrading interferon regulatory factor 1 (IRF1) and damaged mitochondria in hepatic macrophages. Specifically, we will discuss selective autophagy for removal of damaged mitochondria and lipid droplets in hepatocytes and autophagy-mediated degradation of IRF1 in hepatic macrophages as protective mechanisms against alcohol-induced liver injury and steatosis. In addition, selective autophagy for removal of damaged mitochondria and protein adducts for protection against DILI is discussed in this review. Development of new therapeutics for ALD and DILI is greatly needed, and selective autophagy pathways may provide promising targets. Drug and alcohol effects on autophagy regulation as well as protective mechanisms of autophagy against DILI and ALD are highlighted in this review.
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31
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Petrasek J, Erhartova D, Levine B. Protective Effect of SMAD-Specific E3 Ubiquitin Protein Ligase 1 in Alcoholic Steatohepatitis in Mice. Hepatol Commun 2019; 3:1450-1458. [PMID: 31701069 PMCID: PMC6824063 DOI: 10.1002/hep4.1427] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/19/2019] [Accepted: 08/26/2019] [Indexed: 12/11/2022] Open
Abstract
Excessive accumulation of lipids in the liver is crucial in the pathogenesis of alcoholic steatohepatitis and may be partly mediated by impaired degradation of lipid droplets by autophagy. The E3 ubiquitin ligase SMAD-specific E3 ubiquitin protein ligase 1 (SMURF1) regulates selective autophagy by ubiquitinating proteins on cargo destined for autophagic delivery to the lysosome for degradation. Here, we evaluated the role of SMURF1 in the regulation of hepatic lipid degradation in alcoholic steatohepatitis. In patients with severe alcoholic hepatitis, SMURF1 colocalized with lipid droplet membranes in liver explants. In a mouse model of alcoholic steatohepatitis, Smurf1 -/- mice fed an alcohol diet displayed increased hepatocyte accumulation of lipid droplets and triglycerides as well as more severe liver injury compared to wild-type mice. The increased severity of liver steatosis in alcohol-fed Smurf1 -/- mice was rescued by adeno-associated virus (AAV) serotype 8-mediated hepatic expression of wild-type Smurf1 protein but not by mutant Smurf1 proteins either lacking the catalytically active cysteine 699 required for ubiquitin transfer or the N-terminal C2 phospholipid membrane-binding domain. Conclusion: Smurf1 plays a protective role in the pathogenesis of alcoholic steatohepatitis through a mechanism that requires both its ubiquitin-ligase activity and C2 phospholipid-binding domains. These findings have implications for understanding the roles of ubiquitin ligases in fatty liver disease.
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Affiliation(s)
- Jan Petrasek
- Digestive and Liver Diseases Division and Center for Autophagy Research, Department of Internal MedicineUniversity of Texas Southwestern Medical CenterDallasTX
| | - Denisa Erhartova
- Institute for Clinical and Experimental MedicinePragueCzech Republic
| | - Beth Levine
- Howard Hughes Medical Institute and Center for Autophagy Research, Department of Internal MedicineUniversity of Texas Southwestern Medical CenterDallasTX
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32
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Chen Y, Park HJ, Park J, Song HC, Ryter SW, Surh YJ, Kim UH, Joe Y, Chung HT. Carbon monoxide ameliorates acetaminophen-induced liver injury by increasing hepatic HO-1 and Parkin expression. FASEB J 2019; 33:13905-13919. [PMID: 31645120 DOI: 10.1096/fj.201901258rr] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
Acetaminophen (APAP) is widely used as an antifebrile and analgesic drug at recommended doses, whereas an overdose of APAP can cause severe liver damage. The molecular mechanisms underlying APAP-induced liver damage remain incompletely understood. Carbon monoxide (CO), an end-product of heme oxygenase (HO)-1 activity, can confer anti-inflammatory and antiapoptotic properties in cellular models of toxicity via regulation of mitochondrial function. The objective of this study was to evaluate the effects of CO on APAP-induced hepatotoxicity and CO's relationship to regulation of endoplasmic reticulum (ER) stress and mitochondrial signaling using CO-releasing molecules or low concentrations of CO applied as pretreatment or posttreatment. Using genetic deletion or knockdown approaches in alpha mouse liver cells or primary hepatocytes, respectively, we investigated the role of HO-1 and the mitophagy regulator protein Parkin on APAP-induced expression of the ER stress-associated apoptosis regulator cytosine-cytosine-adenosine-adenosine-thymidine (CCAAT)/enhancer-binding protein homologous protein (CHOP). We found that CO induced Parkin expression in hepatocytes via the protein kinase RNA-like ER kinase/eukaryotic translation initiation factor 2-α/activating transcription factor-4 signaling pathway. Additionally, CO gas inhalation significantly alleviated APAP-induced liver damage in vivo and correspondingly reduced serum alanine aminotransferase and aspartate aminotransferase levels as well as proinflammatory cytokines and reduced the expression of CHOP in liver tissues while dramatically increasing hepatic HO-1 and Parkin expression. We found that the protective effects of CO on APAP-induced liver damage were mediated by down-regulation of CHOP at a transcriptional and post-translational level via induction of HO-1 and Parkin, respectively, and associated with decreases in reactive oxygen species production and JNK phosphorylation. We conclude that CO may represent a promising therapeutic agent for APAP-induced liver injury.-Chen, Y., Park, H.-J., Park, J., Song, H.-C., Ryter, S. W., Surh, Y.-J., Kim, U.-H., Joe, Y., Chung, H. T. Carbon monoxide ameliorates acetaminophen-induced liver injury by increasing hepatic HO-1 and Parkin expression.
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Affiliation(s)
- Yingqing Chen
- National Creative Research Laboratory for Ca2+ Signaling Network, Chonbuk National University Medical School, Jeonju, South Korea.,Department of Pharmacology, Dalian University Medical College, Dalian, China
| | - Hyeok-Jun Park
- Department of Biological Sciences, University of Ulsan, Ulsan, South Korea
| | - Jeongmin Park
- Department of Biological Sciences, University of Ulsan, Ulsan, South Korea
| | - Hyun-Chul Song
- Department of Biological Sciences, University of Ulsan, Ulsan, South Korea
| | - Stefan W Ryter
- Division of Pulmonary and Critical Care Medicine, Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medical Center, New York, New York, USA
| | - Young-Joon Surh
- Tumor Microenvironment Global Core Research Center and Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, South Korea
| | - Uh-Hyun Kim
- National Creative Research Laboratory for Ca Signaling Network, Chonbuk National University Medical School, Jeonju, South Korea
| | - Yeonsoo Joe
- Department of Biological Sciences, University of Ulsan, Ulsan, South Korea
| | - Hun Taeg Chung
- Department of Biological Sciences, University of Ulsan, Ulsan, South Korea
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33
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Yan S, Khambu B, Hong H, Liu G, Huda N, Yin XM. Autophagy, Metabolism, and Alcohol-Related Liver Disease: Novel Modulators and Functions. Int J Mol Sci 2019; 20:ijms20205029. [PMID: 31614437 PMCID: PMC6834312 DOI: 10.3390/ijms20205029] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2019] [Revised: 10/02/2019] [Accepted: 10/09/2019] [Indexed: 02/06/2023] Open
Abstract
Alcohol-related liver disease (ALD) is caused by over-consumption of alcohol. ALD can develop a spectrum of pathological changes in the liver, including steatosis, inflammation, cirrhosis, and complications. Autophagy is critical to maintain liver homeostasis, but dysfunction of autophagy has been observed in ALD. Generally, autophagy is considered to protect the liver from alcohol-induced injury and steatosis. In this review, we will summarize novel modulators of autophagy in hepatic metabolism and ALD, including autophagy-mediating non-coding RNAs (ncRNAs), and crosstalk of autophagy machinery and nuclear factors. We will also discuss novel functions of autophagy in hepatocytes and non-parenchymal hepatic cells during the pathogenesis of ALD and other liver diseases.
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Affiliation(s)
- Shengmin Yan
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
| | - Bilon Khambu
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
| | - Honghai Hong
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
| | - Gang Liu
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
| | - Nazmul Huda
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
| | - Xiao-Ming Yin
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
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Kounakis K, Chaniotakis M, Markaki M, Tavernarakis N. Emerging Roles of Lipophagy in Health and Disease. Front Cell Dev Biol 2019; 7:185. [PMID: 31552248 PMCID: PMC6746960 DOI: 10.3389/fcell.2019.00185] [Citation(s) in RCA: 94] [Impact Index Per Article: 15.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2019] [Accepted: 08/21/2019] [Indexed: 12/12/2022] Open
Abstract
The term lipophagy is used to describe the autophagic degradation of lipid droplets, the main lipid storage organelles of eukaryotic cells. Ever since its discovery in 2009, lipophagy has emerged as a significant component of lipid metabolism with important implications for organismal health. This review aims to provide a brief summary of our current knowledge on the mechanisms that are responsible for regulating lipophagy and the impact the process has under physiological and pathological conditions.
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Affiliation(s)
- Konstantinos Kounakis
- Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology - Hellas, Heraklion, Greece.,Department of Basic Sciences, Medical School, University of Crete, Heraklion, Greece
| | - Manos Chaniotakis
- Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology - Hellas, Heraklion, Greece.,Department of Chemistry, University of Crete, Heraklion, Greece
| | - Maria Markaki
- Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology - Hellas, Heraklion, Greece
| | - Nektarios Tavernarakis
- Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology - Hellas, Heraklion, Greece.,Department of Basic Sciences, Medical School, University of Crete, Heraklion, Greece
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Yan S, Zhou J, Chen X, Dong Z, Yin XM. Diverse Consequences in Liver Injury in Mice with Different Autophagy Functional Status Treated with Alcohol. THE AMERICAN JOURNAL OF PATHOLOGY 2019; 189:1744-1762. [PMID: 31199920 DOI: 10.1016/j.ajpath.2019.05.011] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/01/2019] [Revised: 05/01/2019] [Accepted: 05/07/2019] [Indexed: 02/07/2023]
Abstract
Alcoholic fatty liver disease is often complicated by other pathologic insults, such as viral infection or high-fat diet. Autophagy plays a homeostatic role in the liver but can be compromised by alcohol, high-fat diet, or viral infection, which in turn affects the disease process caused by these etiologies. To understand the full impact of autophagy modulation on alcohol-induced liver injury, several genetic models of autophagy deficiency, which have different levels of functional alterations, were examined after acute binge or chronic-plus-binge treatment. Mice given alcohol with either mode and induced with deficiency in liver-specific Atg7 shortly after the induction of Atg7 deletion had elevated liver injury, indicating the protective role of autophagy. Constitutive hepatic Atg7-deficient mice, in which Atg7 was deleted in embryos, were more susceptible with chronic-plus-binge but not with acute alcohol treatment. Constitutive hepatic Atg5-deficient mice, in which Atg5 was deleted in embryos, were more susceptible with acute alcohol treatment, but liver injury was unexpectedly improved with the chronic-plus-binge regimen. A prolonged autophagy deficiency may complicate the hepatic response to alcohol treatment, likely in part due to endogenous liver injury. The complexity of the relationship between autophagy deficiency and alcohol-induced liver injury can thus be affected by the timing of autophagy dysfunction, the exact autophagy gene being affected, and the alcohol treatment regimen.
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Affiliation(s)
- Shengmin Yan
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana
| | - Jun Zhou
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana; Department of Minimal Invasive Surgery, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Xiaoyun Chen
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana
| | - Zheng Dong
- Department of Nephrology, The Second Xiangya Hospital, Central South University, Changsha, China; Department of Cell Biology and Anatomy, Medical College of Georgia and Charlie Norwood Veterans Affairs Medical Center, Augusta, Georgia
| | - Xiao-Ming Yin
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana; Department of Nephrology, The Second Xiangya Hospital, Central South University, Changsha, China.
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Abstract
Autophagy is a self-eating catabolic pathway that contributes to liver homeostasis through its role in energy balance and in the quality control of the cytoplasm, by removing misfolded proteins, damaged organelles and lipid droplets. Autophagy not only regulates hepatocyte functions but also impacts on non-parenchymal cells, such as endothelial cells, macrophages and hepatic stellate cells. Deregulation of autophagy has been linked to many liver diseases and its modulation is now recognized as a potential new therapeutic strategy. Indeed, enhancing autophagy may prevent the progression of a number of liver diseases, including storage disorders (alpha-1 antitrypsin deficiency, Wilson's disease), acute liver injury, non-alcoholic steatohepatitis and chronic alcohol-related liver disease. Nevertheless, in some situations such as fibrosis, targeting specific liver cells must be considered, as autophagy displays opposing functions depending on the cell type. In addition, an optimal therapeutic time-window should be identified, since autophagy might be beneficial in the initial stages of disease, but detrimental at more advanced stages, as in the case of hepatocellular carcinoma. Finally, identifying biomarkers of autophagy and methods to monitor autophagic flux in vivo are important steps for the future development of personalized autophagy-targeting strategies. In this review, we provide an update on the regulatory role of autophagy in various aspects of liver pathophysiology, describing the different strategies to manipulate autophagy and discussing the potential to modulate autophagy as a therapeutic strategy in the context of liver diseases.
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Atef MM, Hafez YM, Alshenawy HA, Emam MN. Ameliorative effects of autophagy inducer, simvastatin on alcohol-induced liver disease in a rat model. J Cell Biochem 2019; 120:7679-7688. [PMID: 30417426 DOI: 10.1002/jcb.28042] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2018] [Accepted: 10/22/2018] [Indexed: 01/24/2023]
Abstract
Alcoholic liver disease (ALD) encompasses a variety of liver injuries with various underlying mechanisms but still no effective treatment. So we aimed to monitor the influence of simvastatin on alcohol-induced liver injury and elucidate the underlying mechanisms of its cytoprotective effect. Thirty male albino rats were randomly divided into five equal groups. Group 1 (control): received a standard diet; group 2: received simvastatin (10 mg kg-1 day -1 ) once a day orally for 8 weeks; group 3: received 20% ethanol (7.9 g kg -1 day -1 ) daily orally for 8 weeks; group 4: received 20% ethanol along with same simvastatin dose daily for 8 weeks; group 5: received 20% ethanol orally for 8 weeks then received the same simvastatin dose for the next 8 weeks. Serum alanine aminotransferase, aspartate aminotransferase, total cholesterol, triglycerides, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol were measured. Liver tissue malondialdehyde, reduced glutathione levels, and superoxide dismutase activity were estimated. B-cell lymphoma 2 and C/EBP homologous protein levels were evaluated by enzyme linked immunosorbent assay (ELISA). Light chain 3-II and peroxisome proliferation-activated receptor gamma messenger RNA expression was assessed by real-time polymerase chain reaction. Immunohistochemical staining was performed using anti-rat tumor necrosis factor-alpha antibody. Our results revealed that simvastatin treatment was able to ameliorate alcohol-induced liver damage; the improved biochemical data were confirmed by histopathological evaluation. Simvastatin being an autophagy inducer was able to prevent and reverse alcohol-induced liver changes via induction of autophagy, attenuation of oxidative stress, inflammation, and endoplasmic reticulum stress-induced apoptosis. Therefore, our findings suggest that treatment with simvastatin may be a useful approach in the management strategy of ALD.
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Affiliation(s)
- Marwa Mohamed Atef
- Medical Biochemistry Department, Faculty of Medicine, Tanta University, Tanta, Egypt
| | - Yasser Mostafa Hafez
- Internal Medicine Department, Faculty of Medicine, Tanta University, Tanta, Egypt
| | | | - Marwa Nagy Emam
- Physiology Department, Faculty of Medicine, Tanta University, Tanta, Egypt
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Ruart M, Chavarria L, Campreciós G, Suárez-Herrera N, Montironi C, Guixé-Muntet S, Bosch J, Friedman SL, Garcia-Pagán JC, Hernández-Gea V. Impaired endothelial autophagy promotes liver fibrosis by aggravating the oxidative stress response during acute liver injury. J Hepatol 2019; 70:458-469. [PMID: 30367898 PMCID: PMC6704477 DOI: 10.1016/j.jhep.2018.10.015] [Citation(s) in RCA: 203] [Impact Index Per Article: 33.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/23/2018] [Revised: 09/30/2018] [Accepted: 10/03/2018] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Endothelial dysfunction plays an essential role in liver injury, yet the phenotypic regulation of liver sinusoidal endothelial cells (LSECs) remains unknown. Autophagy is an endogenous protective system whose loss could undermine LSEC integrity and phenotype. The aim of our study was to investigate the role of autophagy in the regulation of endothelial dysfunction and the impact of its manipulation during liver injury. METHODS We analyzed primary isolated LSECs from Atg7control and Atg7endo mice as well as rats after CCl4 induced liver injury. Liver tissue and primary isolated stellate cells were used to analyze liver fibrosis. Autophagy flux, microvascular function, nitric oxide bioavailability, cellular superoxide content and the antioxidant response were evaluated in endothelial cells. RESULTS Autophagy maintains LSEC homeostasis and is rapidly upregulated during capillarization in vitro and in vivo. Pharmacological and genetic downregulation of endothelial autophagy increases oxidative stress in vitro. During liver injury in vivo, the selective loss of endothelial autophagy leads to cellular dysfunction and reduced intrahepatic nitric oxide. The loss of autophagy also impairs LSECs ability to handle oxidative stress and aggravates fibrosis. CONCLUSIONS Autophagy contributes to maintaining endothelial phenotype and protecting LSECs from oxidative stress during early phases of liver disease. Selectively potentiating autophagy in LSECs during early stages of liver disease may be an attractive approach to modify the disease course and prevent fibrosis progression. LAY SUMMARY Liver endothelial cells are the first liver cell type affected after any kind of liver injury. The loss of their unique phenotype during injury amplifies liver damage by orchestrating the response of the liver microenvironment. Autophagy is a mechanism involved in the regulation of this initial response and its manipulation can modify the progression of liver damage.
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Affiliation(s)
- Maria Ruart
- Barcelona Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clínic-Institut d'Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona, Spain
| | - Laia Chavarria
- Barcelona Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clínic-Institut d'Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona, Spain
| | - Genís Campreciós
- Barcelona Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clínic-Institut d'Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona, Spain; Centro de Investigación Biomédica Red de enfermedades hepáticas y digestivas, Spain
| | - Nuria Suárez-Herrera
- Barcelona Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clínic-Institut d'Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona, Spain
| | - Carla Montironi
- Pathology Department, Liver Cancer Translational Research Laboratory, BCLC Group, IDIBAPS, Liver Unit, Hospital Clinic, Spain
| | | | - Jaume Bosch
- Barcelona Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clínic-Institut d'Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona, Spain; Centro de Investigación Biomédica Red de enfermedades hepáticas y digestivas, Spain; Swiss Liver Centre, Inselspital, Bern University, CH, Switzerland
| | - Scott L Friedman
- Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, United States
| | - Juan Carlos Garcia-Pagán
- Barcelona Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clínic-Institut d'Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona, Spain; Centro de Investigación Biomédica Red de enfermedades hepáticas y digestivas, Spain
| | - Virginia Hernández-Gea
- Barcelona Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clínic-Institut d'Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona, Spain; Centro de Investigación Biomédica Red de enfermedades hepáticas y digestivas, Spain.
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Khambu B, Wang L, Zhang H, Yin XM. The Activation and Function of Autophagy in Alcoholic Liver Disease. Curr Mol Pharmacol 2019; 10:165-171. [PMID: 26278385 DOI: 10.2174/1874467208666150817112654] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2015] [Revised: 07/29/2015] [Accepted: 08/07/2015] [Indexed: 02/07/2023]
Abstract
Autophagy is an important lysosome-mediated intracellular degradation pathway required for tissue homeostasis. Dysregulation of liver autophagy is closely associated with different liver diseases including alcoholic liver disease. Studies now indicate that autophagy may be induced or suppressed depending on the amount and the duration of ethanol treatment. Autophagy induced by ethanol serves as a protective mechanism, probably by selective degradation of the damaged mitochondria (mitophagy) and excess lipid droplets (lipophagy) and in turn attenuates alcohol-induced steatosis and liver injury. However, the detailed molecular mechanism of selective targeting of mitochondria and lipid is still unclear. Autophagy may possess other functions that protect hepatocytes from ethanol. Understanding these molecular entities would be essential in order to therapeutically module autophagy for treatment of alcoholic liver disease.
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Affiliation(s)
- Bilon Khambu
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN 46202. United States
| | - Lin Wang
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN 46202. United States
| | - Hao Zhang
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN 46202. United States
| | - Xiao-Ming Yin
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN 46202. United States
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You M, Jogasuria A, Lee K, Wu J, Zhang Y, Lee YK, Sadana P. Signal Transduction Mechanisms of Alcoholic Fatty Liver Disease: Emer ging Role of Lipin-1. Curr Mol Pharmacol 2019; 10:226-236. [PMID: 26278388 DOI: 10.2174/1874467208666150817112109] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2015] [Revised: 08/07/2015] [Accepted: 08/07/2015] [Indexed: 02/06/2023]
Abstract
Lipin-1, a mammalian phosphatidic acid phosphatase (PAP), is a bi-functional molecule involved in various signaling pathways via its function as a PAP enzyme in the triglyceride synthesis pathway and in the nucleus as a transcriptional co-regulator. In the liver, lipin-1 is known to play a vital role in controlling the lipid metabolism and inflammation process at multiple regulatory levels. Alcoholic fatty liver disease (AFLD) is one of the earliest forms of liver injury and approximately 8-20% of patients with simple steatosis can develop into more severe forms of liver injury, including steatohepatitis, fibrosis/ cirrhosis, and eventually hepatocellular carcinoma (HCC). The signal transduction mechanisms for alcohol-induced detrimental effects in liver involves alteration of complex and multiple signaling pathways largely governed by a central and upstream signaling system, namely, sirtuin 1 (SIRT1)-AMP activated kinase (AMPK) axis. Emerging evidence suggests a pivotal role of lipin-1 as a crucial downstream regulator of SIRT1-AMPK signaling system that is likely to be ultimately responsible for development and progression of AFLD. Several lines of evidence demonstrate that ethanol exposure significantly induces lipin-1 gene and protein expression levels in cultured hepatocytes and in the livers of rodents, induces lipin-1-PAP activity, impairs the functional activity of nuclear lipin-1, disrupts lipin-1 mRNA alternative splicing and induces lipin-1 nucleocytoplasmic shuttling. Such impairment in response to ethanol leads to derangement of hepatic lipid metabolism, and excessive production of inflammatory cytokines in the livers of the rodents and human alcoholics. This review summarizes current knowledge about the role of lipin-1 in the pathogenesis of AFLD and its potential signal transduction mechanisms.
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Affiliation(s)
- Min You
- 4209 State Route 44, Rootstown OH 44272. United States
| | | | | | - Jiashin Wu
- Department of Pharmaceutical Sciences. 0
| | - Yanqiao Zhang
- Department of Integrative Medical Sciences, Northeast Ohio Medical University, College of Pharmacy and College of Medicine, Rootstown OH 44272. United States
| | - Yoon Kwang Lee
- Department of Integrative Medical Sciences, Northeast Ohio Medical University, College of Pharmacy and College of Medicine, Rootstown OH 44272. United States
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Chao X, Ding WX. Role and mechanisms of autophagy in alcohol-induced liver injury. ADVANCES IN PHARMACOLOGY (SAN DIEGO, CALIF.) 2019; 85:109-131. [PMID: 31307584 PMCID: PMC7141786 DOI: 10.1016/bs.apha.2019.01.008] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Alcoholic liver disease (ALD) is one of the major causes of chronic liver disease worldwide. Currently, no successful treatments are available for ALD. The pathogenesis of ALD is characterized as simple steatosis, fibrosis, cirrhosis, alcoholic hepatitis (AH), and eventually hepatocellular carcinoma (HCC). Autophagy is a highly conserved intracellular catabolic process, which aims at recycling cellular components and removing damaged organelles in response to starvation and stresses. Therefore, autophagy is considered as an important cellular adaptive and survival mechanism under various pathophysiological conditions. Recent studies from our lab and others suggest that chronic alcohol consumption may impair autophagy and contribute to the pathogenesis of ALD. In this chapter, we summarize recent progress on the role and mechanisms of autophagy in the development of ALD. Understanding the roles of autophagy in ALD may offer novel therapeutic avenues against ALD by targeting these pathways.
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Affiliation(s)
- Xiaojuan Chao
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS, United States
| | - Wen-Xing Ding
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS, United States.
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Abstract
Hepatic lipid metabolism is a series of complex processes that control influx and efflux of not only hepatic lipid pools, but also organismal pools. Lipid homeostasis is usually tightly controlled by expression, substrate supply, oxidation and secretion that keep hepatic lipid pools relatively constant. However, perturbations of any of these processes can lead to lipid accumulation in the liver. Although it is thought that these responses are hepatic arms of the 'thrifty genome', they are maladaptive in the context of chronic fatty liver diseases. Ethanol is likely unique among toxins, in that it perturbs almost all aspects of hepatic lipid metabolism. This complex response is due in part to the large metabolic demand placed on the organ by alcohol metabolism, but also appears to involve more nuanced changes in expression and substrate supply. The net effect is that steatosis is a rapid response to alcohol abuse. Although transient steatosis is largely an inert pathology, the chronicity of alcohol-related liver disease seems to require steatosis. Better and more specific understanding of the mechanisms by which alcohol causes steatosis may therefore translate into targeted therapies to treat alcohol-related liver disease and/or prevent its progression.
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Ke PY. Diverse Functions of Autophagy in Liver Physiology and Liver Diseases. Int J Mol Sci 2019; 20:E300. [PMID: 30642133 PMCID: PMC6358975 DOI: 10.3390/ijms20020300] [Citation(s) in RCA: 80] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2018] [Revised: 01/05/2019] [Accepted: 01/08/2019] [Indexed: 01/09/2023] Open
Abstract
Autophagy is a catabolic process by which eukaryotic cells eliminate cytosolic materials through vacuole-mediated sequestration and subsequent delivery to lysosomes for degradation, thus maintaining cellular homeostasis and the integrity of organelles. Autophagy has emerged as playing a critical role in the regulation of liver physiology and the balancing of liver metabolism. Conversely, numerous recent studies have indicated that autophagy may disease-dependently participate in the pathogenesis of liver diseases, such as liver hepatitis, steatosis, fibrosis, cirrhosis, and hepatocellular carcinoma. This review summarizes the current knowledge on the functions of autophagy in hepatic metabolism and the contribution of autophagy to the pathophysiology of liver-related diseases. Moreover, the impacts of autophagy modulation on the amelioration of the development and progression of liver diseases are also discussed.
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Affiliation(s)
- Po-Yuan Ke
- Department of Biochemistry & Molecular Biology and Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan.
- Liver Research Center, Chang Gung Memorial Hospital, Taoyuan 33305, Taiwan.
- Division of Allergy, Immunology, and Rheumatology, Chang Gung Memorial Hospital, Taoyuan 33305, Taiwan.
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Liu L, Xie P, Li W, Wu Y, An W. Augmenter of Liver Regeneration Protects against Ethanol-Induced Acute Liver Injury by Promoting Autophagy. THE AMERICAN JOURNAL OF PATHOLOGY 2018; 189:552-567. [PMID: 30553838 DOI: 10.1016/j.ajpath.2018.11.006] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/09/2018] [Revised: 11/02/2018] [Accepted: 11/13/2018] [Indexed: 02/07/2023]
Abstract
Alcoholic liver disease is associated with high morbidity and mortality, and treatment options are limited to date. Augmenter of liver regeneration (ALR) may protect against hepatic injury from chemical poisons, including ethanol. Autophagy appears to positively influence survival in cases of liver dysfunction, although the mechanisms are poorly understood. Herein, we investigated effects of ALR-induced autophagy in vitro and in vivo in an ethanol-induced model of acute liver injury. Decreased serum levels of alanine aminotransferase and aspartate aminotransferase and reduced histologic lesions revealed that mice overexpressing ALR experienced less liver damage than wild-type. ALR-knockdown mice experienced more severe liver damage than wild-type. ALR-transfected HepG2 cells showed increased survival rates, improved maintenance of mitochondrial membrane potential, and increased ATP levels after ethanol treatment. The observed protection was associated with up-regulation of autophagy-markers, including light chain 3II, beclin-1, and autophagy-related gene 5, and down-regulation of p62 by ALR. Autophagy was inhibited in ALR-knockdown mice and HepG2 cells, and autophagy inhibitor bafilomycin A1 attenuated the protective effects of ALR. Results showed phosphorylated mammalian target of rapamycin (mTOR) was down-regulated when ALR was overexpressed and up-regulated when ALR was knocked down. These data show that ALR is protective against ethanol-induced acute liver injury by promoting autophagy, probably via repressing the mTOR pathway. These results have potential implications for the clinical treatment of alcoholic liver disease patients.
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Affiliation(s)
- Limin Liu
- Department of Cell Biology, Capital Medical University and the Municipal Key Laboratory for Liver Protection and Regulation of Regeneration, Beijing, People's Republic of China
| | - Ping Xie
- Department of Cell Biology, Capital Medical University and the Municipal Key Laboratory for Liver Protection and Regulation of Regeneration, Beijing, People's Republic of China
| | - Wen Li
- Department of Cell Biology, Capital Medical University and the Municipal Key Laboratory for Liver Protection and Regulation of Regeneration, Beijing, People's Republic of China
| | - Yuan Wu
- Department of Cell Biology, Capital Medical University and the Municipal Key Laboratory for Liver Protection and Regulation of Regeneration, Beijing, People's Republic of China
| | - Wei An
- Department of Cell Biology, Capital Medical University and the Municipal Key Laboratory for Liver Protection and Regulation of Regeneration, Beijing, People's Republic of China.
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Zhao N, Guo FF, Xie KQ, Zeng T. Targeting Nrf-2 is a promising intervention approach for the prevention of ethanol-induced liver disease. Cell Mol Life Sci 2018; 75:3143-3157. [PMID: 29947925 PMCID: PMC11105722 DOI: 10.1007/s00018-018-2852-6] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2018] [Revised: 05/18/2018] [Accepted: 06/06/2018] [Indexed: 02/07/2023]
Abstract
Alcoholic liver disease (ALD) remains to be a worldwide health problem. It is generally accepted that oxidative stress plays critical roles in the pathogenesis of ALD, and antioxidant therapy represents a logical strategy for the prevention and treatment of ALD. Nuclear factor erythroid-derived 2-like 2 (NFE2L2 or Nrf-2) is essential for the antioxidant responsive element (ARE)-mediated induction of endogenous antioxidant enzymes such as heme oxygenase 1 (HO-1) and glutamate-cysteine ligase [GCL, the rate-limiting enzyme in the synthesis of glutathione (GSH)]. Activation of Nrf-2 pathway by genetic manipulation or pharmacological agents has been demonstrated to provide protection against ALD, which suggests that targeting Nrf-2 may be a promising approach for the prevention and treatment of ALD. Herein, we review the relevant literature about the potential hepatoprotective roles of Nrf-2 activation against ALD.
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Affiliation(s)
- Ning Zhao
- Institute of Toxicology, School of Public Health, Shandong University, 44 Wenhua West Road, Jinan, 250012, Shandong, China
| | - Fang-Fang Guo
- Department of Pharmacy, Qilu Hospital of Shandong University, 107 Wenhua West Road, Jinan, 250012, Shandong, China
| | - Ke-Qin Xie
- Institute of Toxicology, School of Public Health, Shandong University, 44 Wenhua West Road, Jinan, 250012, Shandong, China
| | - Tao Zeng
- Institute of Toxicology, School of Public Health, Shandong University, 44 Wenhua West Road, Jinan, 250012, Shandong, China.
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Sun Y, Zou H, Yang L, Zhou M, Shi X, Yang Y, Chen W, Zhao Y, Mo J, Lu Y. Effect on the liver cancer cell invasion ability by studying the associations between autophagy and TRAP1 expression. Oncol Lett 2018; 16:991-997. [PMID: 29963174 PMCID: PMC6019943 DOI: 10.3892/ol.2018.8774] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2017] [Accepted: 05/03/2018] [Indexed: 12/23/2022] Open
Abstract
Liver cancer is one of the leading causes of cancer associated mortality, particularly in eastern Asia. Autophagy serves an important role in carcinogenesis. Previous studies have reported that TRAP1 is a novel and efficient therapeutic target in various tumors. However, the associations between autophagy and TRAP1 is not clear. In the present study, autophagy activity and TRAP1 expression were examined in 4 different liver cancer cell lines (HepG2, Hep3B2.1–7, Sk-hep1 and HepG2.2.15) with or without rapamycin induction. The cell autophagy level was validated by monodansylcadaverine fluorescent staining, and the expression levels of Beclin1 and light chain (LC)-3-II/LC3-I. The mRNA and protein expression levels of tumor necrosis factor receptor-associated protein-1 (TRAP-1), Beclin1 and LC3-II/LC3-I were measured by reverse transcription-quantitative polymerase chain reaction, Protein Simple Western and western blot analysis. HepG2 cells, with medium invasive ability, exerted the highest basal level of autophagy and TRAP1 expression. In addition, hepatitis B (HBV) infection in HepG2 cells inhibited autophagy activity and TRAP1 expression. Rapamycin treatment also significantly enhanced autophagy in the 4 liver cancer cell lines and increased TRAP1 expression in HepG2, Hep3B2.1–7 and Sk-hep1 cells. Thus, the cell invasive ability, HBV infection and autophagy induction had different effects on TRAP1 expression, and TRAP1 may be associated with autophagy in liver cancer.
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Affiliation(s)
- Yi Sun
- Department of Toxicology, Guilin Medical University, Guilin, Guangxi 541004, P.R. China
| | - Hongling Zou
- Department of Oncology, Second Affiliated Hospital of Guilin Medical College, Guilin, Guangxi 541004, P.R. China
| | - Liu Yang
- Department of Toxicology, Guilin Medical University, Guilin, Guangxi 541004, P.R. China
| | - Mengting Zhou
- Department of Toxicology, Guilin Medical University, Guilin, Guangxi 541004, P.R. China
| | - Xiaoling Shi
- Department of Toxicology, Guilin Medical University, Guilin, Guangxi 541004, P.R. China
| | - Yarui Yang
- Laboratory of Molecular Biology, Shenzhen Nanshan Center for Chronic Disease Control, Shenzhen, Guangdong 518054, P.R. China
| | - Wenjun Chen
- Department of Toxicology, Guilin Medical University, Guilin, Guangxi 541004, P.R. China
| | - Yingqi Zhao
- Department of Toxicology, Guilin Medical University, Guilin, Guangxi 541004, P.R. China
| | - Jie Mo
- Department of Toxicology, Guilin Medical University, Guilin, Guangxi 541004, P.R. China
| | - Yuanming Lu
- Department of Toxicology, Guilin Medical University, Guilin, Guangxi 541004, P.R. China
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Hong T, Ge Z, Meng R, Wang H, Zhang P, Tang S, Lu J, Gu T, Zhu D, Bi Y. Erythropoietin alleviates hepatic steatosis by activating SIRT1-mediated autophagy. Biochim Biophys Acta Mol Cell Biol Lipids 2018. [PMID: 29522896 DOI: 10.1016/j.bbalip.2018.03.001] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Erythropoietin (EPO), besides its stimulatory effect on erythropoiesis, is beneficial to insulin resistance and obesity. However, its role in hepatic steatosis remains unexplored. Activating autophagy seems a promising mechanism for improving fatty liver disease. The present study investigated the role of EPO in alleviating hepatic steatosis and sought to determine whether its function is mediated by the activation of autophagy. Here, we show that EPO decreased hepatic lipid content significantly in vivo and in vitro. Furthermore, EPO/EPO receptor (EPOR) signalling induced autophagy activation in hepatocytes as indicated by western blot assay, transmission electron microscopy, and confocal microscopy. In addition, EPO increased the co-localization of autophagosomes and cellular lipids as shown by double labelling of the autophagy marker light chain microtubule-associated protein 3 (LC3) and lipids. Importantly, suppression of autophagy by an inhibitor or small interfering RNA (siRNA) abolished the EPO-mediated alleviation hepatic steatosis in vitro. Furthermore, EPO up-regulated sirtuin 1 (SIRT1) expression, and siRNA-mediated SIRT1 silencing abrogated the EPO-induced increases in LC3 protein and deacetylation levels, thereby preventing the alleviation of hepatic steatosis. Taken together, this study revealed a new mechanism wherein EPO alleviates hepatic steatosis by activating autophagy via SIRT1-dependent deacetylation of LC3. This finding might have therapeutic value in the treatment of hepatic steatosis.
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Affiliation(s)
- Ting Hong
- Department of Endocrinology, Drum Tower Hospital Affiliated to Nanjing University Medical School, No 321 Zhongshan Road, Nanjing, China
| | - Zhijuan Ge
- Department of Endocrinology, Drum Tower Hospital Affiliated to Nanjing University Medical School, No 321 Zhongshan Road, Nanjing, China
| | - Ran Meng
- Department of Endocrinology, Drum Tower Hospital Affiliated to Nanjing University Medical School, No 321 Zhongshan Road, Nanjing, China
| | - Hongdong Wang
- Department of Endocrinology, Drum Tower Hospital Affiliated to Nanjing University Medical School, No 321 Zhongshan Road, Nanjing, China
| | - Pengzi Zhang
- Department of Endocrinology, Drum Tower Hospital Affiliated to Nanjing University Medical School, No 321 Zhongshan Road, Nanjing, China
| | - Sunyinyan Tang
- Department of Endocrinology, Drum Tower Hospital Affiliated to Nanjing University Medical School, No 321 Zhongshan Road, Nanjing, China
| | - Jing Lu
- Department of Endocrinology, Drum Tower Hospital Affiliated to Nanjing University Medical School, No 321 Zhongshan Road, Nanjing, China
| | - Tianwei Gu
- Department of Endocrinology, Drum Tower Hospital Affiliated to Nanjing University Medical School, No 321 Zhongshan Road, Nanjing, China
| | - Dalong Zhu
- Department of Endocrinology, Drum Tower Hospital Affiliated to Nanjing University Medical School, No 321 Zhongshan Road, Nanjing, China.
| | - Yan Bi
- Department of Endocrinology, Drum Tower Hospital Affiliated to Nanjing University Medical School, No 321 Zhongshan Road, Nanjing, China.
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48
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Williams JA, Ding WX. Mechanisms, pathophysiological roles and methods for analyzing mitophagy - recent insights. Biol Chem 2018; 399:147-178. [PMID: 28976892 DOI: 10.1515/hsz-2017-0228] [Citation(s) in RCA: 67] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2017] [Accepted: 09/13/2017] [Indexed: 12/17/2022]
Abstract
In 2012, we briefly summarized the mechanisms, pathophysiological roles and methods for analyzing mitophagy. As then, the mitophagy field has continued to grow rapidly, and many new molecular mechanisms regulating mitophagy and molecular tools for monitoring mitophagy have been discovered and developed. Therefore, the purpose of this review is to update information regarding these advances in mitophagy while focusing on basic molecular mechanisms of mitophagy in different organisms and its pathophysiological roles. We also discuss the advantage and limitations of current methods to monitor and quantify mitophagy in cultured cells and in vivo mouse tissues.
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Affiliation(s)
- Jessica A Williams
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Blvd., Kansas City, KS 66160, USA
| | - Wen-Xing Ding
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA
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49
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Shi X, Sun R, Zhao Y, Fu R, Wang R, Zhao H, Wang Z, Tang F, Zhang N, Tian X, Yao J. Promotion of autophagosome–lysosome fusion via salvianolic acid A-mediated SIRT1 up-regulation ameliorates alcoholic liver disease. RSC Adv 2018; 8:20411-20422. [PMID: 35541657 PMCID: PMC9080827 DOI: 10.1039/c8ra00798e] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2018] [Accepted: 05/17/2018] [Indexed: 12/20/2022] Open
Abstract
Autophagosome and lysosome fusion was restored by salvianolic acid A-mediated SIRT1 up-regulation and protected against chronic ethanol-induced liver injury.
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50
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Zhang Z, Yao Z, Chen Y, Qian L, Jiang S, Zhou J, Shao J, Chen A, Zhang F, Zheng S. Lipophagy and liver disease: New perspectives to better understanding and therapy. Biomed Pharmacother 2017; 97:339-348. [PMID: 29091883 DOI: 10.1016/j.biopha.2017.07.168] [Citation(s) in RCA: 51] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2017] [Revised: 07/10/2017] [Accepted: 07/30/2017] [Indexed: 02/07/2023] Open
Abstract
Intracellular lipid droplets (LDs) are remarkably dynamic and complex organelles that enact regulated storage and release of lipids to fulfil their fundamental roles in energy metabolism, membrane synthesis and provision of lipid-derived signaling molecules. The recent finding that LDs can be selectively degraded by the lysosomal pathway of autophagy through a process termed lipophagy has opened up a new understanding of how lipid metabolism regulates cellular physiology and pathophysiology. Many new functions for autophagic lipid metabolism have now been defined in various diseases including liver disease. Lipophagy was originally described in hepatocytes, where it is critical for maintaining cellular energy homeostasis in obesity and metabolic syndrome. In vitro and in vivo studies have demonstrated the selective uptake of LDs by autophagosomes, and inhibition of autophagy has been shown to reduce the β-oxidation of free fatty acids due to the increased accumulation of lipids and LDs. The identification of lipophagy as a new process dedicated to cellular lipid removal has mapped autophagy as an emerging player in cellular lipid metabolism. Pharmacological or genetic modulation of lipophagy might point to possible therapeutic strategies for combating a broad range of liver diseases. This review summarizes recent work focusing on lipophagy and liver disease as well as highlighting challenges and future directions of research. On the other hand, it also offers a glimpse into different strategies that have been used in experimental models to counteract excessive pathological lipophagy in the prevention and treatment of liver disease.
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Affiliation(s)
- Zili Zhang
- Department of Pharmacology, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Zhen Yao
- Department of Pharmacology, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Yifan Chen
- Department of Pharmacology, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Lei Qian
- Department of Pharmacology, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Shuoyi Jiang
- Department of Pharmacology, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Jingyi Zhou
- Department of Pharmacology, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Jiangjuan Shao
- Department of Pharmacology, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Anping Chen
- Department of Pathology, School of Medicine, Saint Louis University, St Louis, MO 63104, USA
| | - Feng Zhang
- Department of Pharmacology, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China; Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China; Jiangsu Key Laboratory of Therapeutic Material of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Shizhong Zheng
- Department of Pharmacology, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China; Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China; Jiangsu Key Laboratory of Therapeutic Material of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China.
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