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Liu J, Deng L, Yao B, Zhang Y, Huang J, Huang S, Liang C, Shen Y, Wang X. Carboxylesterase 2A gene knockout or enzyme inhibition alleviates steatohepatitis in rats by regulating PPARγ and endoplasmic reticulum stress. Free Radic Biol Med 2025; 232:279-291. [PMID: 40089078 DOI: 10.1016/j.freeradbiomed.2025.03.021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2025] [Revised: 03/09/2025] [Accepted: 03/13/2025] [Indexed: 03/17/2025]
Abstract
Metabolic dysfunction associated steatotic liver disease (MASLD) is a widespread liver disease that progresses from simple steatosis to severe steatohepatitis stage. Despite the recognized importance of carboxylesterase 2 (CES2) in hepatic lipid metabolism, the role of CES2 in hepatic inflammation remains unclear. The rat genome encodes six Ces2 genes and Ces2a shows high expression in the liver and intestine. Lipid metabolism, inflammation, fibrosis, and endoplasmic reticulum (ER) stress were investigated in Ces2a knockout (KO) rats. KO rats showed spontaneous liver lipid accumulation due to increased lipogenesis and reduced fatty acid oxidation. Non-targeted lipidomic analysis revealed enhanced lysophosphatidylcholines (LPCs) and phosphatidylcholines (PCs) in KO rats and increased concentrations of ligands, thus activating the expression of PPARγ. Although there was simple lipid accumulation in the liver of KO rats, Ces2a deficiency showed a significant protective effect against LPS and diet-induced hepatic steatohepatitis by inhibiting ER stress regulated by PPARγ activation. In line with this, treatment with tanshinone IIA, a CES2 inhibitor, significantly alleviated the progression of steatohepatitis induced by the MCD diet. In conclusion, the increased PPARγ expression in Ces2a deficiency may counteract liver inflammation and ER stress despite the presence of simple steatosis. Therefore, CES2 inhibition represents a potential therapeutic approach for steatohepatitis.
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Affiliation(s)
- Jie Liu
- Changning Maternity and Infant Health Hospital and School of Life Sciences, Shanghai Key Laboratory of Regulatory Biology, East China Normal University, Shanghai, China
| | - Luyao Deng
- Changning Maternity and Infant Health Hospital and School of Life Sciences, Shanghai Key Laboratory of Regulatory Biology, East China Normal University, Shanghai, China
| | - Bingyi Yao
- Changning Maternity and Infant Health Hospital and School of Life Sciences, Shanghai Key Laboratory of Regulatory Biology, East China Normal University, Shanghai, China
| | - Yuanjin Zhang
- Changning Maternity and Infant Health Hospital and School of Life Sciences, Shanghai Key Laboratory of Regulatory Biology, East China Normal University, Shanghai, China
| | - Junze Huang
- Changning Maternity and Infant Health Hospital and School of Life Sciences, Shanghai Key Laboratory of Regulatory Biology, East China Normal University, Shanghai, China
| | - Shengbo Huang
- Changning Maternity and Infant Health Hospital and School of Life Sciences, Shanghai Key Laboratory of Regulatory Biology, East China Normal University, Shanghai, China
| | - Chenmeizi Liang
- Changning Maternity and Infant Health Hospital and School of Life Sciences, Shanghai Key Laboratory of Regulatory Biology, East China Normal University, Shanghai, China
| | - Yifei Shen
- Changning Maternity and Infant Health Hospital and School of Life Sciences, Shanghai Key Laboratory of Regulatory Biology, East China Normal University, Shanghai, China
| | - Xin Wang
- Changning Maternity and Infant Health Hospital and School of Life Sciences, Shanghai Key Laboratory of Regulatory Biology, East China Normal University, Shanghai, 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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Cao P, Chao X, Ni HM, Ding WX. An Update on Animal Models of Alcohol-Associated Liver Disease. THE AMERICAN JOURNAL OF PATHOLOGY 2025:S0002-9440(25)00032-X. [PMID: 39884572 DOI: 10.1016/j.ajpath.2024.11.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/05/2024] [Revised: 11/06/2024] [Accepted: 11/20/2024] [Indexed: 02/01/2025]
Abstract
Alcohol-associated liver disease (ALD) is a significant global health concern and a leading cause of liver disease-related deaths. However, the treatment options are limited due to the lack of animal models that accurately replicate ALD pathogenesis. An ideal ALD animal model should have pathological characteristics similar to those of human ALD, with a clear pathological process and ease of drug intervention. Over the years, researchers have focused on developing ideal ALD preclinical animal models by testing various methods, such as ad libitum drinking water with ethanol, acute, single large doses of ethanol gavage, multiple alcohol gavages in a short period, the Lieber-DeCarli liquid diet feeding model, the intragastric infusion model, and the Gao-binge model. With the increasing occurrence of obesity and metabolic dysfunction-associated steatotic liver disease, a new category of metabolic and alcohol-associated liver disease (MetALD) is also emerging. Studies have investigated the combined effects of a high-fat diet combined with binge alcohol or drinking water containing ethanol to mimic MetALD. In addition to mice, other species such as rats, guinea pigs, zebrafish, and non-human primates have also been tested to establish ALD preclinical models. This review aims to summarize current animal ALD models, particularly the emerging MetALD models, with the hope of providing a valuable reference for establishing more effective animal models in ALD studies in the future.
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Affiliation(s)
- Peng Cao
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas
| | - Xiaojuan Chao
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas
| | - Hong-Min Ni
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas
| | - Wen-Xing Ding
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas; Department of Internal Medicine, Division of Gastroenterology, Hepatology & Mobility, University of Kansas Medical Center, Kansas City, Kansas.
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Ma XZ, Jia GR, Li MY, Zhang SH, Wang ZX, Song N, Liu YJ, Xie JX. Elevated CXCL1 triggers dopaminergic neuronal loss in the substantia nigra of C57BL/6J mice: Evaluation of a novel Parkinsonian mouse model. Zool Res 2025; 46:225-235. [PMID: 39846198 PMCID: PMC11890994 DOI: 10.24272/j.issn.2095-8137.2024.228] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2024] [Accepted: 11/22/2024] [Indexed: 01/24/2025] Open
Abstract
Substantial evidence points to the early onset of peripheral inflammation in the development of Parkinson's disease (PD), supporting the "body-first" hypothesis. However, there remains a notable absence of PD-specific animal models induced by inflammatory cytokines. This study introduces a novel mouse model of PD driven by the proinflammatory cytokine CXCL1, identified in our previous research. The involvement of CXCL1 in PD pathogenesis was validated using subacute and chronic MPTP-induced mouse models. Based on these findings, 2-month-old C57BL/6J mice were intravenously administered CXCL1 (20 ng/kg/day) for 2 weeks (5 days per week), successfully replicating motor deficits and pathological alterations in the substantia nigra observed in the chronic MPTP model. These results demonstrate the potential of CXCL1-induced inflammation as a mechanism for PD modeling. The model revealed activation of the PPAR signaling pathway in CXCL1-mediated neuronal damage by CXCL1. Linoleic acid, a PPAR-γ activator, significantly mitigated MPTP- and CXCL1-induced toxicity and reduced serum CXCL1 levels. In addition, the CXCL1-injected mouse model shortened the timeline for developing chronic PD mouse model to 2 weeks, offering an efficient platform for studying inflammation-driven processes in PD. The findings provide critical insights into the inflammatory mechanisms underlying PD and identify promising therapeutic targets for intervention.
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Affiliation(s)
- Xi-Zhen Ma
- Institute of Brain Science and Disease, School of Basic Medicine, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders, Qingdao University, Qingdao, Shandong 266071, China
- College of Life Sciences and Health, University of Health and Rehabilitation Science, Qingdao, Shandong 266113, China
| | - Guo-Rui Jia
- Institute of Brain Science and Disease, School of Basic Medicine, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders, Qingdao University, Qingdao, Shandong 266071, China
| | - Meng-Yu Li
- Institute of Brain Science and Disease, School of Basic Medicine, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders, Qingdao University, Qingdao, Shandong 266071, China
| | - Sheng-Han Zhang
- Institute of Brain Science and Disease, School of Basic Medicine, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders, Qingdao University, Qingdao, Shandong 266071, China
| | - Zhao-Xin Wang
- Institute of Brain Science and Disease, School of Basic Medicine, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders, Qingdao University, Qingdao, Shandong 266071, China
| | - Ning Song
- Institute of Brain Science and Disease, School of Basic Medicine, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders, Qingdao University, Qingdao, Shandong 266071, China
| | - Ying-Juan Liu
- Institute of Brain Science and Disease, School of Basic Medicine, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders, Qingdao University, Qingdao, Shandong 266071, China. E-mail:
| | - Jun-Xia Xie
- Institute of Brain Science and Disease, School of Basic Medicine, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders, Qingdao University, Qingdao, Shandong 266071, China. E-mail:
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Feng D, Hwang S, Guillot A, Wang Y, Guan Y, Chen C, Maccioni L, Gao B. Inflammation in Alcohol-Associated Hepatitis: Pathogenesis and Therapeutic Targets. Cell Mol Gastroenterol Hepatol 2024; 18:101352. [PMID: 38697358 PMCID: PMC11234022 DOI: 10.1016/j.jcmgh.2024.04.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2024] [Revised: 04/25/2024] [Accepted: 04/25/2024] [Indexed: 05/05/2024]
Abstract
Alcohol-associated hepatitis (AH) is an acute-on-chronic liver injury that occurs in patients with chronic alcohol-associated liver disease (ALD). Patients with severe AH have high short-term mortality and lack effective pharmacologic therapies. Inflammation is believed to be one of the key factors promoting AH progression and has been actively investigated as therapeutic targets over the last several decades, but no effective inflammatory targets have been identified so far. In this review, we discuss how inflammatory cells and the inflammatory mediators produced by these cells contribute to the development and progression of AH, with focus on neutrophils and macrophages. The crosstalk between inflammatory cells and liver nonparenchymal cells in the pathogenesis of AH is elaborated. We also deliberate the application of recent cutting-edge technologies in characterizing liver inflammation in AH. Finally, the potential therapeutic targets of inflammatory mediators for AH are briefly summarized.
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Affiliation(s)
- Dechun Feng
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland.
| | - Seonghwan Hwang
- College of Pharmacy and Research Institute for Drug Development, Pusan National University, Busan, Republic of Korea
| | - Adrien Guillot
- Department of Hepatology and Gastroenterology, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Yang Wang
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland
| | - Yukun Guan
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland
| | - Cheng Chen
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland
| | - Luca Maccioni
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland
| | - Bin Gao
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland.
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da Silva SEB, da Silva Moura JA, Branco Júnior JF, de Moraes Gomes PAT, de Paula SKS, Viana DCF, de Freitas Ramalho EAV, de Melo Gomes JV, Pereira MC, da Rocha Pitta MG, da Rocha Pitta I, da Rocha Pitta MG. Synthesis and In vitro and In silico Anti-inflammatory Activity of New Thiazolidinedione-quinoline Derivatives. Curr Top Med Chem 2024; 24:1264-1277. [PMID: 38523516 DOI: 10.2174/0115680266295582240318060802] [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: 12/07/2023] [Revised: 02/22/2024] [Accepted: 02/29/2024] [Indexed: 03/26/2024]
Abstract
BACKGROUND Inflammation is a series of complex defense-related reactions. The inflammation cascade produces various pro-inflammatory mediators. Unregulated production of these pro-inflammatory mediators can lead to a wide range of diseases, including rheumatoid arthritis, sepsis, and inflammatory bowel disease. In the literature, the anti-inflammatory action of quinoline and thiazolidinedione nuclei are well established, alone, and associated with other nuclei. The synthesis of hybrid molecules is a strategy for obtaining more efficient molecules due to the union of pharmacophoric nuclei known to be related to pharmacological activity. OBJECTIVES Based on this, this work presents the synthesis of thiazolidinedione-quinoline molecular hybrids and their involvement in the modulation of cytokines involved in the inflammatory reaction cascade. METHODS After synthesis and characterization, the compounds were submitted to cell viability test (MTT), ELISA IFN-γ and TNF-α, adipogenic differentiation, and molecular docking assay with PPARy and COX-2 targets. RESULTS LPSF/ZKD2 and LPSF/ZKD7 showed a significant decrease in the concentration of IFN- γ and TNF-α, with a dose-dependent behavior. LPSF/ZKD4 at a concentration of 50 μM significantly reduced IL-6 expression. LPSF/ZKD4 demonstrates lipid accumulation with significant differences between the untreated and negative control groups, indicating a relevant agonist action on the PPARγ receptor. Molecular docking showed that all synthesized compounds have good affinity with PPARγ e COX-2, with binding energy close to -10,000 Kcal/mol. CONCLUSION These results demonstrate that the synthesis of quinoline-thiazolidinedione hybrids may be a useful strategy for obtaining promising candidates for new anti-inflammatory agents.
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Affiliation(s)
- Sandra Elizabeth Barbosa da Silva
- Federal University of Pernambuco, Laboratory of Design and Drug Synthesis - LPSF, Recife, PE, Brazil
- Federal University of Pernambuco, Keizo Asami Institute - iLIKA, Recife, PE, Brazil
| | - José Arion da Silva Moura
- Federal University of Pernambuco, Laboratory of Design and Drug Synthesis - LPSF, Recife, PE, Brazil
| | | | | | | | | | | | - João Victor de Melo Gomes
- Federal University of Pernambuco, Laboratory of Design and Drug Synthesis - LPSF, Recife, PE, Brazil
| | - Michelly Cristiny Pereira
- Federal University of Pernambuco, Laboratory of Design and Drug Synthesis - LPSF, Recife, PE, Brazil
- Federal University of Pernambuco, Laboratory of Immunomodulation and New Therapeutic Approaches - LINAT, Recife, PE, Brazil
| | | | - Ivan da Rocha Pitta
- Federal University of Pernambuco, Laboratory of Design and Drug Synthesis - LPSF, Recife, PE, Brazil
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Yang Z, Danzeng A, Liu Q, Zeng C, Xu L, Mo J, Pingcuo C, Wang X, Wang C, Zhang B, Zhang B. The Role of Nuclear Receptors in the Pathogenesis and Treatment of Non-alcoholic Fatty Liver Disease. Int J Biol Sci 2024; 20:113-126. [PMID: 38164174 PMCID: PMC10750283 DOI: 10.7150/ijbs.87305] [Citation(s) in RCA: 13] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2023] [Accepted: 09/21/2023] [Indexed: 01/03/2024] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a global health burden closely linked to insulin resistance, obesity, and type 2 diabetes. The complex pathophysiology of NAFLD involves multiple cellular pathways and molecular factors. Nuclear receptors (NRs) have emerged as crucial regulators of lipid metabolism and inflammation in NAFLD, offering potential therapeutic targets for NAFLD. Targeting PPARs and FXRs has shown promise in ameliorating NAFLD symptoms and halting disease progression. However, further investigation is needed to address side effects and personalize therapy approaches. This review summarizes the current understanding of the involvement of NRs in the pathogenesis of NAFLD and explores their therapeutic potential. We discuss the role of several NRs in modulating lipid homeostasis in the liver, including peroxisome proliferator-activated receptors (PPARs), liver X receptors (LXRs), farnesoid X receptors (FXRs), REV-ERB, hepatocyte nuclear factor 4α (HNF4α), constitutive androstane receptor (CAR) and pregnane X receptor (PXR).The expanding knowledge of NRs in NAFLD offers new avenues for targeted therapies, necessitating exploration of novel treatment strategies and optimization of existing approaches to combat this increasingly prevalent disease.
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Affiliation(s)
- Zhenhua Yang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
- Clinical Medicine Research Center for Hepatic Surgery of Hubei Province, Wuhan 430030, Hubei Province, China
| | - Awang Danzeng
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
- Clinical Medicine Research Center for Hepatic Surgery of Hubei Province, Wuhan 430030, Hubei Province, China
| | - Qiumeng Liu
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
- Clinical Medicine Research Center for Hepatic Surgery of Hubei Province, Wuhan 430030, Hubei Province, China
| | - Chenglong Zeng
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
- Clinical Medicine Research Center for Hepatic Surgery of Hubei Province, Wuhan 430030, Hubei Province, China
| | - Lei Xu
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
- Clinical Medicine Research Center for Hepatic Surgery of Hubei Province, Wuhan 430030, Hubei Province, China
| | - Jie Mo
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
- Clinical Medicine Research Center for Hepatic Surgery of Hubei Province, Wuhan 430030, Hubei Province, China
| | - Ciren Pingcuo
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
- Clinical Medicine Research Center for Hepatic Surgery of Hubei Province, Wuhan 430030, Hubei Province, China
| | - Xiaojing Wang
- Department and Institute of Infectious Disease, Tongji Hospital, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonostic Infectious Disease, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
| | - Chao Wang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
- Clinical Medicine Research Center for Hepatic Surgery of Hubei Province, Wuhan 430030, Hubei Province, China
| | - Bixiang Zhang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
- Clinical Medicine Research Center for Hepatic Surgery of Hubei Province, Wuhan 430030, Hubei Province, China
| | - Binhao Zhang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
- Clinical Medicine Research Center for Hepatic Surgery of Hubei Province, Wuhan 430030, Hubei Province, China
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Ran Y, Hu C, Wan J, Kang Q, Zhou R, Liu P, Ma D, Wang J, Tang L. Integrated investigation and experimental validation of PPARG as an oncogenic driver: implications for prognostic assessment and therapeutic targeting in hepatocellular carcinoma. Front Pharmacol 2023; 14:1298341. [PMID: 38044948 PMCID: PMC10690586 DOI: 10.3389/fphar.2023.1298341] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2023] [Accepted: 11/06/2023] [Indexed: 12/05/2023] Open
Abstract
Peroxisome proliferator-activated receptor gamma (PPARG), a key transcription factor involved in lipid metabolism and glucose homeostasis, has been implicated in various types of cancer. However, its precise role in cancer remains unclear. In this study, we conducted a comprehensive pan-cancer analysis of PPARG expression using various types of cancer obtained from public databases. We observed significant heterogeneity in PPARG expression across different types of cancer. The association between PPARG expression and patient prognosis was investigated using Cox proportional hazards regression models and survival analysis. Clinical features and protein expression levels in the cohort showed that PPARG expression was strongly associated, suggesting its potential as a therapeutic target. We also evaluated the prognostic potential of PPARG by analyzing immune infiltration and genomic stability. We experimentally validated the potential of PPARG as a therapeutic target by analyzing drug sensitivity profiles, molecular docking simulations, and in vitro cell proliferation assays associated with PPARG expression. We identified common expression patterns of PPARG with other genes involved in key carcinogenic pathways. This provides deeper insights into the molecular mechanisms underlying its carcinogenic role. Additionally, functional enrichment analysis revealed significant enrichment of genes related to drug metabolism, cell proliferation, and immune response pathways associated with PPARG. Our findings highlight the importance of PPARG in the broader biology of cancer and suggest its potential as a diagnostic and therapeutic target for specific types of cancer. The results of our study provide strong support for the potential role of PPARG as a promising prognostic biomarker and immunotherapeutic target across various types of cancer.
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Affiliation(s)
- Yunsheng Ran
- School of Pharmacy, Guizhou Medical University, Guiyang, China
- Guizhou Provincial Engineering Technology Research Center for Chemical Drug R&D, Guizhou Medical University, Guiyang, China
| | - Chujiao Hu
- Guizhou Provincial Engineering Technology Research Center for Chemical Drug R&D, Guizhou Medical University, Guiyang, China
- State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang, China
| | - Junzhao Wan
- School of Pharmacy, Guizhou Medical University, Guiyang, China
- Guizhou Provincial Engineering Technology Research Center for Chemical Drug R&D, Guizhou Medical University, Guiyang, China
| | - Qian Kang
- Department of Hematology, Affiliated Hospital of Guizhou Medical University, Guiyang, China
| | - Ruixian Zhou
- Department of Acupuncture and Moxibustion, Affiliated Hospital of Guizhou Medical University, Guiyang, China
| | - Ping Liu
- Department of Hematology, Affiliated Hospital of Guizhou Medical University, Guiyang, China
| | - Dan Ma
- Guizhou Provincial Engineering Technology Research Center for Chemical Drug R&D, Guizhou Medical University, Guiyang, China
- State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang, China
- Department of Hematology, Affiliated Hospital of Guizhou Medical University, Guiyang, China
| | - Jianta Wang
- Guizhou Provincial Engineering Technology Research Center for Chemical Drug R&D, Guizhou Medical University, Guiyang, China
- State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang, China
| | - Lei Tang
- Guizhou Provincial Engineering Technology Research Center for Chemical Drug R&D, Guizhou Medical University, Guiyang, China
- State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang, China
- Key Laboratory of Endemic and Ethnic Diseases, Ministry of Education and Key Laboratory of Medical Molecular Biology of Guizhou Province, Guizhou Medical University, Guiyang, Guizhou, China
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Malnassy G, Keating CR, Gad S, Bridgeman B, Perera A, Hou W, Cotler SJ, Ding X, Choudhry M, Sun Z, Koleske AJ, Qiu W. Inhibition of Abelson Tyrosine-Protein Kinase 2 Suppresses the Development of Alcohol-Associated Liver Disease by Decreasing PPARgamma Expression. Cell Mol Gastroenterol Hepatol 2023; 16:685-709. [PMID: 37460041 PMCID: PMC10520367 DOI: 10.1016/j.jcmgh.2023.07.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2023] [Revised: 07/11/2023] [Accepted: 07/12/2023] [Indexed: 08/07/2023]
Abstract
BACKGROUND & AIMS Alcohol-associated liver disease (ALD) represents a spectrum of alcohol use-related liver diseases. Outside of alcohol abstinence, there are currently no Food and Drug Administration-approved treatments for advanced ALD, necessitating a greater understanding of ALD pathogenesis and potential molecular targets for therapeutic intervention. The ABL-family proteins, including ABL1 and ABL2, are non-receptor tyrosine kinases that participate in a diverse set of cellular functions. We investigated the role of the ABL kinases in alcohol-associated liver disease. METHODS We used samples from patients with ALD compared with healthy controls to elucidate a clinical phenotype. We established strains of liver-specific Abl1 and Abl2 knockout mice and subjected them to the National Institute on Alcohol Abuse and Alcoholism acute-on-chronic alcohol feeding regimen. Murine samples were subjected to RNA sequencing, AST, Oil Red O staining, H&E staining, Western blotting, and quantitative polymerase chain reaction to assess phenotypic changes after alcohol feeding. In vitro modeling in HepG2 cells as well as primary hepatocytes from C57BL6/J mice was used to establish this mechanistic link of ALD pathogenesis. RESULTS We demonstrate that the ABL kinases are highly activated in ALD patient liver samples as well as in liver tissues from mice subjected to an alcohol feeding regimen. We found that the liver-specific knockout of Abl2, but not Abl1, attenuated alcohol-induced steatosis, liver injury, and inflammation. Subsequent RNA sequencing and gene set enrichment analyses of mouse liver tissues revealed that relative to wild-type alcohol-fed mice, Abl2 knockout alcohol-fed mice exhibited numerous pathway changes, including significantly decreased peroxisome proliferator activated receptor (PPAR) signaling. Further examination revealed that PPARγ, a previously identified regulator of ALD pathogenesis, was induced upon alcohol feeding in wild-type mice, but not in Abl2 knockout mice. In vitro analyses revealed that shRNA-mediated knockdown of ABL2 abolished the alcohol-induced accumulation of PPARγ as well as subsequent lipid accumulation. Conversely, forced overexpression of ABL2 resulted in increased PPARγ protein expression. Furthermore, we demonstrated that the regulation of hypoxia inducible factor 1 subunit alpha (HIF1α) by ABL2 is required for alcohol-induced PPARγ expression. Furthermore, treatment with ABL kinase inhibitors attenuated alcohol-induced PPARγ expression, lipid droplet formation, and liver injury. CONCLUSIONS On the basis of our current evidence, we propose that alcohol-induced ABL2 activation promotes ALD through increasing HIF1α and the subsequent PPARγ expression, and ABL2 inhibition may serve as a promising target for the treatment of ALD.
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Affiliation(s)
- Greg Malnassy
- Department of Surgery, Loyola University Chicago Stritch School of Medicine, Maywood, Illinois; Department of Cancer Biology, Loyola University Chicago Stritch School of Medicine, Maywood, Illinois
| | - Claudia R Keating
- Department of Surgery, Loyola University Chicago Stritch School of Medicine, Maywood, Illinois; Department of Cancer Biology, Loyola University Chicago Stritch School of Medicine, Maywood, Illinois
| | - Shaimaa Gad
- Department of Surgery, Loyola University Chicago Stritch School of Medicine, Maywood, Illinois; Department of Cancer Biology, Loyola University Chicago Stritch School of Medicine, Maywood, Illinois; Department of Pharmacology, Medical Research and Clinical Studies Institute, National Research Centre, Cairo, Egypt
| | - Bryan Bridgeman
- Department of Surgery, Loyola University Chicago Stritch School of Medicine, Maywood, Illinois; Department of Cancer Biology, Loyola University Chicago Stritch School of Medicine, Maywood, Illinois
| | - Aldeb Perera
- Department of Surgery, Loyola University Chicago Stritch School of Medicine, Maywood, Illinois; Department of Cancer Biology, Loyola University Chicago Stritch School of Medicine, Maywood, Illinois
| | - Wei Hou
- Department of Surgery, Loyola University Chicago Stritch School of Medicine, Maywood, Illinois; Department of Cancer Biology, Loyola University Chicago Stritch School of Medicine, Maywood, Illinois
| | - Scott J Cotler
- Department of Medicine, Loyola University Chicago Stritch School of Medicine, Maywood, Illinois
| | - Xianzhong Ding
- Department of Pathology, Loyola University Chicago Stritch School of Medicine, Maywood, Illinois
| | - Mashkoor Choudhry
- Department of Surgery, Loyola University Chicago Stritch School of Medicine, Maywood, Illinois
| | - Zhaoli Sun
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Anthony J Koleske
- Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, Connecticut
| | - Wei Qiu
- Department of Surgery, Loyola University Chicago Stritch School of Medicine, Maywood, Illinois; Department of Cancer Biology, Loyola University Chicago Stritch School of Medicine, Maywood, Illinois.
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10
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Lee SM, Muratalla J, Sierra-Cruz M, Cordoba-Chacon J. Role of hepatic peroxisome proliferator-activated receptor γ in non-alcoholic fatty liver disease. J Endocrinol 2023; 257:e220155. [PMID: 36688873 PMCID: PMC10048618 DOI: 10.1530/joe-22-0155] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2022] [Accepted: 01/23/2023] [Indexed: 01/24/2023]
Abstract
Peroxisome proliferator-activated receptor γ (PPARγ) belongs to a family of nuclear receptors that could serve as lipid sensors. PPARγ is the target of a group of insulin sensitizers called thiazolidinediones (TZDs) which regulate the expression of genes involved in glucose and lipid metabolism as well as adipokines that regulate metabolic function in other tissues. Non-alcoholic fatty liver disease (NAFLD) has a high prevalence worldwide and is even higher in patients with obesity and insulin resistance. TZD-mediated activation of PPARγ could serve as a good treatment for NAFLD because TZDs have shown anti-fibrogenic and anti-inflammatory effectsin vitro and increase insulin sensitivity in peripheral tissues which improves liver pathology. However, mechanistic studies in mouse models suggest that the activation of PPARγ in hepatocytes might reduce or limit the therapeutic potential of TZD against NAFLD. In this review, we briefly describe the short history of PPAR isoforms, the relevance of their expression in different tissues, as well as the pathogenesis and potential therapeutics for NAFLD. We also discuss some evidence derived from mouse models that could be useful for endocrinologists to assess tissue-specific roles of PPARs, complement reverse endocrinology approaches, and understand the direct role that PPARγ has in hepatocytes and non-parenchymal cells.
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Affiliation(s)
- Samuel M. Lee
- Department of Medicine. Division of Endocrinology, Diabetes and Metabolism. University of Illinois at Chicago, Chicago. IL
| | - Jose Muratalla
- Department of Medicine. Division of Endocrinology, Diabetes and Metabolism. University of Illinois at Chicago, Chicago. IL
| | - Marta Sierra-Cruz
- Department of Medicine. Division of Endocrinology, Diabetes and Metabolism. University of Illinois at Chicago, Chicago. IL
| | - Jose Cordoba-Chacon
- Department of Medicine. Division of Endocrinology, Diabetes and Metabolism. University of Illinois at Chicago, Chicago. IL
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11
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Afonso MB, Islam T, Magusto J, Amorim R, Lenoir V, Simões RF, Teixeira J, Silva LC, Wendum D, Jéru I, Vigouroux C, Castro RE, Oliveira PJ, Prip‐Buus C, Ratziu V, Gautheron J, Rodrigues CMP. RIPK3 dampens mitochondrial bioenergetics and lipid droplet dynamics in metabolic liver disease. Hepatology 2023; 77:1319-1334. [PMID: 36029129 PMCID: PMC10026966 DOI: 10.1002/hep.32756] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2022] [Revised: 08/16/2022] [Accepted: 08/17/2022] [Indexed: 12/15/2022]
Abstract
BACKGROUND AND AIMS Receptor-interacting protein kinase 3 (RIPK3) mediates NAFLD progression, but its metabolic function is unclear. Here, we aimed to investigate the role of RIPK3 in modulating mitochondria function, coupled with lipid droplet (LD) architecture in NAFLD. APPROACH AND RESULTS Functional studies evaluating mitochondria and LD biology were performed in wild-type (WT) and Ripk3-/- mice fed a choline-deficient, amino acid-defined (CDAA) diet for 32 and 66 weeks and in CRISPR-Cas9 Ripk3 -null fat-loaded immortalized hepatocytes. The association between hepatic perilipin (PLIN) 1 and 5, RIPK3, and disease severity was also addressed in a cohort of patients with NAFLD and in PLIN1 -associated familial partial lipodystrophy. Ripk3 deficiency rescued impairment in mitochondrial biogenesis, bioenergetics, and function in CDAA diet-fed mice and fat-loaded hepatocytes. Ripk3 deficiency was accompanied by a strong upregulation of antioxidant systems, leading to diminished oxidative stress upon fat loading both in vivo and in vitro. Strikingly, Ripk3-/- hepatocytes displayed smaller size LD in higher numbers than WT cells after incubation with free fatty acids. Ripk3 deficiency upregulated adipocyte and hepatic levels of LD-associated proteins PLIN1 and PLIN5. PLIN1 upregulation controlled LD structure and diminished mitochondrial stress upon free fatty acid overload in Ripk3-/- hepatocytes and was associated with diminished human NAFLD severity. Conversely, a pathogenic PLIN1 frameshift variant was associated with NAFLD and fibrosis, as well as with increased hepatic RIPK3 levels in familial partial lipodystrophy. CONCLUSIONS Ripk3 deficiency restores mitochondria bioenergetics and impacts LD dynamics. RIPK3 inhibition is promising in ameliorating NAFLD.
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Affiliation(s)
- Marta B. Afonso
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
| | - Tawhidul Islam
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
| | - Julie Magusto
- Institute of Cardiometabolism and Nutrition, Paris, France
- Sorbonne Université, Inserm, Centre de Recherche Saint‐Antoine, Paris, France
| | - Ricardo Amorim
- CNC ‐ Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal
| | - Véronique Lenoir
- Université de Paris, Institut Cochin, INSERM, CNRS, Paris, France
| | - Rui F. Simões
- CNC ‐ Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal
| | - José Teixeira
- CNC ‐ Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal
| | - Liana C. Silva
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
| | - Dominique Wendum
- Sorbonne Université, Inserm, Centre de Recherche Saint‐Antoine, Paris, France
- Service d'Anatomo‐Pathologie, Service d'Hépatologie, Centre de Référence Maladie Rare Maladies Inflammatoires des Voies Biliaires‐Hépatites Auto‐immunes, Paris, France
| | - Isabelle Jéru
- Institute of Cardiometabolism and Nutrition, Paris, France
- Sorbonne Université, Inserm, Centre de Recherche Saint‐Antoine, Paris, France
- Laboratoire commun de Biologie et Génétique Moléculaires, Hôpital Saint‐Antoine, Paris, France
| | - Corinne Vigouroux
- Institute of Cardiometabolism and Nutrition, Paris, France
- Sorbonne Université, Inserm, Centre de Recherche Saint‐Antoine, Paris, France
- Centre National de Référence des Pathologies Rares de l'Insulino‐Sécrétion et de l'Insulino‐Sensibilité, Service de Diabétologie et Endocrinologie de la Reproduction, Hôpital Saint‐Antoine, Paris, France
| | - Rui E. Castro
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
| | - Paulo J. Oliveira
- CNC ‐ Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal
| | - Carina Prip‐Buus
- Université de Paris, Institut Cochin, INSERM, CNRS, Paris, France
| | - Vlad Ratziu
- Institute of Cardiometabolism and Nutrition, Paris, France
- Department of Hepatology, Assistance Publique‐Hôpitaux de Paris, Pitié‐Salpêtrière Hospital, Paris, France
- Sorbonne Université, Inserm, Centre de Recherche des Cordeliers, and ICAN Institute of Cardiometabolism and Nutrition, Paris, France
| | - Jérémie Gautheron
- Institute of Cardiometabolism and Nutrition, Paris, France
- Sorbonne Université, Inserm, Centre de Recherche Saint‐Antoine, Paris, France
| | - Cecília M. P. Rodrigues
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
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Zuo RM, Jiao JY, Chen N, Jiang XL, Wu YL, Nan JX, Lian LH. Carnosic acid suppressed the formation of NETs in alcoholic hepatosteatosis based on P2X7R-NLRP3 axis. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2023; 110:154599. [PMID: 36577209 DOI: 10.1016/j.phymed.2022.154599] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/28/2022] [Revised: 11/24/2022] [Accepted: 12/10/2022] [Indexed: 06/17/2023]
Abstract
BACKGROUND Alcoholic liver disease (ALD) is accompanied by a disruption of lipid metabolism and an inflammatory response in the liver during the process of disease. Carnosic acid (CA), a natural diterpene extracted from Rosmarinus officinalis (rosemary) and Salvia officinalis (sage), has more pharmacological activities, which is known to be useful in the treatment of obesity and acts by regulating energy metabolism. However, the role and regulation mechanism of CA against ALD remain unclear. HYPOTHESIS We hypothesized that CA might improve alcoholic-induced hepatosteatosis. STUDY DESIGN AND METHODS The alcoholic liver disease model was established a mouse chronic ethanol feeding by Lieber-DeCarli control liquid feed (10 d) plus a single binge with or without CA administration. AML12 cells were exposed to ethanol for 24 h. Murine peritoneal macrophages (MPM) were stimulated with LPS and ATP. RESULTS CA ameliorated lipid accumulation in the liver of mice in the NIAAA model, acting by inhibiting the expression of genes related to lipid synthesis. CA reduced alcohol-induced immune cell infiltration in the liver, and inhibited the activation of P2X7R-NLRP3 inflammasome, meanwhile blocked the formation of NETs in mouse livers tissue. In AML12 cells, CA attenuated the lipid accumulation triggered by ethanol stimulation, which was achieved by inhibiting the expression of SREBP1 and CA reduced the release of inflammatory factor IL-1β by inhibiting the activation of P2X7R-NLRP3. In MPM, IL-1β and HMGB1 were reduced after LPS/ATP stimulation in CA-treated cells and supernatant. CONCLUSIONS CA attenuated alcohol-induced fat accumulation, suppressed the formation of NETs based on P2X7R-NLRP3 axis in mouse livers. Our data indicated that CA exerted hepatoprotective effects, which might be a promising candidate.
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Affiliation(s)
- Rong-Mei Zuo
- Key Laboratory of Traditional Chinese Korean Medicine Research (Yanbian University) of State Ethnic Affairs Commission, College of Pharmacy, Yanbian University, Yanji, Jilin 133002, China; Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, Jilin 133002, China
| | - Jing-Ya Jiao
- Key Laboratory of Traditional Chinese Korean Medicine Research (Yanbian University) of State Ethnic Affairs Commission, College of Pharmacy, Yanbian University, Yanji, Jilin 133002, China; Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, Jilin 133002, China
| | - Nan Chen
- Key Laboratory of Traditional Chinese Korean Medicine Research (Yanbian University) of State Ethnic Affairs Commission, College of Pharmacy, Yanbian University, Yanji, Jilin 133002, China; Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, Jilin 133002, China; Interdisciplinary of Biological Functional Molecules, College of Integration Science, Yanbian University, Yanji, Jilin 133002, China
| | - Xue-Li Jiang
- Key Laboratory of Traditional Chinese Korean Medicine Research (Yanbian University) of State Ethnic Affairs Commission, College of Pharmacy, Yanbian University, Yanji, Jilin 133002, China; Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, Jilin 133002, China
| | - Yan-Ling Wu
- Key Laboratory of Traditional Chinese Korean Medicine Research (Yanbian University) of State Ethnic Affairs Commission, College of Pharmacy, Yanbian University, Yanji, Jilin 133002, China; Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, Jilin 133002, China; Interdisciplinary of Biological Functional Molecules, College of Integration Science, Yanbian University, Yanji, Jilin 133002, China
| | - Ji-Xing Nan
- Key Laboratory of Traditional Chinese Korean Medicine Research (Yanbian University) of State Ethnic Affairs Commission, College of Pharmacy, Yanbian University, Yanji, Jilin 133002, China; Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, Jilin 133002, China; Interdisciplinary of Biological Functional Molecules, College of Integration Science, Yanbian University, Yanji, Jilin 133002, China.
| | - Li-Hua Lian
- Key Laboratory of Traditional Chinese Korean Medicine Research (Yanbian University) of State Ethnic Affairs Commission, College of Pharmacy, Yanbian University, Yanji, Jilin 133002, China; Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, Jilin 133002, China; Interdisciplinary of Biological Functional Molecules, College of Integration Science, Yanbian University, Yanji, Jilin 133002, China.
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13
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Lee SM, Muratalla J, Karimi S, Diaz-Ruiz A, Frutos MD, Guzman G, Ramos-Molina B, Cordoba-Chacon J. Hepatocyte PPARγ contributes to the progression of non-alcoholic steatohepatitis in male and female obese mice. Cell Mol Life Sci 2023; 80:39. [PMID: 36629912 PMCID: PMC10082675 DOI: 10.1007/s00018-022-04629-z] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2022] [Revised: 10/14/2022] [Accepted: 11/10/2022] [Indexed: 01/12/2023]
Abstract
Non-alcoholic steatohepatitis (NASH) is associated with obesity and increased expression of hepatic peroxisome proliferator-activated receptor γ (PPARγ). However, the relevance of hepatocyte PPARγ in NASH associated with obesity is still poorly understood. In this study, hepatocyte PPARγ was knocked out (PpargΔHep) in male and female mice after the development of high-fat diet-induced obesity. The diet-induced obese mice were then maintained on their original diet or switched to a high fat, cholesterol, and fructose (HFCF) diet to induce NASH. Hepatic PPARγ expression was mostly derived from hepatocytes and increased by high fat diets. PpargΔHep reduced HFCF-induced NASH progression without altering steatosis, reduced the expression of key genes involved in hepatic fibrosis in HFCF-fed male and female mice, and decreased the area of collagen-stained fibrosis in the liver of HFCF-fed male mice. Moreover, transcriptomic and metabolomic data suggested that HFCF-diet regulated hepatic amino acid metabolism in a hepatocyte PPARγ-dependent manner. PpargΔHep increased betaine-homocysteine s-methyltransferase expression and reduced homocysteine levels in HFCF-fed male mice. In addition, in a cohort of 102 obese patients undergoing bariatric surgery with liver biopsies, 16 cases were scored with NASH and were associated with increased insulin resistance and hepatic PPARγ expression. Our study shows that hepatocyte PPARγ expression is associated with NASH in mice and humans. In male mice, hepatocyte PPARγ negatively regulates methionine metabolism and contributes to the progression of fibrosis.
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Affiliation(s)
- Samuel M Lee
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Illinois at Chicago, 835 S. Wolcott Ave (North Entrance) Suite E625, M/C 640, Chicago, IL, USA
| | - Jose Muratalla
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Illinois at Chicago, 835 S. Wolcott Ave (North Entrance) Suite E625, M/C 640, Chicago, IL, USA
| | - Saman Karimi
- Department of Pathology, University of Illinois at Chicago, Chicago, IL, USA
| | | | - Maria Dolores Frutos
- Department of General and Digestive System Surgery, Virgen de La Arrixaca University Hospital, Murcia, Spain
| | - Grace Guzman
- Department of Pathology, University of Illinois at Chicago, Chicago, IL, USA
| | - Bruno Ramos-Molina
- Obesity and Metabolism Group, Biomedical Research Institute of Murcia (IMIB), Murcia, Spain
| | - Jose Cordoba-Chacon
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Illinois at Chicago, 835 S. Wolcott Ave (North Entrance) Suite E625, M/C 640, Chicago, IL, USA.
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14
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Ma Y, Bao Y, Wu L, Ke Y, Tan L, Ren H, Song J, Zhang Q, Jin Y. IL-8 exacerbates CCl4-induced liver fibrosis in human IL-8-expressing mice via the PI3K/Akt/HIF-1α pathway. Mol Immunol 2022; 152:111-122. [PMID: 36327908 DOI: 10.1016/j.molimm.2022.10.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2022] [Revised: 08/25/2022] [Accepted: 10/24/2022] [Indexed: 11/06/2022]
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Li XY, Ji PX, Ni XX, Chen YX, Sheng L, Lian M, Guo CJ, Hua J. Regulation of PPAR-γ activity in lipid-laden hepatocytes affects macrophage polarization and inflammation in nonalcoholic fatty liver disease. World J Hepatol 2022; 14:1365-1381. [PMID: 36158922 PMCID: PMC9376780 DOI: 10.4254/wjh.v14.i7.1365] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2022] [Revised: 05/09/2022] [Accepted: 06/26/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Lipid metabolism disorder and inflammatory-immune activation are vital triggers in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). Various studies have shown that PPAR-γ exerts potent anti-inflammatory and immunomodulatory properties. However, little is known about the regulation of PPAR-γ activity in modulating cell crosstalk in NAFLD.
AIM To investigate whether the regulation of PPAR-γ activity in lipid-laden hepatocytes affects macrophage polarization and inflammation.
METHODS Primary hepatocytes were isolated from wild-type C57BL6/J mice or hepatocyte-specific PPAR-γ knockout mice and incubated with free fatty acids (FFAs). Macrophages were incubated with conditioned medium (CM) from lipid-laden hepatocytes with or without a PPAR-γ agonist. Wild-type C57BL/6J mice were fed a high-fat (HF) diet and administered rosiglitazone.
RESULTS Primary hepatocytes exhibited significant lipid deposition and increased ROS production after incubation with FFAs. CM from lipid-laden hepatocytes promoted macrophage polarization to the M1 type and activation of the TLR4/NF-κB pathway. A PPAR-γ agonist ameliorated oxidative stress and NLRP3 inflammasome activation in lipid-laden hepatocytes and subsequently prevented M1 macrophage polarization. Hepatocyte-specific PPAR-γ deficiency aggravated oxidative stress and NLRP3 inflammasome activation in lipid-laden hepatocytes, which further promoted M1 macrophage polarization. Rosiglitazone administration improved oxidative stress and NLRP3 inflammasome activation in HF diet-induced NAFLD mice in vivo.
CONCLUSION Upregulation of PPAR-γ activity in hepatocytes alleviated NAFLD by modulating the crosstalk between hepatocytes and macrophages via the reactive oxygen species-NLRP3-IL-1β pathway.
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Affiliation(s)
- Xiao-Yun Li
- Department of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, NHC Key Laboratory of Digestive Diseases (Renji Hospital, Shanghai Jiaotong University School of Medicine), Shanghai 200127, China
| | - Pei-Xuan Ji
- Department of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, NHC Key Laboratory of Digestive Diseases (Renji Hospital, Shanghai Jiaotong University School of Medicine), Shanghai 200127, China
| | - Xi-Xi Ni
- Department of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, NHC Key Laboratory of Digestive Diseases (Renji Hospital, Shanghai Jiaotong University School of Medicine), Shanghai 200127, China
| | - Yu-Xin Chen
- Department of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, NHC Key Laboratory of Digestive Diseases (Renji Hospital, Shanghai Jiaotong University School of Medicine), Shanghai 200127, China
| | - Li Sheng
- Department of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, NHC Key Laboratory of Digestive Diseases (Renji Hospital, Shanghai Jiaotong University School of Medicine), Shanghai 200127, China
| | - Min Lian
- Department of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, NHC Key Laboratory of Digestive Diseases (Renji Hospital, Shanghai Jiaotong University School of Medicine), Shanghai 200127, China
| | - Can-Jie Guo
- Department of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, NHC Key Laboratory of Digestive Diseases (Renji Hospital, Shanghai Jiaotong University School of Medicine), Shanghai 200127, China
| | - Jing Hua
- Department of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, NHC Key Laboratory of Digestive Diseases (Renji Hospital, Shanghai Jiaotong University School of Medicine), Shanghai 200127, China
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Wang M, Zhou X, Jiang Z, Wang J. Angiogenesis Inhibitor ZM 306416 Reduces Non-Alcoholic Fatty Liver Disease in Mice Induced by High-Fat Diet. J BIOMATER TISS ENG 2022. [DOI: 10.1166/jbt.2022.3027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD) causes countless burden to people worldwide, especially when the quality of people’s life is improved constantly. It has clinical significance to find novel methods to deal with this common disease. Here, we aimed to assess whether angiogenesis
inhibitor ZM306416 could improve NAFLD. Mice were fed with different diets for 15 weeks and treated with ZM306416 followed by analysis of weight and inflammatory infiltration of adipose tissue, fatty degeneration, and fibrosis by immunohistochemistry, fibrosis-related proteins level by qRT-PCR.
Compared to control group, ZM306416 treatment significantly declined mice weight and adipose tissue weight. In addition, ZM306416 decreased blood vessel density of adipose tissues, mitigated inflammatory infiltration, fatty degeneration, and fibrosis. Moreover, ZM304616 alleviated adipose
fibrosis-related protein expression, and transcription of inflammatory genes and adipogenesis genes. However, the inhibitor enhanced β-oxidation of fatty acid, Nrf2, and SOD2, while decreased serum markers of liver injury. In conclsuion, angiogenesis inhibitor ZM306416 attenuates
adipose fibrosis and degradation, promotes adipose functions and lipid metabolism, thereby alleviating obesity-induced nonalcoholic fatty liver.
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Affiliation(s)
- Miaojuan Wang
- Department of General Practice, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, 310053, Zhengjiang, China
| | - Xiajuan Zhou
- Department of General Practice, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, 310053, Zhengjiang, China
| | - Zhenghao Jiang
- Department of General Practice, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, 310053, Zhengjiang, China
| | - Jingyuan Wang
- Health Management Center, Zhejiang Provincial People’s Hospital, Hangzhou, 310000, Zhejiang, China
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Zhang DG, Xu XJ, Pantopoulos K, Zhao T, Zheng H, Luo Z. HSF1-SELENOS pathway mediated dietary inorganic Se-induced lipogenesis via the up-regulation of PPARγ expression in yellow catfish. BIOCHIMICA ET BIOPHYSICA ACTA. GENE REGULATORY MECHANISMS 2022; 1865:194802. [PMID: 35248747 DOI: 10.1016/j.bbagrm.2022.194802] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/11/2021] [Revised: 02/14/2022] [Accepted: 02/22/2022] [Indexed: 02/08/2023]
Abstract
At present, studies involved in the effects of dietary Se sources on lipid metabolism were very scarce and the underlying mechanism remains unknown. Previous studies reported that dietary Se sources differentially affected selenoprotein S (SELENOS) expression and SELENOS affected lipid metabolism via the inositol-requiring enzyme 1α (IRE1α)- spliced X-box binding protein 1 (XBP1s) pathway. Thus, we used yellow catfish as an experimental model to explore whether dietary selenium sources affected the hepatic lipid metabolism, and further determined the role of SELENOS-IRE1α-XBP1s pathway in dietary selenium sources affecting hepatic lipid metabolism. Compared with the selenomethionine (S-M) group, sodium selenite (SS) group possessed higher liver triglycerides (TGs) (34.7%), lipogenic enzyme activities (57.9-70.6%), and lower antioxidant enzyme activities (23.3-35.5%), increased protein levels of heat shock transcription factor 1 (HSF1) and SELENOS (1.17-fold and 47.4%, respectively), and XBP1s- peroxisome proliferators-activated receptor γ (PPARγ) pathway. Blocking SELENOS and PPARγ by RNA interference demonstrated that the SELENOS/XBP1s/PPARγ axis was critical for S-S-induced lipid accumulation. Moreover, S-S-induced upregulation of SELENOS was via the increased DNA binding capacity of HSF1 to SELENOS promoter, which activated the XBP1s/PPARγ pathway and promoted lipogenesis and lipid accumulation. XBP1s is required for S-S-induced upregulation of PPARγ expression. Our finding elucidated the mechanism of dietary Se sources affecting the lipid metabolism in the liver of yellow catfish and demonstrated novel function of SELENOS in metabolic regulation. Our study also suggested that seleno-methionine was a better Se source than selenite against abnormal lipid deposition in the liver of yellow catfish.
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Affiliation(s)
- Dian-Guang Zhang
- Hubei Hongshan Laboratory, Fishery College, Huazhong Agriculture University, Wuhan 430070, China
| | - Xiao-Jian Xu
- Hubei Hongshan Laboratory, Fishery College, Huazhong Agriculture University, Wuhan 430070, China
| | - Kostas Pantopoulos
- Lady Davis Institute for Medical Research, Department of Medicine, McGill University, Montreal H3T 1E2, Quebec, Canada
| | - Tao Zhao
- Hubei Hongshan Laboratory, Fishery College, Huazhong Agriculture University, Wuhan 430070, China
| | - Hua Zheng
- Hubei Hongshan Laboratory, Fishery College, Huazhong Agriculture University, Wuhan 430070, China
| | - Zhi Luo
- Hubei Hongshan Laboratory, Fishery College, Huazhong Agriculture University, Wuhan 430070, China; Laboratory for Marine Fisheries Science and Food Production Processes, Qingdao National Laboratory for Marine Science and Technology, Qingdao 266237, China.
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He Z, Guo T, Cui Z, Xu J, Wu Z, Yang X, Hu H, Mei H, Zhou J, Zhang Y, Wang K. New understanding of Angelica sinensis polysaccharide improving fatty liver: The dual inhibition of lipid synthesis and CD36-mediated lipid uptake and the regulation of alcohol metabolism. Int J Biol Macromol 2022; 207:813-825. [PMID: 35358574 DOI: 10.1016/j.ijbiomac.2022.03.148] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2021] [Revised: 03/20/2022] [Accepted: 03/23/2022] [Indexed: 12/01/2022]
Abstract
Angelica sinensis polysaccharide (ASP) has presented increasingly recognized lipid regulation and antioxidant abilities. However, there is little direct evidence to explain why ASP possesses the observed lipid-lowering and anti-oxidation effects. In vivo and in vitro models of alcoholic fatty liver disease (AFLD) were established to examine the direct effect of ASP on hepatic fat accumulation. Our results showed that the lipid-lowering effect of ASP might result from the dual inhibition of lipid synthesis and CD36-mediated lipid uptake. The antioxidation of ASP might be attributed to the reversal of alcohol metabolic pathways from CYP2E1 catalysis to ADH catalysis. Taken together, the study demonstrated the direct role of ASP in lipid metabolism for the first time and revealed the underlying mechanism of reducing ROS, providing an available strategy for ASP as a potential agent to treat AFLD.
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Affiliation(s)
- Zihao He
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430030 Wuhan, PR China; Hubei Province Clinical Research Center for Precision Medicine for Critical Illness, 430030 Wuhan, PR China
| | - Tingting Guo
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430030 Wuhan, PR China; Hubei Province Clinical Research Center for Precision Medicine for Critical Illness, 430030 Wuhan, PR China
| | - Zheng Cui
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430030 Wuhan, PR China; Hubei Province Clinical Research Center for Precision Medicine for Critical Illness, 430030 Wuhan, PR China
| | - Jingya Xu
- Hubei Key Laboratory of Nature Medicinal Chemistry and Resource Evaluation, Tongji Medical College of Pharmacy, Huazhong University of Science and Technology, 430030 Wuhan, PR China
| | - Zhijing Wu
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430030 Wuhan, PR China; Hubei Province Clinical Research Center for Precision Medicine for Critical Illness, 430030 Wuhan, PR China
| | - Xiawen Yang
- Hubei Key Laboratory of Nature Medicinal Chemistry and Resource Evaluation, Tongji Medical College of Pharmacy, Huazhong University of Science and Technology, 430030 Wuhan, PR China
| | - Huiping Hu
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430030 Wuhan, PR China; Hubei Province Clinical Research Center for Precision Medicine for Critical Illness, 430030 Wuhan, PR China
| | - Hao Mei
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430030 Wuhan, PR China; Hubei Province Clinical Research Center for Precision Medicine for Critical Illness, 430030 Wuhan, PR China
| | - Jing Zhou
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430030 Wuhan, PR China; Hubei Province Clinical Research Center for Precision Medicine for Critical Illness, 430030 Wuhan, PR China
| | - Yu Zhang
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430030 Wuhan, PR China; Hubei Province Clinical Research Center for Precision Medicine for Critical Illness, 430030 Wuhan, PR China.
| | - Kaiping Wang
- Hubei Key Laboratory of Nature Medicinal Chemistry and Resource Evaluation, Tongji Medical College of Pharmacy, Huazhong University of Science and Technology, 430030 Wuhan, PR China.
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Xenobiotic-Induced Aggravation of Metabolic-Associated Fatty Liver Disease. Int J Mol Sci 2022; 23:ijms23031062. [PMID: 35162986 PMCID: PMC8834714 DOI: 10.3390/ijms23031062] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Revised: 01/11/2022] [Accepted: 01/15/2022] [Indexed: 01/09/2023] Open
Abstract
Metabolic-associated fatty liver disease (MAFLD), which is often linked to obesity, encompasses a large spectrum of hepatic lesions, including simple fatty liver, steatohepatitis, cirrhosis and hepatocellular carcinoma. Besides nutritional and genetic factors, different xenobiotics such as pharmaceuticals and environmental toxicants are suspected to aggravate MAFLD in obese individuals. More specifically, pre-existing fatty liver or steatohepatitis may worsen, or fatty liver may progress faster to steatohepatitis in treated patients, or exposed individuals. The mechanisms whereby xenobiotics can aggravate MAFLD are still poorly understood and are currently under deep investigations. Nevertheless, previous studies pointed to the role of different metabolic pathways and cellular events such as activation of de novo lipogenesis and mitochondrial dysfunction, mostly associated with reactive oxygen species overproduction. This review presents the available data gathered with some prototypic compounds with a focus on corticosteroids and rosiglitazone for pharmaceuticals as well as bisphenol A and perfluorooctanoic acid for endocrine disruptors. Although not typically considered as a xenobiotic, ethanol is also discussed because its abuse has dire consequences on obese liver.
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Eguchi A, Mizukami S, Nakamura M, Masuda S, Murayama H, Kawashima M, Inohana M, Nagahara R, Kobayashi M, Yamashita R, Uomoto S, Makino E, Ohtsuka R, Takahashi N, Hayashi SM, Maronpot RR, Shibutani M, Yoshida T. Metronidazole enhances steatosis-related early-stage hepatocarcinogenesis in high fat diet-fed rats through DNA double-strand breaks and modulation of autophagy. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2022; 29:779-789. [PMID: 34341928 DOI: 10.1007/s11356-021-15689-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/13/2021] [Accepted: 07/23/2021] [Indexed: 06/13/2023]
Abstract
Nonalcoholic fatty liver disease is a hepatic disorder with deposition of fat droplets and has a high risk of progression to steatosis-related hepatitis and irreversible hepatic cancer. Metronidazole (MNZ) is an antiprotozoal and antimicrobial agent widely used to treat patients infected with anaerobic bacteria and intestinal parasites; however, MNZ has also been shown to induce liver tumors in rodents. To investigate the effects of MNZ on steatosis-related early-stage hepatocarcinogenesis, male rats treated with N-nitrosodiethylamine following 2/3 hepatectomy at week 3 were received a control basal diet, high fat diet (HFD), or HFD containing 0.5% MNZ. The HFD induced obesity and steatosis in the liver, accompanied by altered expression of Pparg and Fasn, genes related to lipid metabolism. MNZ increased nuclear translocation of lipid metabolism-related transcription factor peroxisome proliferator-activated receptor gamma in hepatocytes, together with altered liver expression of lipid metabolism genes (Srebf1, Srebf2, Pnpla2). Furthermore, MNZ significantly increased the number of preneoplastic liver foci, accompanied by DNA double-strand breaks and late-stage autophagy inhibition, as reflected by increased levels of γ-H2AX, LC3, and p62. Therefore, MNZ could induce steatosis-related hepatocarcinogenesis by inducing DNA double-strand breaks and modulating autophagy in HFD-fed rats.
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Affiliation(s)
- Ayumi Eguchi
- Laboratory of Veterinary Pathology, Cooperative Department of Veterinary Medicine, Faculty of Agriculture, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu-shi, Tokyo, 183-8509, Japan
| | - Sayaka Mizukami
- Laboratory of Veterinary Pathology, Cooperative Department of Veterinary Medicine, Faculty of Agriculture, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu-shi, Tokyo, 183-8509, Japan
- Pathogenetic Veterinary Science, United Graduate School of Veterinary Sciences, Gifu University, 1-1 Yanagido, Gifu-shi, Gifu, 501-1193, Japan
| | - Misato Nakamura
- Laboratory of Veterinary Pathology, Cooperative Department of Veterinary Medicine, Faculty of Agriculture, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu-shi, Tokyo, 183-8509, Japan
| | - Sousuke Masuda
- Laboratory of Veterinary Pathology, Cooperative Department of Veterinary Medicine, Faculty of Agriculture, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu-shi, Tokyo, 183-8509, Japan
| | - Hirotada Murayama
- Laboratory of Veterinary Pathology, Cooperative Department of Veterinary Medicine, Faculty of Agriculture, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu-shi, Tokyo, 183-8509, Japan
| | - Masashi Kawashima
- Laboratory of Veterinary Pathology, Cooperative Department of Veterinary Medicine, Faculty of Agriculture, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu-shi, Tokyo, 183-8509, Japan
| | - Mari Inohana
- Laboratory of Veterinary Pathology, Cooperative Department of Veterinary Medicine, Faculty of Agriculture, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu-shi, Tokyo, 183-8509, Japan
| | - Rei Nagahara
- Laboratory of Veterinary Pathology, Cooperative Department of Veterinary Medicine, Faculty of Agriculture, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu-shi, Tokyo, 183-8509, Japan
| | - Mio Kobayashi
- Laboratory of Veterinary Pathology, Cooperative Department of Veterinary Medicine, Faculty of Agriculture, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu-shi, Tokyo, 183-8509, Japan
| | - Risako Yamashita
- Laboratory of Veterinary Pathology, Cooperative Department of Veterinary Medicine, Faculty of Agriculture, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu-shi, Tokyo, 183-8509, Japan
| | - Suzuka Uomoto
- Laboratory of Veterinary Pathology, Cooperative Department of Veterinary Medicine, Faculty of Agriculture, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu-shi, Tokyo, 183-8509, Japan
| | - Emi Makino
- The Institute of Environmental Toxicology, 4321, Uchimoriya-machi, Joso-shi, Ibaraki, 303-0043, Japan
| | - Ryoichi Ohtsuka
- The Institute of Environmental Toxicology, 4321, Uchimoriya-machi, Joso-shi, Ibaraki, 303-0043, Japan
| | - Naofumi Takahashi
- The Institute of Environmental Toxicology, 4321, Uchimoriya-machi, Joso-shi, Ibaraki, 303-0043, Japan
| | - Shim-Mo Hayashi
- Global Scientific and Regulatory Affairs, San-Ei Gen F. F. I., Inc., 1-1-11 Sanwa-cho, Toyonaka, Osaka, 561-8588, Japan
| | | | - Makoto Shibutani
- Laboratory of Veterinary Pathology, Cooperative Department of Veterinary Medicine, Faculty of Agriculture, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu-shi, Tokyo, 183-8509, Japan
| | - Toshinori Yoshida
- Laboratory of Veterinary Pathology, Cooperative Department of Veterinary Medicine, Faculty of Agriculture, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu-shi, Tokyo, 183-8509, Japan.
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21
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Tang H, Yang M, Liu Y, Liu H, Sun L, Song P. The CXCL1-CXCR2 Axis Mediates Tubular Injury in Diabetic Nephropathy Through the Regulation of the Inflammatory Response. Front Physiol 2021; 12:782677. [PMID: 34975537 PMCID: PMC8716832 DOI: 10.3389/fphys.2021.782677] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2021] [Accepted: 11/15/2021] [Indexed: 12/28/2022] Open
Abstract
Diabetic nephropathy (DN) is one of the most severe complications of diabetes. Inflammation mediated by inflammatory factors is thought to accelerate the progression of renal damage in DN. However, which inflammatory factors mediate the inflammatory response in DN remains unclear. In this study, we determined that the CXCL1-mediated inflammatory response may play an essential role in DN progression through bioassays. Subsequently, we observed that the expression of CXCL1 and its receptor (CXCR2) was significantly increased in the kidneys of mice with HFD + STZ induced diabetes and DN patients. In addition, inhibition of the CXCL1/CXCR2 axis by repertaxin alleviates renal inflammation and pathological damage in the kidneys of db/db mice. Finally, we noted that the CXCL1/CXCR2 axis might lead to inflammatory damage through phosphorylated NF-κB and further activate the NLRP3 inflammasome. Our results revealed the role of the CXCL1/CXCR2 axis in DN progression for the first time, which may be a novel therapeutic target for DN.
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Affiliation(s)
- Hanfen Tang
- Department of Nephrology, Second Xiangya Hospital, Central South University, Changsha, China
- Department of Nutrition, Second Xiangya Hospital, Central South University, Changsha, China
| | - Ming Yang
- Department of Nephrology, Second Xiangya Hospital, Central South University, Changsha, China
- Key Laboratory of Kidney Disease and Blood Purification in Hunan Province, Institute of Nephrology, Central South University, Changsha, China
| | - Yinghong Liu
- Department of Nephrology, Second Xiangya Hospital, Central South University, Changsha, China
- Key Laboratory of Kidney Disease and Blood Purification in Hunan Province, Institute of Nephrology, Central South University, Changsha, China
| | - Hong Liu
- Department of Nephrology, Second Xiangya Hospital, Central South University, Changsha, China
- Key Laboratory of Kidney Disease and Blood Purification in Hunan Province, Institute of Nephrology, Central South University, Changsha, China
| | - Lin Sun
- Department of Nephrology, Second Xiangya Hospital, Central South University, Changsha, China
- Key Laboratory of Kidney Disease and Blood Purification in Hunan Province, Institute of Nephrology, Central South University, Changsha, China
| | - Panai Song
- Department of Nephrology, Second Xiangya Hospital, Central South University, Changsha, China
- Key Laboratory of Kidney Disease and Blood Purification in Hunan Province, Institute of Nephrology, Central South University, Changsha, China
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22
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Afonso MB, Rodrigues PM, Mateus-Pinheiro M, Simão AL, Gaspar MM, Majdi A, Arretxe E, Alonso C, Santos-Laso A, Jimenez-Agüero R, Eizaguirre E, Bujanda L, Pareja MJ, Banales JM, Ratziu V, Gautheron J, Castro RE, Rodrigues CMP. RIPK3 acts as a lipid metabolism regulator contributing to inflammation and carcinogenesis in non-alcoholic fatty liver disease. Gut 2021; 70:2359-2372. [PMID: 33361348 PMCID: PMC8588316 DOI: 10.1136/gutjnl-2020-321767] [Citation(s) in RCA: 65] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2020] [Revised: 09/22/2020] [Accepted: 11/25/2020] [Indexed: 12/24/2022]
Abstract
OBJECTIVE Receptor-interacting protein kinase 3 (RIPK3) is a key player in necroptosis execution and an emerging metabolic regulator, whose contribution to non-alcoholic fatty liver disease (NAFLD) is controversial. We aimed to clarify the impact of RIPK3 signalling in the pathogenesis of human and experimental NAFLD. DESIGN RIPK3 levels were evaluated in two large independent cohorts of patients with biopsy proven NAFLD diagnosis and correlated with clinical and biochemical parameters. Wild-type (WT) or Ripk3-deficient (Ripk3-/-) mice were fed a choline-deficient L-amino acid-defined diet (CDAA) or an isocaloric control diet for 32 and 66 weeks. RESULTS RIPK3 increased in patients with non-alcoholic steatohepatitis (NASH) in both cohorts, correlating with hepatic inflammation and fibrosis. Accordingly, Ripk3 deficiency ameliorated CDAA-induced inflammation and fibrosis in mice at both 32 and 66 weeks. WT mice on the CDAA diet for 66 weeks developed preneoplastic nodules and displayed increased hepatocellular proliferation, which were reduced in Ripk3-/- mice. Furthermore, Ripk3 deficiency hampered tumourigenesis. Intriguingly, Ripk3-/- mice displayed increased body weight gain, while lipidomics showed that deletion of Ripk3 shifted hepatic lipid profiles. Peroxisome proliferator-activated receptor γ (PPARγ) was increased in Ripk3-/- mice and negatively correlated with hepatic RIPK3 in patients with NAFLD. Mechanistic studies established a functional link between RIPK3 and PPARγ in controlling fat deposition and fibrosis. CONCLUSION Hepatic RIPK3 correlates with NAFLD severity in humans and mice, playing a key role in managing liver metabolism, damage, inflammation, fibrosis and carcinogenesis. Targeting RIPK3 and its intricate signalling arises as a novel promising approach to treat NASH and arrest disease progression.
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Affiliation(s)
- Marta B Afonso
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
| | - Pedro M Rodrigues
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
| | - Miguel Mateus-Pinheiro
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
| | - André L Simão
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
| | - Maria M Gaspar
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
| | - Amine Majdi
- Sorbonne Université, Inserm, Centre de Recherche Saint-Antoine (CRSA), Paris, France
- Institute of Cardiometabolism and Nutrition (ICAN), Paris, France
| | - Enara Arretxe
- OWL Metabolomics, Bizkaia Technology Park, Derio, Spain
| | | | - Alvaro Santos-Laso
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), Ikerbasque, CIBERehd, San Sebastian, Spain
| | - Raul Jimenez-Agüero
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), Ikerbasque, CIBERehd, San Sebastian, Spain
| | - Emma Eizaguirre
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), Ikerbasque, CIBERehd, San Sebastian, Spain
| | - Luis Bujanda
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), Ikerbasque, CIBERehd, San Sebastian, Spain
| | | | - Jesus M Banales
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), Ikerbasque, CIBERehd, San Sebastian, Spain
| | - Vlad Ratziu
- Institute of Cardiometabolism and Nutrition (ICAN), Paris, France
- Department of Hepatology, Assistance Publique-Hôpitaux de Paris (AP-HP), Pitié-Salpêtrière Hospital, Paris, France
- Sorbonne Université, Inserm, Centre de Recherche des Cordeliers (CRC), Paris, France
| | - Jeremie Gautheron
- Sorbonne Université, Inserm, Centre de Recherche Saint-Antoine (CRSA), Paris, France
- Institute of Cardiometabolism and Nutrition (ICAN), Paris, France
| | - Rui E Castro
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
| | - Cecília M P Rodrigues
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
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Lu X, Wang F. Lactobacillus acidophilus and vitamin C attenuate ethanol-induced intestinal and liver injury in mice. Exp Ther Med 2021; 22:1005. [PMID: 34345287 PMCID: PMC8311231 DOI: 10.3892/etm.2021.10438] [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: 12/27/2020] [Accepted: 05/14/2021] [Indexed: 11/05/2022] Open
Abstract
Ethanol exposure frequently induces intestinal and liver injury, dysbiosis of the gut microbiota and vitamin C (VC) deficiency. Gut microbiota-targeted therapy is emerging as an important adjuvant method for protecting the body against ethanol-induced injury, particularly probiotics containing Lactobacillus acidophilus (LA). However, the feasibility and efficiency of using synbiotics containing LA and VC against ethanol-induced injury remained largely undetermined. To examine the advantages of LA+VC, their effect was evaluated in an ethanol-fed mouse model. The results suggested that LA+VC restored gut microbiota homeostasis and reinstated the immune balance of colonic T-regulatory cells (CD4+CD45+forkhead box p3+). In addition, intestinal barrier disorders were improved via upregulating tight junction proteins (claudin-2, zona occludens-1 and occludin) and mucus secretion, which prevented the translocation of lipopolysaccharide into circulatory systems and subsequently reduced the expression of Toll-like receptor 4 in liver tissues. In this context, LA+VC treatment reduced the inflammatory response in the liver, which was likely responsible for the improved liver function in ethanol-challenged mice. Collectively, these results indicated that LA+VC treatment significantly protected the intestine and liver from ethanol damage by enhancing intestinal barrier function and reducing systemic inflammation. The present study paved the way for further exploration of synbiotics based on Lactobacillus species and VC.
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Affiliation(s)
- Xing Lu
- The Third Central Clinical College, Tianjin Medical University, Tianjin 300170, P.R. China
| | - Fengmei Wang
- The Third Central Clinical College, Tianjin Medical University, Tianjin 300170, P.R. China.,Department of Gastroenterology and Hepatology, The Third Central Hospital of Tianjin, Tianjin 300170, P.R. China
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24
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Wu R, Wang X, Shao Y, Jiang Y, Zhou Y, Lu C. NFATc4 mediates ethanol-triggered hepatocyte senescence. Toxicol Lett 2021; 350:10-21. [PMID: 34192554 DOI: 10.1016/j.toxlet.2021.06.018] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Revised: 06/18/2021] [Accepted: 06/23/2021] [Indexed: 12/19/2022]
Abstract
BACKGROUND Hepatocyte senescence is a core event that mediates the occurrence and development of alcoholic liver disease. Nuclear factor of activated T-cells 4 (NFATc4) is a key driver of nonalcoholic steatohepatitis. However, little was known about the implication of NFATc4 for alcoholic liver disease. This study was aimed to investigate the role of NFATc4 in hepatocyte senescence and further elucidate the underlying mechanism. METHODS Real-time PCR, Western blot, immunofluorescence staining, and enzyme-linked immunosorbent assay were performed to explore the role of NFATc4 in hepatocyte senescence. RESULTS NFATc4 was induced in ethanol-incubated hepatocytes. NFATc4 knockdown recovered cell viability and reduced the release of aspartate transaminase, alanine transaminase, and lactic dehydrogenase from ethanol-incubated hepatocytes. NFATc4 knockdown protected mice from alcoholic liver injury and inflammation. NFATc4 knockdown counteracted ethanol-induced hepatocyte senescence, evidenced by decreased senescence-associated β-galactosidase positivity and reduced p16, p21, HMGA1, and γH2AX, which was validated in in vivo studies. Peroxisome proliferator-activated receptor (PPAR)γ was inhibited by NFATc4 in ethanol-treated hepatocytes. PPARγ deficiency abrogated the inhibitory effects of NFATc4 knockdown on hepatocyte senescence, oxidative stress, and hepatic steatosis in mice with alcoholic liver disease. CONCLUSIONS This work discovered that ethanol enhanced NFATc4 expression, which further triggered hepatocyte senescence via repression of PPARγ.
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Affiliation(s)
- Ruoman Wu
- School of Pharmacy, Nantong University, Nantong, Jiangsu, China
| | - Xinqi Wang
- School of Pharmacy, Nantong University, Nantong, Jiangsu, China
| | - Yunyun Shao
- School of Pharmacy, Nantong University, Nantong, Jiangsu, China
| | - Yiming Jiang
- School of Pharmacy, Nantong University, Nantong, Jiangsu, China
| | - Ying Zhou
- School of Pharmacy, Nantong University, Nantong, Jiangsu, China
| | - Chunfeng Lu
- School of Pharmacy, Nantong University, Nantong, Jiangsu, China.
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Zhang Y, Chatzistamou I, Kiaris H. Transcriptomic coordination at hepatic steatosis indicates robust immune cell engagement prior to inflammation. BMC Genomics 2021; 22:454. [PMID: 34134614 PMCID: PMC8210377 DOI: 10.1186/s12864-021-07784-y] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Accepted: 06/07/2021] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Deregulation in lipid metabolism leads to the onset of hepatic steatosis while at subsequent stages of disease development, the induction of inflammation, marks the transition of steatosis to non-alcoholic steatohepatitis. While differential gene expression unveils individual genes that are deregulated at different stages of disease development, how the whole transcriptome is deregulated in steatosis remains unclear. METHODS Using outbred deer mice fed with high fat as a model, we assessed the correlation of each transcript with every other transcript in the transcriptome. The onset of steatosis in the liver was also evaluated histologically. RESULTS Our results indicate that transcriptional reprogramming directing immune cell engagement proceeds robustly, even in the absence of histologically detectable steatosis, following administration of high fat diet. In the liver transcriptomes of animals with steatosis, a preference for the engagement of regulators of T cell activation and myeloid leukocyte differentiation was also recorded as opposed to the steatosis-free livers at which non-specific lymphocytic activation was seen. As compared to controls, in the animals with steatosis, transcriptome was subjected to more widespread reorganization while in the animals without steatosis, reorganization was less extensive. Comparison of the steatosis and non-steatosis livers showed high retention of coordination suggesting that diet supersedes pathology in shaping the transcriptome's profile. CONCLUSIONS This highly versatile strategy suggests that the molecular changes inducing inflammation proceed robustly even before any evidence of steatohepatitis is recorded, either histologically or by differential expression analysis.
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Affiliation(s)
- Youwen Zhang
- Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, CLS 713, 715 Sumter Str., Columbia, SC, 29208-3402, USA
| | - Ioulia Chatzistamou
- Department of Pathology, Microbiology and Immunology, School of Medicine, University of South Carolina, Columbia, SC, USA
| | - Hippokratis Kiaris
- Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, CLS 713, 715 Sumter Str., Columbia, SC, 29208-3402, USA.
- Peromyscus Genetic Stock Center, University of South Carolina, Columbia, SC, USA.
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Skinner RC, Hagaman JA. The interplay of Western diet and binge drinking on the onset, progression, and outlook of liver disease. Nutr Rev 2021; 80:503-512. [PMID: 33969426 DOI: 10.1093/nutrit/nuab031] [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] [Indexed: 12/13/2022] Open
Abstract
Non-alcoholic fatty liver disease and alcoholic liver disease, the two most prevalent liver diseases worldwide, share a common pathology but have largely been considered disparate diseases. Liver diseases are widely underestimated, but their prevalence is increasing worldwide. The Western diet (high-fat, high-sugar) and binge drinking (rapid consumption of alcohol in a short period of time) are two highly prevalent features of standard life in the United States, and both are linked to the development and progression of liver disease. Yet, few studies have been conducted to elucidate their potential interactions. Data shows binge drinking is on the rise in several age groups, and poor dietary trends continue to be prevalent. This review serves to summarize the sparse findings on the hepatic consequences of the combination of binge drinking and consuming a Western diet, while also drawing conclusions on potential future impacts. The data suggest the potential for a looming liver disease epidemic, indicating that more research on its progression as well as its prevention is needed on this critical topic.
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Affiliation(s)
- R Chris Skinner
- R. C. Skinner and J. A. Hagaman are with the Division of Natural Sciences and Mathematics, University of the Ozarks, Clarksville, Arkansas, USA
| | - Joel A Hagaman
- R. C. Skinner and J. A. Hagaman are with the Division of Natural Sciences and Mathematics, University of the Ozarks, Clarksville, Arkansas, USA
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Chen M, Sun X, Wei W, Cucarella C, Martín-Sanz P, Casado M, Pi L, Ren B, Cao Q. Hepatic COX-2 expression protects mice from an alcohol-high fat diet-induced metabolic disorder by involving protein acetylation related energy metabolism. Alcohol 2021; 92:41-52. [PMID: 33662521 PMCID: PMC8095085 DOI: 10.1016/j.alcohol.2020.08.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2019] [Revised: 08/12/2020] [Accepted: 08/24/2020] [Indexed: 11/24/2022]
Abstract
PURPOSE A diet high in fat and ethanol often results in chronic metabolic disorder, hepatic steatosis, and liver inflammation. Constitutive hepatic cyclooxygenase-2 (COX-2) expression could protect from high fat-induced metabolism disturbance in a murine model. In this study, we explored the influence of hCOX-2 transgenic [TG] to high fat with ethanol-induced metabolic disorder and liver injury using a mouse animal model. METHODS 12-week-old male hepatic hCOX-2 transgenic (TG) or wild type mice (WT) were fed either a high fat and ethanol liquid diet (HF+Eth) or a regular control diet (RCD) for 5 weeks (four groups: RCD/WT, RCD/TG; HF+Eth/TG, HF+Eth/WT). We assessed metabolic biomarkers, cytokine profiles, histomorphology, and gene expression to study the impact of persistent hepatic COX-2 expression on diet-induced liver injury. RESULTS In the HF+Eth diet, constitutively hepatic human COX-2 expression protects mice from body weight gain and white adipose tissue accumulation, accompanied by improved IPGTT response, serum triglyceride/cholesterol levels, and lower levels of serum and liver inflammatory cytokines. Histologically, hCOX-2 mice showed decreased hepatic lipid droplets accumulation, decreased hepatocyte ballooning, and improved steatosis scores. Hepatic hCOX-2 overexpression enhanced AKT insulin signaling and increased fatty acid synthesis in both RCD and HF+Eth diet groups. The anti-lipogenic effect of hCOX-2 TG in the HF+Eth diet animals was mediated by increasing lipid disposal through enhanced β-oxidation via elevations in the expression of PPARα and PPARγ, and increased hepatic autophagy as assessed by the ratio of autophagy markers LC3 II/I in hepatic tissue. Various protein acetylation pathway components, including HAT, HDAC1, SIRT1, and SNAIL1, were modulated in hCOX-2 TG mice in either RCD or HF+Eth diet. CONCLUSIONS Hepatic human COX-2 expression protected mice from the metabolic disorder and liver injury induced by a high fat and ethanol diet by enhancing hepatic lipid expenditure. Epigenetic reprogramming of diverse metabolic genes might be involved in the anti-lipogenic effect of COX-2.
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Affiliation(s)
- Minjie Chen
- Diagnostic Radiology & Nuclear Medicine, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Xicui Sun
- Diagnostic Radiology & Nuclear Medicine, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Wei Wei
- Diagnostic Radiology & Nuclear Medicine, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Carme Cucarella
- Instituto de Biomedicina de Valencia, IBV-CSIC, Jaume Roig 11, Valencia, 46010, Spain
| | - Paloma Martín-Sanz
- Instituto de Investigaciones Biomédicas (IIB) "Alberto Sols", CSIC-UAM, Arturo Duperier 4, Madrid, 28029, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Monforte de Lemos 3-5, Madrid, 28029, Spain
| | - Marta Casado
- Instituto de Biomedicina de Valencia, IBV-CSIC, Jaume Roig 11, Valencia, 46010, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Monforte de Lemos 3-5, Madrid, 28029, Spain
| | - Liya Pi
- Department of Pediatrics, College of Medicine, Gainesville, FL, USA
| | - Bin Ren
- Department of Surgery, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Qi Cao
- Diagnostic Radiology & Nuclear Medicine, University of Maryland School of Medicine, Baltimore, MD, USA.
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Lee SM, Pusec CM, Norris GH, De Jesus A, Diaz-Ruiz A, Muratalla J, Sarmento-Cabral A, Guzman G, Layden BT, Cordoba-Chacon J. Hepatocyte-Specific Loss of PPARγ Protects Mice From NASH and Increases the Therapeutic Effects of Rosiglitazone in the Liver. Cell Mol Gastroenterol Hepatol 2021; 11:1291-1311. [PMID: 33444819 PMCID: PMC8005819 DOI: 10.1016/j.jcmgh.2021.01.003] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2020] [Revised: 01/04/2021] [Accepted: 01/05/2021] [Indexed: 02/06/2023]
Abstract
BACKGROUND & AIMS Nonalcoholic steatohepatitis (NASH) is commonly observed in patients with type 2 diabetes, and thiazolidinediones (TZD) are considered a potential therapy for NASH. Although TZD increase insulin sensitivity and partially reduce steatosis and alanine aminotransferase, the efficacy of TZD on resolving liver pathology is limited. In fact, TZD may activate peroxisome proliferator-activated receptor gamma (PPARγ) in hepatocytes and promote steatosis. Therefore, we assessed the role that hepatocyte-specific PPARγ plays in the development of NASH, and how it alters the therapeutic effects of TZD on the liver of mice with diet-induced NASH. METHODS Hepatocyte-specific PPARγ expression was knocked out in adult mice before and after the development of NASH induced with a high fat, cholesterol, and fructose (HFCF) diet. RESULTS HFCF diet increased PPARγ expression in hepatocytes, and rosiglitazone further activated PPARγ in hepatocytes of HFCF-fed mice in vivo and in vitro. Hepatocyte-specific loss of PPARγ reduced the progression of HFCF-induced NASH in male mice and increased the benefits derived from the effects of TZD on extrahepatic tissues and non-parenchymal cells. RNAseq and metabolomics indicated that HFCF diet promoted inflammation and fibrogenesis in a hepatocyte PPARγ-dependent manner and was associated with dysregulation of hepatic metabolism. Specifically, hepatocyte-specific loss of PPARγ plays a positive role in the regulation of methionine metabolism, and that could reduce the progression of NASH. CONCLUSIONS Because of the negative effect of hepatocyte PPARγ in NASH, inhibition of mechanisms promoted by endogenous PPARγ in hepatocytes may represent a novel strategy that increases the efficiency of therapies for NAFLD.
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Affiliation(s)
- Samuel M. Lee
- Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Illinois at Chicago, Chicago, Illinois
| | - Carolina M. Pusec
- Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Illinois at Chicago, Chicago, Illinois
| | - Gregory H. Norris
- Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Illinois at Chicago, Chicago, Illinois
| | | | | | - Jose Muratalla
- Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Illinois at Chicago, Chicago, Illinois
| | - Andre Sarmento-Cabral
- Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Illinois at Chicago, Chicago, Illinois
| | - Grace Guzman
- Department of Pathology, University of Illinois at Chicago, Chicago, Illinois
| | - Brian T. Layden
- Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Illinois at Chicago, Chicago, Illinois,Research and Development, Jesse Brown VA Medical Center, Chicago, Illinois
| | - Jose Cordoba-Chacon
- Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Illinois at Chicago, Chicago, Illinois,Correspondence Address correspondence to: Jose Cordoba-Chacon, PhD, Department of Medicine, Section of Endocrinology, Diabetes and Metabolism, 835 South Wolcott Avenue (North Entrance), Suite E625, M/C 640, Chicago, Illinois 60612. fax (312) 413-0437.
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Wang Z, Li B, Jiang H, Ma Y, Bao Y, Zhu X, Xia H, Jin Y. IL-8 exacerbates alcohol-induced fatty liver disease via the Akt/HIF-1α pathway in human IL-8-expressing mice. Cytokine 2020; 138:155402. [PMID: 33352397 DOI: 10.1016/j.cyto.2020.155402] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2020] [Revised: 12/04/2020] [Accepted: 12/05/2020] [Indexed: 12/16/2022]
Abstract
Alcoholic fatty liver disease (AFLD) is a disease that causes liver damage due to chronic heavy drinking. AFLD is related to lipid accumulation in liver cells caused by alcohol intake. Interleukin-8 (IL-8) is an inflammatory cytokine associated with chemotaxis (deletion in mice) that has robust effects on the occurrence and development of disease by activating related signal transduction pathways to promote inflammation and cell proliferation. There is significantly increased IL-8 expression in liver disease, which may be related to the pathogenesis of AFLD. In this study, we used hydrodynamic injection to deliver the liver-specific expression vector pLIVE-hIL-8 into mice. We found that hIL-8 can exacerbate alcohol-induced fatty liver disease via the Akt/HIF-1α pathway. Exacerbated liver lipid degeneration in mice, which is characterized by excessive accumulation of triglycerides, and liver damage markers were significantly increased. Moreover, hIL-8 could increase the alcohol-induced release of ROS in fatty liver caused by alcohol and exacerbate fatty liver disease. The expression of liver lipid metabolism-related gene sterol regulatory element-binding protein-1c (SREBP-1c) was increased. Furthermore, the expression of peroxisome proliferator-activated receptor alpha (PPARα), which is related to liver fatty acid oxidation, was decreased. The findings obtained in this study of hIL-8 will help identify a potential target for the clinical treatment of AFLD.
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Affiliation(s)
- Zhihao Wang
- Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, School of Pharmacy, Anhui Medical University, 230032 Hefei, China; The Key Laboratory of Major Autoimmune Diseases, Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, 230032 Hefei, China; Institute for Liver Diseases of Anhui Medical University, 230032 Hefei, China
| | - Biao Li
- Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, School of Pharmacy, Anhui Medical University, 230032 Hefei, China; The Key Laboratory of Major Autoimmune Diseases, Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, 230032 Hefei, China; Institute for Liver Diseases of Anhui Medical University, 230032 Hefei, China
| | - Haiyan Jiang
- Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, School of Pharmacy, Anhui Medical University, 230032 Hefei, China; The Key Laboratory of Major Autoimmune Diseases, Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, 230032 Hefei, China; Institute for Liver Diseases of Anhui Medical University, 230032 Hefei, China
| | - Yuchen Ma
- Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, School of Pharmacy, Anhui Medical University, 230032 Hefei, China; The Key Laboratory of Major Autoimmune Diseases, Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, 230032 Hefei, China; Institute for Liver Diseases of Anhui Medical University, 230032 Hefei, China
| | - Yanni Bao
- Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, School of Pharmacy, Anhui Medical University, 230032 Hefei, China; The Key Laboratory of Major Autoimmune Diseases, Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, 230032 Hefei, China; Institute for Liver Diseases of Anhui Medical University, 230032 Hefei, China
| | - Xiangyu Zhu
- Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, School of Pharmacy, Anhui Medical University, 230032 Hefei, China
| | - Hongguang Xia
- Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, School of Pharmacy, Anhui Medical University, 230032 Hefei, China
| | - Yong Jin
- Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, School of Pharmacy, Anhui Medical University, 230032 Hefei, China; The Key Laboratory of Major Autoimmune Diseases, Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, 230032 Hefei, China; Institute for Liver Diseases of Anhui Medical University, 230032 Hefei, China.
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Zhan ZY, Wu M, Shang Y, Jiang M, Liu J, Qiao CY, Ye H, Lin YC, Piao MH, Sun RH, Zhang ZH, Jiao JY, Wu YL, Nan JX, Lian LH. Taxifolin ameliorate high-fat-diet feeding plus acute ethanol binge-induced steatohepatitis through inhibiting inflammatory caspase-1-dependent pyroptosis. Food Funct 2020; 12:362-372. [PMID: 33325949 DOI: 10.1039/d0fo02653k] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Excessive alcohol drinking and a high-fat diet (HFD) promote steatohepatitis in the comorbidity of NAFLD and AFLD. Taxifolin (TAX) is a rich dihydroxyflavone compound found in onions, milk thistle and Douglas fir. We aimed to explore the intervention mechanism of TAX on chronic steatohepatitis induced by HFD feeding plus acute ethanol binge. We established an in vivo model by HFD feeding plus a single dose of ethanol binge, and established an in vitro model by oleic acid or palmitic acid on HepG2 cells to induce lipid accumulation. TAX regulated lipid synthesis by inhibiting the expression of SREBP1 and upregulating the PPARγ level. In addition, TAX inhibited the expression of P2X7R, IL-1β, and caspase-1. Moreover, TAX reduced the expression of caspase-1 activation; thereby inhibiting the recruitment of macrophages and neutrophils. TAX also improved the inflammatory response caused by caspase-1 activation in steatotic hepatocytes. TAX exhibited an inhibitory effect on lipid accumulation and caspase-1-related pyroptosis. Collectively, TAX has therapeutic potential as an intervention of steatohepatitis induced by alcohol combined with HFD and for preventing non-alcoholic fatty liver degeneration targeting caspase-1-dependent pyroptosis.
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Affiliation(s)
- Zi-Ying Zhan
- Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China. and Key Laboratory for Traditional Chinese Korean Medicine of Jilin Province, College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China
| | - Mei Wu
- Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China. and Key Laboratory for Traditional Chinese Korean Medicine of Jilin Province, College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China
| | - Yue Shang
- Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China. and Key Laboratory for Traditional Chinese Korean Medicine of Jilin Province, College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China
| | - Min Jiang
- Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China. and Key Laboratory for Traditional Chinese Korean Medicine of Jilin Province, College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China
| | - Jian Liu
- Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China. and Key Laboratory for Traditional Chinese Korean Medicine of Jilin Province, College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China
| | - Chun-Ying Qiao
- Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China. and Key Laboratory for Traditional Chinese Korean Medicine of Jilin Province, College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China
| | - Huan Ye
- Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China. and Key Laboratory for Traditional Chinese Korean Medicine of Jilin Province, College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China
| | - Yong-Ce Lin
- Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China. and Key Laboratory for Traditional Chinese Korean Medicine of Jilin Province, College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China
| | - Mei-Hua Piao
- Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China. and Key Laboratory for Traditional Chinese Korean Medicine of Jilin Province, College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China
| | - Rong-Hui Sun
- Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China. and Key Laboratory for Traditional Chinese Korean Medicine of Jilin Province, College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China
| | - Zhi-Hong Zhang
- Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China. and Key Laboratory for Traditional Chinese Korean Medicine of Jilin Province, College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China
| | - Jing-Ya Jiao
- Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China. and Key Laboratory for Traditional Chinese Korean Medicine of Jilin Province, College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China
| | - Yan-Ling Wu
- Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China. and Key Laboratory for Traditional Chinese Korean Medicine of Jilin Province, College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China
| | - Ji-Xing Nan
- Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China. and Key Laboratory for Traditional Chinese Korean Medicine of Jilin Province, College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China and Clinical Research Centre, Yanbian University Hospital, Yanji, Jilin Province 133002, China
| | - Li-Hua Lian
- Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China. and Key Laboratory for Traditional Chinese Korean Medicine of Jilin Province, College of Pharmacy, Yanbian University, Yanji, Jilin Province 133002, China
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Takahashi Y, Watabe S, Togashi-Kumagai A, Watanabe M, Dungubat E, Kusano H, Kobayashi Y, Harada N, Yamaji R, Sugimoto K, Fukusato T. Effects of low ethanol consumption on nonalcoholic steatohepatitis in mice. Alcohol 2020; 87:51-61. [PMID: 32553943 DOI: 10.1016/j.alcohol.2020.04.004] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2019] [Revised: 03/25/2020] [Accepted: 04/15/2020] [Indexed: 12/11/2022]
Abstract
Several recent clinical and epidemiological studies have suggested inhibitory effects of light-to-moderate alcohol consumption on nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH); however, these effects have not been confirmed in experimental studies. Therefore, in this study, we examined the effects of small amounts of ethanol consumption on a mouse model of NASH. Nine-week-old male obese mice (db/db mice) were divided into the following groups: control, high-fat, and low-ethanol groups. The control group was provided ad libitum access to a control liquid diet, the high-fat group was provided access to a high-fat liquid diet, and the low-ethanol group was provided access to the high-fat liquid diet supplemented with 0.1% (w/w) ethanol. Eight weeks later, the mice were sacrificed and serum biochemical, histopathological, and molecular analyses were performed. Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels were significantly lower in the low-ethanol group than in the high-fat group (p = 0.033 and 0.037, respectively). Liver histopathological analysis showed that intralobular and portal inflammation was significantly milder in the low-ethanol group than in the high-fat group (p = 0.018 and 0.041, respectively). However, no significant differences were observed among the groups in serum insulin and adiponectin levels, hepatic 4-hydroxynonenal (oxidative injury marker) levels, and hepatic cytokine and receptor gene expression levels. In conclusion, the serum transaminase levels and hepatic inflammation in NASH model mice improved after administration of small amounts of ethanol. This study directly demonstrated inhibitory effects of small amounts of ethanol on NASH in mice. The mechanisms underlying these inhibitory effects remain to be elucidated.
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Affiliation(s)
- Yoshihisa Takahashi
- Department of Pathology, School of Medicine, International University of Health and Welfare, 4-3 Kouzunomori, Narita, Chiba, 286-8686, Japan.
| | - Shiori Watabe
- Department of Pathology, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi-ku, Tokyo, 173-8605, Japan
| | - Arisa Togashi-Kumagai
- Department of Pathology, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi-ku, Tokyo, 173-8605, Japan
| | - Masato Watanabe
- Department of Pathology, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi-ku, Tokyo, 173-8605, Japan
| | - Erdenetsogt Dungubat
- Department of Pathology, School of Medicine, International University of Health and Welfare, 4-3 Kouzunomori, Narita, Chiba, 286-8686, Japan; Department of Pathology, School of Biomedicine, (University Hospital), Mongolian National University of Medical Sciences, S. Zorig's Street 3, Sukhbaatar District, 14210, Ulaanbaatar, Mongolia
| | - Hiroyuki Kusano
- Department of Pathology, School of Medicine, International University of Health and Welfare, 4-3 Kouzunomori, Narita, Chiba, 286-8686, Japan
| | - Yasuyuki Kobayashi
- Division of Applied Life Sciences, Graduate School of Life and Environmental Sciences, Osaka Prefecture University, 1-1 Gakuen-cho, Naka-ku, Sakai, Osaka, 599-8531, Japan
| | - Naoki Harada
- Division of Applied Life Sciences, Graduate School of Life and Environmental Sciences, Osaka Prefecture University, 1-1 Gakuen-cho, Naka-ku, Sakai, Osaka, 599-8531, Japan
| | - Ryoichi Yamaji
- Division of Applied Life Sciences, Graduate School of Life and Environmental Sciences, Osaka Prefecture University, 1-1 Gakuen-cho, Naka-ku, Sakai, Osaka, 599-8531, Japan
| | - Keiichiro Sugimoto
- Research and Development Center, Nagaoka Co. Ltd., 1-3-30 Itsukaichi, Ibaraki, Osaka, 567-0005, Japan
| | - Toshio Fukusato
- General Medical Education and Research Center, Teikyo University, 2-11-1 Kaga, Itabashi-ku, Tokyo, 173-8605, Japan
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Hwang S, He Y, Xiang X, Seo W, Kim SJ, Ma J, Ren T, Park SH, Zhou Z, Feng D, Kunos G, Gao B. Interleukin-22 Ameliorates Neutrophil-Driven Nonalcoholic Steatohepatitis Through Multiple Targets. Hepatology 2020; 72:412-429. [PMID: 31705800 PMCID: PMC7210045 DOI: 10.1002/hep.31031] [Citation(s) in RCA: 121] [Impact Index Per Article: 24.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2019] [Accepted: 10/30/2019] [Indexed: 12/17/2022]
Abstract
BACKGROUND AND AIMS Nonalcoholic fatty liver disease encompasses a spectrum of diseases ranging from simple steatosis to nonalcoholic steatohepatitis (NASH), cirrhosis, and liver cancer. At present, how simple steatosis progresses to NASH remains obscure and effective pharmacological therapies are lacking. Hepatic expression of C-X-C motif chemokine ligand 1 (CXCL1), a key chemokine for neutrophil infiltration (a hallmark of NASH), is highly elevated in NASH patients but not in fatty livers in obese individuals or in high-fat diet (HFD)-fed mice. The aim of this study was to test whether overexpression of CXCL1 itself in the liver can induce NASH in HFD-fed mice and to test the therapeutic potential of IL-22 in this new NASH model. APPROACH AND RESULTS Overexpression of Cxcl1 in the liver alone promotes steatosis-to-NASH progression in HFD-fed mice by inducing neutrophil infiltration, oxidative stress, and stress kinase (such as apoptosis signal-regulating kinase 1 and p38 mitogen-activated protein kinase) activation. Myeloid cell-specific deletion of the neutrophil cytosolic factor 1 (Ncf1)/p47phox gene, which encodes a component of the NADPH oxidase 2 complex that mediates neutrophil oxidative burst, markedly reduced CXCL1-induced NASH and stress kinase activation in HFD-fed mice. Treatment with interleukin (IL)-22, a cytokine with multiple targets, ameliorated CXCL1/HFD-induced NASH or methionine-choline deficient diet-induced NASH in mice. Mechanistically, IL-22 blocked hepatic oxidative stress and its associated stress kinases via the induction of metallothionein, one of the most potent antioxidant proteins. Moreover, although it does not target immune cells, IL-22 treatment attenuated the inflammatory functions of hepatocyte-derived, mitochondrial DNA-enriched extracellular vesicles, thereby suppressing liver inflammation in NASH. CONCLUSIONS Hepatic overexpression of CXCL1 is sufficient to drive steatosis-to-NASH progression in HFD-fed mice through neutrophil-derived reactive oxygen species and activation of stress kinases, which can be reversed by IL-22 treatment via the induction of metallothionein.
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Affiliation(s)
- Seonghwan Hwang
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Yong He
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Xiaogang Xiang
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Wonhyo Seo
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Seung-Jin Kim
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Jing Ma
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Tianyi Ren
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Seol Hee Park
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Zhou Zhou
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Dechun Feng
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, 20892, USA
| | - George Kunos
- Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Bin Gao
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, 20892, USA
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Fougerat A, Montagner A, Loiseau N, Guillou H, Wahli W. Peroxisome Proliferator-Activated Receptors and Their Novel Ligands as Candidates for the Treatment of Non-Alcoholic Fatty Liver Disease. Cells 2020; 9:E1638. [PMID: 32650421 PMCID: PMC7408116 DOI: 10.3390/cells9071638] [Citation(s) in RCA: 89] [Impact Index Per Article: 17.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2020] [Revised: 06/26/2020] [Accepted: 07/04/2020] [Indexed: 12/11/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a major health issue worldwide, frequently associated with obesity and type 2 diabetes. Steatosis is the initial stage of the disease, which is characterized by lipid accumulation in hepatocytes, which can progress to non-alcoholic steatohepatitis (NASH) with inflammation and various levels of fibrosis that further increase the risk of developing cirrhosis and hepatocellular carcinoma. The pathogenesis of NAFLD is influenced by interactions between genetic and environmental factors and involves several biological processes in multiple organs. No effective therapy is currently available for the treatment of NAFLD. Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors that regulate many functions that are disturbed in NAFLD, including glucose and lipid metabolism, as well as inflammation. Thus, they represent relevant clinical targets for NAFLD. In this review, we describe the determinants and mechanisms underlying the pathogenesis of NAFLD, its progression and complications, as well as the current therapeutic strategies that are employed. We also focus on the complementary and distinct roles of PPAR isotypes in many biological processes and on the effects of first-generation PPAR agonists. Finally, we review novel and safe PPAR agonists with improved efficacy and their potential use in the treatment of NAFLD.
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Affiliation(s)
- Anne Fougerat
- Institut National de la Recherche Agronomique (INRAE), ToxAlim, UMR1331 Toulouse, France; (A.M.); (N.L.); (H.G.)
| | - Alexandra Montagner
- Institut National de la Recherche Agronomique (INRAE), ToxAlim, UMR1331 Toulouse, France; (A.M.); (N.L.); (H.G.)
- Institut National de la Santé et de la Recherche Médicale (Inserm), Institute of Metabolic and Cardiovascular Diseases, UMR1048 Toulouse, France
- Institute of Metabolic and Cardiovascular Diseases, University of Toulouse, UMR1048 Toulouse, France
| | - Nicolas Loiseau
- Institut National de la Recherche Agronomique (INRAE), ToxAlim, UMR1331 Toulouse, France; (A.M.); (N.L.); (H.G.)
| | - Hervé Guillou
- Institut National de la Recherche Agronomique (INRAE), ToxAlim, UMR1331 Toulouse, France; (A.M.); (N.L.); (H.G.)
| | - Walter Wahli
- Institut National de la Recherche Agronomique (INRAE), ToxAlim, UMR1331 Toulouse, France; (A.M.); (N.L.); (H.G.)
- Lee Kong Chian School of Medicine, Nanyang Technological University Singapore, Clinical Sciences Building, 11 Mandalay Road, Singapore 308232, Singapore
- Center for Integrative Genomics, Université de Lausanne, Le Génopode, CH-1015 Lausanne, Switzerland
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Loss of Hepatocyte-Specific PPAR γ Expression Ameliorates Early Events of Steatohepatitis in Mice Fed the Methionine and Choline-Deficient Diet. PPAR Res 2020; 2020:9735083. [PMID: 32411189 PMCID: PMC7211257 DOI: 10.1155/2020/9735083] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2019] [Revised: 03/16/2020] [Accepted: 03/26/2020] [Indexed: 12/15/2022] Open
Abstract
The prevalence of nonalcoholic fatty liver disease (NAFLD) is increasing worldwide. To date, there is not a specific and approved treatment for NAFLD yet, and therefore, it is important to understand the molecular mechanisms that lead to the progression of NAFLD. Methionine- and choline-deficient (MCD) diets are used to reproduce some features of NAFLD in mice. MCD diets increase the expression of hepatic peroxisome proliferator-activated receptor gamma (PPARγ, Pparg) and the fatty acid translocase (CD36, Cd36) which could increase hepatic fatty acid uptake and promote the progression of NAFLD in mice and humans. In this study, we assessed the contribution of hepatocyte-specific PPARγ and CD36 expression to the development of early events induced by the MCD diet. Specifically, mice with adult-onset, hepatocyte-specific PPARγ knockout with and without hepatocyte CD36 overexpression were fed a MCD diet for three weeks. Hepatocyte PPARγ and/or CD36 expression did not contribute to the development of steatosis induced by the MCD diet. However, the expression of inflammatory and fibrogenic genes seems to be dependent on the expression of hepatocyte PPARγ and CD36. The expression of PPARγ and CD36 in hepatocytes may be relevant in the regulation of some features of NAFLD and steatohepatitis.
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de Conti A, Tryndyak V, Willett RA, Borowa-Mazgaj B, Watson A, Patton R, Khare S, Muskhelishvili L, Olson GR, Avigan MI, Cerniglia CE, Ross SA, Sanyal AJ, Beland FA, Rusyn I, Pogribny IP. Characterization of the variability in the extent of nonalcoholic fatty liver induced by a high-fat diet in the genetically diverse Collaborative Cross mouse model. FASEB J 2020; 34:7773-7785. [PMID: 32304142 DOI: 10.1096/fj.202000194r] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2020] [Revised: 03/24/2020] [Accepted: 03/25/2020] [Indexed: 02/06/2023]
Abstract
Interindividual variability and sexual dimorphisms in the development of nonalcoholic fatty liver disease (NAFLD) are still poorly understood. In the present study, male and female strains of Collaborative Cross (CC) mice were fed a high-fat and high-sucrose (HF/HS) diet or a control diet for 12 weeks to investigate interindividual- and sex-specific variations in the development of NAFLD. The severity of liver steatosis varied between sexes and individual strains and was accompanied by an elevation of serum markers of insulin resistance, including increases in total cholesterol, low-density lipoproteins, high-density lipoproteins, phospholipids, and glucose. The development of NAFLD was associated with overexpression of the critical fatty acid uptake and de novo lipogenesis genes Pparg, Mogat1, Cd36, Acaab1, Fabp2, and Gdf15 in male and female mice. The expression of Pparg, Mogat1, and Cd36 was positively correlated with liver triglycerides in male mice, and Mogat1 and Cd36 expression were positively correlated with liver triglycerides in female mice. Our results indicate the value of CC mice in combination with HF/HS diet-induced alterations as an approach to study the susceptibility and interindividual variabilities in the pathogenesis of nonalcoholic fatty liver and early nonalcoholic steatohepatitis at the population level, uncovering of susceptible and resistant cohorts, and identifying sex-specific molecular determinants of disease susceptibility.
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Affiliation(s)
- Aline de Conti
- Division of Biochemical Toxicology, FDA-National Center for Toxicological Research, Jefferson, AR, USA
| | - Volodymyr Tryndyak
- Division of Biochemical Toxicology, FDA-National Center for Toxicological Research, Jefferson, AR, USA
| | - Rose A Willett
- Division of Biochemical Toxicology, FDA-National Center for Toxicological Research, Jefferson, AR, USA
| | - Barbara Borowa-Mazgaj
- Division of Biochemical Toxicology, FDA-National Center for Toxicological Research, Jefferson, AR, USA
| | - Anna Watson
- Division of Biochemical Toxicology, FDA-National Center for Toxicological Research, Jefferson, AR, USA
| | - Ralph Patton
- Toxicologic Pathology Associates, Jefferson, AR, USA
| | - Sangeeta Khare
- Division of Microbiology, FDA-National Center for Toxicological Research, Jefferson, AR, USA
| | | | - Greg R Olson
- Toxicologic Pathology Associates, Jefferson, AR, USA
| | - Mark I Avigan
- Office of Pharmacovigilance and Epidemiology, FDA-Center for Drug Evaluation and Research, Silver Spring, MD, USA
| | - Carl E Cerniglia
- Division of Microbiology, FDA-National Center for Toxicological Research, Jefferson, AR, USA
| | - Sharon A Ross
- Division of Cancer Prevention, National Cancer Institute, Bethesda, MD, USA
| | - Arun J Sanyal
- Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA, USA
| | - Frederick A Beland
- Division of Biochemical Toxicology, FDA-National Center for Toxicological Research, Jefferson, AR, USA
| | - Ivan Rusyn
- Department of Veterinary Integrative Biosciences, Texas A&M University, College Station, TX, USA
| | - Igor P Pogribny
- Division of Biochemical Toxicology, FDA-National Center for Toxicological Research, Jefferson, AR, USA
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Addolorato G, Abenavoli L, Dallio M, Federico A, Germani G, Gitto S, Leandro G, Loguercio C, Marra F, Stasi E. Alcohol associated liver disease 2020: A clinical practice guideline by the Italian Association for the Study of the Liver (AISF). Dig Liver Dis 2020; 52:374-391. [PMID: 32001151 DOI: 10.1016/j.dld.2019.12.008] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/29/2019] [Revised: 11/06/2019] [Accepted: 12/17/2019] [Indexed: 12/11/2022]
Abstract
Alcohol use disorder which includes alcohol abuse and dependence represents one of the leading risk factors for premature mortality in Europe and it is responsible of over 200 conditions, including neuropsychiatric disorders, chronic diseases, cancers and accidents leading to permanent disability. Alcohol use disorder represents the most common cause of liver damage in the Western world, with a wide spectrum of diseases ranging from steatosis, steatohepatitis, fibrosis, cirrhosis and cancer. The present clinical practice guidelines by the Italian Association for the Study of the Liver (AISF) are focused on the current knowledge about epidemiology, pathophysiology, clinical features, diagnosis and treatment of alcohol associated liver disease, aiming to provide practical recommendations on the management of this complex pathological condition.
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Affiliation(s)
- Giovanni Addolorato
- Alcohol Use Disorder Unit, Division of Internal Medicine, Gastroenterology and Hepatology Unit, Catholic University of Rome, A. Gemelli Hospital, Rome, Italy; "Agostino Gemelli" Hospital Foundation - IRCCS, Rome, Italy.
| | - Ludovico Abenavoli
- Department of Health Sciences, University Magna Graecia, Catanzaro, Italy
| | - Marcello Dallio
- Department of Precision Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Alessandro Federico
- Department of Precision Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Giacomo Germani
- Multivisceral Transplant Unit, Department of Surgery, Oncology and Gastroenterology, Padova University Hospital, Padova, Italy
| | - Stefano Gitto
- Department of Experimental and Clinical Medicine, University of Florence, Italy
| | - Gioacchino Leandro
- National Institute of Gastroenterology "S. De Bellis" Research Hospital, Castellana Grotte, Italy
| | - Carmelina Loguercio
- Department of Precision Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Fabio Marra
- Department of Experimental and Clinical Medicine, University of Florence, Italy; Research Center Denothe, University of Florence, Italy
| | - Elisa Stasi
- National Institute of Gastroenterology "S. De Bellis" Research Hospital, Castellana Grotte, Italy
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Avila MA, Dufour JF, Gerbes AL, Zoulim F, Bataller R, Burra P, Cortez-Pinto H, Gao B, Gilmore I, Mathurin P, Moreno C, Poznyak V, Schnabl B, Szabo G, Thiele M, Thursz MR. Recent advances in alcohol-related liver disease (ALD): summary of a Gut round table meeting. Gut 2020; 69:764-780. [PMID: 31879281 PMCID: PMC7236084 DOI: 10.1136/gutjnl-2019-319720] [Citation(s) in RCA: 139] [Impact Index Per Article: 27.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2019] [Revised: 11/28/2019] [Accepted: 12/06/2019] [Indexed: 12/14/2022]
Abstract
Alcohol-related liver disease (ALD), which includes a range of disorders of different severity and is one of the most prevalent types of liver disease worldwide, has recently regained increased attention. Among other reasons, the realisation that any alcohol intake, regardless of type of beverage represents a health risk, and the new therapeutic strategies tested in recently published or undergoing clinical trials spur scientific interest in this area.In April 2019, Gut convened a round table panel of experts during the European Association for the Study of the Liver International Liver Congress in Vienna to discuss critical and up-to-date issues and clinical trial data regarding ALD, its epidemiology, diagnosis, management, pathomechanisms, possible future treatments and prevention. This paper summarises the discussion and its conclusions.
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Affiliation(s)
- Matias A Avila
- Hepatology, CIBERehd, IdiSNA, CIMA, University of Navarra, Pamplona, Spain
| | - Jean-François Dufour
- Hepatology, Department of Clinical Research and University Clinic for Visceral Surgery and Medicine, Inselspital, University of Bern, Bern, Switzerland
| | - Alexander L Gerbes
- Liver Centre Munich, Department of Medicine II, University Hospital, LMU Munich, Munich, Germany
| | - Fabien Zoulim
- Hepatology Department, INSERM U1052, Hospices Civils de Lyon, Cancer Research Centerl of Lyon, University of Lyon, Lyon, France
| | - Ramon Bataller
- Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Patrizia Burra
- Multivisceral Transplant Unit, Gastroenterology, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, Padua, Italy
| | - Helena Cortez-Pinto
- Departamento de Gastroenterologia, CHLN, Laboratorio de Nutriçao, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal
| | - Bin Gao
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland, USA
| | - Ian Gilmore
- Liverpool Centre for Alcohol Research, University of Liverpool, Liverpool, UK
| | - Philippe Mathurin
- Service des Maladies de l'Appareil Digestif, INSERM U795, Hôpital Huriez, Lille, France
| | - Christophe Moreno
- Service de Gastroentérologie, Hépatopancréatologie et Oncologie Digestive, CUB Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium
| | - Vladimir Poznyak
- Department of Mental Health and Substance Abuse, World Health Organization, Geneve, Switzerland
| | - Bernd Schnabl
- Department of Medicine, University of California San Diego, La Jolla, California, USA
| | - Gyongyi Szabo
- Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
| | - Maja Thiele
- Department of Gastroenterology and Hepatology, and Department of Clinical Research, Odense University Hospital and University of Southern Denmark, Odense, Denmark
| | - Mark R Thursz
- Department of Metabolism, Faculty of Medicine, Imperial College, London, UK
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Gopal T, Kumar N, Perriotte-Olson C, Casey CA, Donohue TM, Harris EN, Talmon G, Kabanov AV, Saraswathi V. Nanoformulated SOD1 ameliorates the combined NASH and alcohol-associated liver disease partly via regulating CYP2E1 expression in adipose tissue and liver. Am J Physiol Gastrointest Liver Physiol 2020; 318:G428-G438. [PMID: 31928222 PMCID: PMC7099493 DOI: 10.1152/ajpgi.00217.2019] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Enhanced free fatty acid (FFA) flux from adipose tissue (AT) to liver plays an important role in the development of nonalcoholic steatohepatitis (NASH) and alcohol-associated liver disease (AALD). We determined the effectiveness of nanoformulated superoxide dismutase 1 (Nano) in attenuating liver injury in a mouse model exhibiting a combination of NASH and AALD. Male C57BL6/J mice were fed a chow diet (CD) or a high-fat diet (HF) for 10 wk followed by pair feeding of the Lieber-DeCarli control (control) or ethanol (ET) diet for 4 wk. Nano was administered once every other day for the last 2 wk of ET feeding. Mice were divided into 1) CD + control diet (CD + Cont), 2) high-fat diet (HF) + control diet (HF + Cont), 3) HF + Cont + Nano, 4) HF + ET diet (HF + ET), and 5) HF + ET + Nano. The total fat mass, visceral AT mass (VAT), and VAT perilipin 1 content were significantly lower only in HF + ET-fed mice but not in HF + ET + Nano-treated mice compared with controls. The HF + ET-fed mice showed an upregulation of VAT CYP2E1 protein, and Nano abrogated this effect. We noted a significant rise in plasma FFAs, ALT, and monocyte chemoattractant protein-1 in HF + ET-fed mice, which was blunted in HF + ET + Nano-treated mice. HF + ET-induced increases in hepatic steatosis and inflammatory markers were attenuated upon Nano treatment. Nano reduced hepatic CYP2E1 and enhanced catalase levels in HF + ET-fed mice with a concomitant increase in SOD1 protein and activity in liver. Nano was effective in attenuating AT and liver injury in mice exhibiting a combination of NASH and AALD, partly via reduced CYP2E1-mediated ET metabolism in these organs.NEW & NOTEWORTHY Increased free fatty acid flux from adipose tissue (AT) to liver accompanied by oxidative stress promotes nonalcoholic steatohepatitis (NASH) and alcohol-associated liver injury (AALD). Obesity increases the severity of AALD. Using a two-hit model involving a high-fat diet and chronic ethanol feeding to mice, and treating them with nanoformulated superoxide dismutase (nanoSOD), we have shown that nanoSOD improves AT lipid storage, reduces CYP2E1 in AT and liver, and attenuates the combined NASH/AALD in mice.
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Affiliation(s)
- Thiyagarajan Gopal
- 1Division of Diabetes, Endocrinology, and Metabolism, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska
| | - Narendra Kumar
- 1Division of Diabetes, Endocrinology, and Metabolism, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska
| | - Curtis Perriotte-Olson
- 1Division of Diabetes, Endocrinology, and Metabolism, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska
| | - Carol A. Casey
- 2Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska,3Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, Nebraska
| | - Terrence M. Donohue
- 2Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska,3Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, Nebraska
| | - Edward N. Harris
- 4Department of Biochemistry, University of Nebraska Lincoln, Lincoln, Nebraska
| | - Geoffrey Talmon
- 5Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska
| | - Alexander V. Kabanov
- 6Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina
| | - Viswanathan Saraswathi
- 1Division of Diabetes, Endocrinology, and Metabolism, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska,3Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, Nebraska
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Magee N, Zou A, Ghosh P, Ahamed F, Delker D, Zhang Y. Disruption of hepatic small heterodimer partner induces dissociation of steatosis and inflammation in experimental nonalcoholic steatohepatitis. J Biol Chem 2020. [DOI: 10.1016/s0021-9258(17)49910-8] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
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40
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Magee N, Zou A, Ghosh P, Ahamed F, Delker D, Zhang Y. Disruption of hepatic small heterodimer partner induces dissociation of steatosis and inflammation in experimental nonalcoholic steatohepatitis. J Biol Chem 2019; 295:994-1008. [PMID: 31831621 DOI: 10.1074/jbc.ra119.010233] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2019] [Revised: 11/23/2019] [Indexed: 12/16/2022] Open
Abstract
Nonalcoholic steatohepatitis (NASH) is a leading cause of chronic liver disease worldwide and is characterized by steatosis, inflammation, and fibrosis. The molecular mechanisms underlying NASH development remain obscure. The nuclear receptor small heterodimer partner (Shp) plays a complex role in lipid metabolism and inflammation. Here, we sought to determine SHP's role in regulating steatosis and inflammation in NASH. Shp deletion in murine hepatocytes (Shp Hep-/-) resulted in massive infiltration of macrophages and CD4+ T cells in the liver. Shp Hep-/- mice developed reduced steatosis, but surprisingly increased hepatic inflammation and fibrosis after being fed a high-fat, -cholesterol, and -fructose (HFCF) diet. RNA-Seq analysis revealed that pathways involved in inflammation and fibrosis are significantly activated in the liver of Shp Hep-/- mice fed a chow diet. After having been fed the HFCF diet, WT mice displayed up-regulated peroxisome proliferator-activated receptor γ (Pparg) signaling in the liver; however, this response was completely abolished in the Shp Hep-/- mice. In contrast, livers of Shp Hep-/- mice had consistent NF-κB activation. To further characterize the role of Shp specifically in the transition of steatosis to NASH, mice were fed the HFCF diet for 4 weeks, followed by Shp deletion. Surprisingly, Shp deletion after steatosis development exacerbated hepatic inflammation and fibrosis without affecting liver steatosis. Together, our results indicate that, depending on NASH stage, hepatic Shp plays an opposing role in steatosis and inflammation. Mechanistically, Shp deletion in hepatocytes activated NF-κB and impaired Pparg activation, leading to the dissociation of steatosis, inflammation, and fibrosis in NASH development.
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Affiliation(s)
- Nancy Magee
- Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas 66160
| | - An Zou
- Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas 66160
| | - Priyanka Ghosh
- Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas 66160
| | - Forkan Ahamed
- Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas 66160
| | - Don Delker
- Department of Medicine, University of Utah School of Medicine, Salt Lake City, Utah 84108
| | - Yuxia Zhang
- Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas 66160 .,Liver Center, University of Kansas Medical Center, Kansas City, Kansas 66160
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41
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Parker R, Kim SJ, Im GY, Nahas J, Dhesi B, Vergis N, Sinha A, Ghezzi A, Rink MR, McCune A, Aithal GP, Newsome PN, Weston CJ, Holt A, Gao B. Obesity in acute alcoholic hepatitis increases morbidity and mortality. EBioMedicine 2019; 45:511-518. [PMID: 31278069 PMCID: PMC6642069 DOI: 10.1016/j.ebiom.2019.03.046] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2019] [Revised: 03/15/2019] [Accepted: 03/18/2019] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND Alcohol and obesity synergise to increase the risk of liver-related mortality. We examined the influence of adiposity on clinical outcomes in alcoholic hepatitis (AH) and the underlying inflammatory crosstalk between adipose tissue (AT) and the liver. METHODS A cohort of 233 patients with AH from the UK and USA provided data to analyse the effects of obesity in AH. Body mass index was corrected for the severity of ascites, termed cBMI. Inflammatory and metabolic profiling was undertaken by proteome analysis of human serum samples. The effect of alcohol on adipose tissue and CXCL11 expression was studied in 3 T3-derived adipocytes and in mice using the high-fat diet-plus-binge ethanol model. FINDINGS Obesity was common amongst patients with AH, seen in 19% of individuals. Obesity (HR 2.22, 95%CI 1.1-4.3, p = .022) and underweight (HR 2.38, 1.00-5.6, p = .049) were independently associated with mortality at 3 months. Proteome analysis demonstrated multiple metabolic and inflammatory factors differentially expressed in obese AH verse lean AH, with CXCL11 being the most elevated factor in obese AH. In vitro analysis of cultured adipocytes and in vivo analysis of mouse models showed that alcohol induced CXCL11 expression in AT, but not in liver. INTERPRETATION Obesity is common in AH and associated with a greater than two-fold increase in short-term mortality. Obese AH is associated with a different inflammatory phenotype, with the greatest elevation in CXCL11. These data confirm that adiposity is clinically important in acute alcohol-related liver disease and illustrate the adipose-liver inflammatory axis in AH. FUND: This work was supported in part by an EASL Sheila Sherlock Physician Scientist Fellowship. The funder played no role in gathering or analysing data or writing the manuscript. This paper presents independent research supported by the NIHR Birmingham Biomedical Research Centre at the University Hospitals Birmingham NHS Foundation Trust and the University of Birmingham. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care.
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Affiliation(s)
- Richard Parker
- Liver and Hepatobiliary Unit, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK; Centre for Liver Research, University of Birmingham, Birmingham, UK; National Institute for Alcoholism and Alcohol Abuse, National Institutes of Health, Rockville, MD, USA.
| | - S J Kim
- National Institute for Alcoholism and Alcohol Abuse, National Institutes of Health, Rockville, MD, USA
| | - G Y Im
- Mount Sinai Medical Centre, New York, NY, USA
| | - J Nahas
- Mount Sinai Medical Centre, New York, NY, USA
| | - B Dhesi
- Liver and Hepatobiliary Unit, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
| | - N Vergis
- Imperial College Healthcare NHS Foundation Trust, UK
| | - A Sinha
- Department of Liver Medicine, University Hospitals Bristol NHS Foundation Trust, UK
| | - A Ghezzi
- NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and the University Of Nottingham, Nottingham, UK
| | - M R Rink
- Centre for Liver Research, University of Birmingham, Birmingham, UK
| | - A McCune
- Department of Liver Medicine, University Hospitals Bristol NHS Foundation Trust, UK
| | - G P Aithal
- NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and the University Of Nottingham, Nottingham, UK
| | - P N Newsome
- Liver and Hepatobiliary Unit, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK; Centre for Liver Research, University of Birmingham, Birmingham, UK
| | - C J Weston
- Centre for Liver Research, University of Birmingham, Birmingham, UK
| | - A Holt
- Liver and Hepatobiliary Unit, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
| | - B Gao
- National Institute for Alcoholism and Alcohol Abuse, National Institutes of Health, Rockville, MD, USA
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Kim SJ, Feng D, Guillot A, Dai S, Liu F, Hwang S, Parker R, Seo W, He Y, Godlewski G, Jeong WI, Lin Y, Qin X, Kunos G, Gao B. Adipocyte Death Preferentially Induces Liver Injury and Inflammation Through the Activation of Chemokine (C-C Motif) Receptor 2-Positive Macrophages and Lipolysis. Hepatology 2019; 69:1965-1982. [PMID: 30681731 PMCID: PMC6461506 DOI: 10.1002/hep.30525] [Citation(s) in RCA: 46] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2018] [Accepted: 12/21/2018] [Indexed: 12/16/2022]
Abstract
Adipocyte death occurs under various physiopathological conditions, including obesity and alcohol drinking, and can trigger organ damage particularly in the liver, but the underlying mechanisms remain obscure. To explore these mechanisms, we developed a mouse model of inducible adipocyte death by overexpressing the human CD59 (hCD59) on adipocytes (adipocyte-specific hCD59 transgenic mice). Injection of these mice with intermedilysin (ILY), which rapidly lyses hCD59 expressing cells exclusively by binding to the hCD59 but not mouse CD59, resulted in the acute selective death of adipocytes, adipose macrophage infiltration, and elevation of serum free fatty acid (FFA) levels. ILY injection also resulted in the secondary damage to multiple organs with the strongest injury observed in the liver, with inflammation and hepatic macrophage activation. Mechanistically, acute adipocyte death elevated epinephrine and norepinephrine levels and activated lipolysis pathways in adipose tissue in a chemokine (C-C motif) receptor 2-positive (CCR2+ ) macrophage-dependent manner, which was followed by FFA release and lipotoxicity in the liver. Additionally, acute adipocyte death caused hepatic CCR2+ macrophage activation and infiltration, further exacerbating liver injury. Conclusion: Adipocyte death predominantly induces liver injury and inflammation, which is probably due to the superior sensitivity of hepatocytes to lipotoxicity and the abundance of macrophages in the liver.
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Affiliation(s)
- Seung-Jin Kim
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA
| | - Dechun Feng
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA
| | - Adrien Guillot
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA
| | - Shen Dai
- Department of Neuroscience, School of Medicine, Temple University, Philadelphia, PA, USA
| | - Fengming Liu
- Department of Neuroscience, School of Medicine, Temple University, Philadelphia, PA, USA
| | - Seonghwan Hwang
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA
| | - Richard Parker
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA,NIHR Centre for Liver Research, University of Birmingham, UK
| | - Wonhyo Seo
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA
| | - Yong He
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA
| | - Grzegorz Godlewski
- Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892; USA
| | - Won-Il Jeong
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA,Laboratory of Liver Research, Biomedical Science and Engineering Interdisciplinary Program, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Republic of Korea
| | - Yuhong Lin
- Laboratory of Membrane Biochemistry and Biophysics, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892; USA
| | - Xuebin Qin
- Department of Neuroscience, School of Medicine, Temple University, Philadelphia, PA, USA
| | - George Kunos
- Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892; USA
| | - Bin Gao
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA,Corresponding author: Bin Gao, M.D., Ph.D., Laboratory of Liver Diseases, NIAAA/NIH, 5625 Fishers Lane, Bethesda, MD 20892. Tel: 301-443-3998;
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Torres-Hernandez A, Wang W, Nikiforov Y, Tejada K, Torres L, Kalabin A, Wu Y, Haq MIU, Khan MY, Zhao Z, Su W, Camargo J, Hundeyin M, Diskin B, Adam S, Rossi JAK, Kurz E, Aykut B, Shadaloey SAA, Leinwand J, Miller G. Targeting SYK signaling in myeloid cells protects against liver fibrosis and hepatocarcinogenesis. Oncogene 2019; 38:4512-4526. [PMID: 30742098 DOI: 10.1038/s41388-019-0734-5] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2018] [Revised: 01/02/2019] [Accepted: 01/04/2019] [Indexed: 02/07/2023]
Abstract
Liver fibrosis and fibrosis-associated hepatocarcinogenesis are driven by chronic inflammation and are leading causes of morbidity and death worldwide. SYK signaling regulates critical processes in innate and adaptive immunity, as well as parenchymal cells. We discovered high SYK expression in the parenchymal hepatocyte, hepatic stellate cell (HSC), and the inflammatory compartments in the fibrotic liver. We postulated that targeting SYK would mitigate hepatic fibrosis and oncogenic progression. We found that inhibition of SYK with the selective small molecule inhibitors Piceatannol and PRT062607 markedly protected against toxin-induced hepatic fibrosis, associated hepatocellular injury and intra-hepatic inflammation, and hepatocarcinogenesis. SYK inhibition resulted in increased intra-tumoral expression of the p16 and p53 but decreased expression of Bcl-xL and SMAD4. Further, hepatic expression of genes regulating angiogenesis, apoptosis, cell cycle regulation, and cellular senescence were affected by targeting SYK. We found that SYK inhibition mitigated both HSC trans-differentiation and acquisition of an inflammatory phenotype in T cells, B cells, and myeloid cells. However, in vivo experiments employing selective targeted deletion of SYK indicated that only SYK deletion in the myeloid compartment was sufficient to confer protection against fibrogenic progression. Targeting SYK promoted myeloid cell differentiation into hepato-protective TNFαlow CD206hi phenotype downregulating mTOR, IL-8 signaling and oxidative phosphorylation. Collectively, these data suggest that SYK is an attractive target for experimental therapeutics in treating hepatic fibrosis and oncogenesis.
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Affiliation(s)
- Alejandro Torres-Hernandez
- S.A. Localio Laboratory, Departments of Surgery, New York University School of Medicine, 450 East 29th Street, New York, NY, 10016, USA
| | - Wei Wang
- S.A. Localio Laboratory, Departments of Surgery, New York University School of Medicine, 450 East 29th Street, New York, NY, 10016, USA
| | - Yuri Nikiforov
- S.A. Localio Laboratory, Departments of Surgery, New York University School of Medicine, 450 East 29th Street, New York, NY, 10016, USA
| | - Karla Tejada
- S.A. Localio Laboratory, Departments of Surgery, New York University School of Medicine, 450 East 29th Street, New York, NY, 10016, USA
| | - Luisana Torres
- S.A. Localio Laboratory, Departments of Surgery, New York University School of Medicine, 450 East 29th Street, New York, NY, 10016, USA
| | - Aleksandr Kalabin
- S.A. Localio Laboratory, Departments of Surgery, New York University School of Medicine, 450 East 29th Street, New York, NY, 10016, USA
| | - Yue Wu
- S.A. Localio Laboratory, Departments of Surgery, New York University School of Medicine, 450 East 29th Street, New York, NY, 10016, USA
| | - Muhammad Israr Ul Haq
- S.A. Localio Laboratory, Departments of Surgery, New York University School of Medicine, 450 East 29th Street, New York, NY, 10016, USA
| | - Mohammed Y Khan
- S.A. Localio Laboratory, Departments of Surgery, New York University School of Medicine, 450 East 29th Street, New York, NY, 10016, USA
| | - Zhen Zhao
- S.A. Localio Laboratory, Departments of Surgery, New York University School of Medicine, 450 East 29th Street, New York, NY, 10016, USA
| | - Wenyu Su
- S.A. Localio Laboratory, Departments of Surgery, New York University School of Medicine, 450 East 29th Street, New York, NY, 10016, USA
| | - Jimmy Camargo
- S.A. Localio Laboratory, Departments of Surgery, New York University School of Medicine, 450 East 29th Street, New York, NY, 10016, USA
| | - Mautin Hundeyin
- S.A. Localio Laboratory, Departments of Surgery, New York University School of Medicine, 450 East 29th Street, New York, NY, 10016, USA
| | - Brian Diskin
- S.A. Localio Laboratory, Departments of Surgery, New York University School of Medicine, 450 East 29th Street, New York, NY, 10016, USA
| | - Salma Adam
- S.A. Localio Laboratory, Departments of Surgery, New York University School of Medicine, 450 East 29th Street, New York, NY, 10016, USA
| | - Juan A Kochen Rossi
- S.A. Localio Laboratory, Departments of Surgery, New York University School of Medicine, 450 East 29th Street, New York, NY, 10016, USA
| | - Emma Kurz
- S.A. Localio Laboratory, Departments of Surgery, New York University School of Medicine, 450 East 29th Street, New York, NY, 10016, USA
| | - Berk Aykut
- S.A. Localio Laboratory, Departments of Surgery, New York University School of Medicine, 450 East 29th Street, New York, NY, 10016, USA
| | - Sorin A A Shadaloey
- S.A. Localio Laboratory, Departments of Surgery, New York University School of Medicine, 450 East 29th Street, New York, NY, 10016, USA
| | - Joshua Leinwand
- S.A. Localio Laboratory, Departments of Surgery, New York University School of Medicine, 450 East 29th Street, New York, NY, 10016, USA
| | - George Miller
- S.A. Localio Laboratory, Departments of Surgery, New York University School of Medicine, 450 East 29th Street, New York, NY, 10016, USA. .,Departments of Cell Biology, New York University School of Medicine, 450 East 29th Street, New York, NY, 10016, USA.
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Gao B, Ahmad MF, Nagy LE, Tsukamoto H. Inflammatory pathways in alcoholic steatohepatitis. J Hepatol 2019; 70:249-259. [PMID: 30658726 PMCID: PMC6361545 DOI: 10.1016/j.jhep.2018.10.023] [Citation(s) in RCA: 260] [Impact Index Per Article: 43.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2018] [Revised: 10/16/2018] [Accepted: 10/23/2018] [Indexed: 12/12/2022]
Abstract
Inflammatory processes are primary contributors to the development and progression of alcoholic steatohepatitis (ASH), with severe alcoholic hepatitis characterised by non-resolving inflammation. Inflammation in the progression of ASH is a complex response to microbial dysbiosis, loss of barrier integrity in the intestine, hepatocellular stress and death, as well as inter-organ crosstalk. Herein, we review the roles of multiple cell types that are involved in inflammation in ASH, including resident macrophages and infiltrating monocytes, as well as other cell types in the innate and adaptive immune system. In response to chronic, heavy alcohol exposure, hepatocytes themselves also contribute to the inflammatory process; hepatocytes express a large number of chemokines and inflammatory mediators and can also release damage-associated molecular patterns during injury and death. These cellular responses are mediated and accompanied by changes in the expression of pro- and anti-inflammatory cytokines and chemokines, as well as by signals which orchestrate the recruitment of immune cells and activation of the inflammatory process. Additional mechanisms for cell-cell and inter-organ communication in ASH are also reviewed, including the roles of extracellular vesicles and microRNAs, as well as inter-organ crosstalk. We highlight the concept that inflammation also plays an important role in promoting liver repair and controlling bacterial infection. Understanding the complex regulatory processes that are disrupted during the progression of ASH will likely lead to better targeted strategies for therapeutic interventions.
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Affiliation(s)
- Bin Gao
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD 20892, United States.
| | - Maleeha F Ahmad
- Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, OH, United States
| | - Laura E Nagy
- Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, OH, United States; Northern Ohio Alcohol Center, Departments of Molecular Medicine, Inflammation and Immunity, Cleveland Clinic, Cleveland, OH, United States.
| | - Hidekazu Tsukamoto
- Southern California Research Center for ALPD and Cirrhosis, Department of Pathology, University of Southern California, Greater Los Angeles VA Healthcare System, Los Angeles, CA, United States.
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Chen L, Gu J, Qian Y, Li M, Qian Y, Xu M, Li J, Wen Y, Xia L, Li J, Xia Q, Kong X, Wu H. Deletion of C-C Motif Chemokine Ligand 5 Worsens Invariant Natural Killer T-Cell-Mediated Hepatitis via Compensatory Up-regulation of CXCR2-Related Chemokine Activity. Cell Mol Gastroenterol Hepatol 2019; 7:623-639. [PMID: 30630119 PMCID: PMC6434496 DOI: 10.1016/j.jcmgh.2018.12.009] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2018] [Revised: 12/29/2018] [Accepted: 12/31/2018] [Indexed: 12/13/2022]
Abstract
BACKGROUND & AIMS Chemokine-mediated immune cell recruitment plays pivotal roles in liver inflammation. C-C motif chemokine ligand 5 (CCL5) has been shown to be responsible for the recruitment of monocytes/macrophages and has been implicated in various liver diseases, including nonalcoholic fatty liver disease, fibrosis, and hepatocellular carcinoma. Previous studies have also shown that inhibition of CCL5 appears to be a promising therapeutic approach for several chronic liver diseases. However, whether blocking CCL5 could benefit immune cell-mediated hepatitis remains largely elusive. METHODS By adopting a specific agonist, alpha-galactosylceramide (α-Galcer), of invariant natural killer T cells (iNKTs), we investigated the function and mechanism of CCL5 in the iNKT induced murine hepatitis model. RESULTS We found significantly increased CCL5 expression in α-Galcer-induced hepatitis murine model. Such an increase in CCL5 is mainly enriched in non-parenchymal cells such as macrophages and iNKTs but not in hepatocytes. Surprisingly, CCL5 blockage by genetic deletion of Ccl5 does not affect the α-Galcer-induced iNKT activation but greatly worsens α-Galcer-induced liver injury accompanied by an increased hepatic neutrophil infiltration. Mechanistically, we demonstrated that greater neutrophil accumulation in the liver is responsible for the enhanced liver injury in Ccl5-/- mice. Such an increased hepatic neutrophil infiltration is mainly caused by an enhanced CXCL1-CXCR2 signal in Ccl5-/- mice. Therapeutically, either antibody-mediated neutrophil depletion or a CXCR2 antagonist, SB225002, mediated CXCR2 signaling blockage significantly ameliorated α-Galcer-induced liver injury in Ccl5-/- mice. CONCLUSIONS Our present study demonstrates that (1) α-Galcer-induced murine hepatitis could greatly induce CCL5 production in macrophages and iNKT cells; (2) loss of CCL5 could enhance CXCL1 expression in hepatocytes and activate CXCL1-CXCR2 axis in neutrophils to augment their hepatic infiltration; and (3) neutrophil depletion or blockage of CXCL1-CXCR2 axis greatly improves α-Galcer-induced liver injury in Ccl5-/- mice. This study suggests that clinical utilization of CCL5 blockage may compensatorily induce the activation of other chemokine pathways to enhance neutrophil recruitment and liver injury in hepatitis.
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Affiliation(s)
- Lili Chen
- Shanghai Key Laboratory for Molecular Imaging, Collaborative Research Center, Shanghai University of Medicine and Health Sciences, Shanghai, China; Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Jinyang Gu
- Department of Transplantation, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Yihan Qian
- School of Pharmacy, Fudan University, Shanghai, China
| | - Meng Li
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Yongbing Qian
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Min Xu
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Jichang Li
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Yankai Wen
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Lei Xia
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Jiaxin Li
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Qiang Xia
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Xiaoni Kong
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
| | - Hailong Wu
- Shanghai Key Laboratory for Molecular Imaging, Collaborative Research Center, Shanghai University of Medicine and Health Sciences, Shanghai, China.
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Chen Z, Liu F, Zheng N, Guo M, Bao L, Zhan Y, Zhang M, Zhao Y, Guo W, Ding G. Wuzhi capsule (Schisandra Sphenanthera extract) attenuates liver steatosis and inflammation during non-alcoholic fatty liver disease development. Biomed Pharmacother 2018; 110:285-293. [PMID: 30522014 DOI: 10.1016/j.biopha.2018.11.069] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2018] [Revised: 11/11/2018] [Accepted: 11/19/2018] [Indexed: 02/08/2023] Open
Abstract
OBJECTIVE Wuzhi (WZ) capsule contains an ethanol extract of Schisandra sphenanthera. The efficacy of WZ in treating non-alcoholic fatty liver disease (NAFLD) has not yet been elucidated. The present study assessed the effects of WZ on NAFLD. MATERIAL AND METHODS A C57BL/6 male mouse model of NAFLD was established by feeding the animals a methionine-choline-deficient (MCD) diet. Mice fed the basal diet were used as controls. Both groups were randomly administered WZ or vehicle by gavage for 5 weeks. Body weight change, liver/body weight ratio, metabolic parameters, and histological changes were assessed. Serum levels of IL-1β, IL-6, IL-10, and TNF-α were analysed by ELISA; mRNA expression of these genes in the liver was studied by real-time PCR. Western blotting was used to analyse the protein levels of PPAR-α, PPAR-γ, MCAD, LCAD, and p65 in the liver. RESULTS After 5 weeks of the MCD diet, the liver/body weight ratio of WZ mice was higher than that of control mice. Liver histology revealed significantly less steatosis, inflammation, and necrosis, which was confirmed by decreased intrahepatic triglycerides and serum ALT in WZ-treated mice. WZ also reduced the liver mRNA expression of IL-1β, IL-6, and TNF-α and the serum levels of IL-1β and IL-6. Sensitivity to steatohepatitis due to WZ administration correlated significantly with alterations in the expression of PPAR-α/γ, as well as the NF-κB signalling pathway. CONCLUSIONS WZ plays a protective role against MCD-induced steatohepatitis. The underlying mechanism likely involves the upregulation of PPAR-α/γ and downregulation of the NF-κB signalling pathway. Based on its beneficial effects on the liver, WZ is a promising therapeutic for NAFLD patients.
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Affiliation(s)
- Ziqi Chen
- Department of Organ Transplantation, ChangZheng Hospital, Second Military Medical University, Shanghai, 200003, China
| | - Fang Liu
- Department of Organ Transplantation, ChangZheng Hospital, Second Military Medical University, Shanghai, 200003, China
| | - Nanxin Zheng
- Department of Colorectal Surgery, Changhai Hospital, Second Military Medical University, Shanghai, 200433, China
| | - Meng Guo
- Department of Organ Transplantation, ChangZheng Hospital, Second Military Medical University, Shanghai, 200003, China
| | - Leilei Bao
- National Key Laboratory of Medical Immunology, Second Military Medical University, Shanghai, 200433, China
| | - Yangyang Zhan
- National Key Laboratory of Medical Immunology, Second Military Medical University, Shanghai, 200433, China
| | - Mingjian Zhang
- National Key Laboratory of Medical Immunology, Second Military Medical University, Shanghai, 200433, China
| | - Yuanyu Zhao
- Department of Organ Transplantation, ChangZheng Hospital, Second Military Medical University, Shanghai, 200003, China
| | - Wenyuan Guo
- Department of Organ Transplantation, ChangZheng Hospital, Second Military Medical University, Shanghai, 200003, China.
| | - Guoshan Ding
- Department of Organ Transplantation, ChangZheng Hospital, Second Military Medical University, Shanghai, 200003, China.
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Murayama H, Eguchi A, Nakamura M, Kawashima M, Nagahara R, Mizukami S, Kimura M, Makino E, Takahashi N, Ohtsuka R, Koyanagi M, Hayashi SM, Maronpot RR, Shibutani M, Yoshida T. Spironolactone in Combination with α-glycosyl Isoquercitrin Prevents Steatosis-related Early Hepatocarcinogenesis in Rats through the Observed NADPH Oxidase Modulation. Toxicol Pathol 2018; 46:530-539. [PMID: 29843569 DOI: 10.1177/0192623318778508] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Administration of the diuretic, spironolactone (SR), can inhibit chronic liver diseases. We determined the effects of SR alone or in combination with the antioxidant α-glycosyl isoquercitrin (AGIQ) on hyperlipidemia- and steatosis-related precancerous lesions in high-fat diet (HFD)-fed rats subjected to a two-stage hepatocarcinogenesis model. Rats were fed with control basal diet or HFD, which was administered with SR alone or in combination with an antioxidant AGIQ in drinking water. An HFD increased body weight, intra-abdominal fat (adipose) tissue weight, and plasma lipids, which were reduced by coadministration of SR and AGIQ. SR and AGIQ coadministration also reduced hepatic steatosis and preneoplastic glutathione S-transferase placental form-positive foci, in association with decrease in NADPH oxidase (NOX) subunit p22phox-positive cells and an increase in active-caspase-3-positive cells in the foci. Hepatic gene expression analysis revealed that the coadministration of SR and AGIQ altered mRNA levels of lipogenic enzymes ( Scd1 and Fasn), antioxidant-related enzymes ( Catalase), NOX component ( P67phox), and anti-inflammatory transcriptional factor ( Pparg). Our results indicated that SR in combination with AGIQ had the potential of suppressing hyperlipidemia- and steatosis-related early hepatocarcinogenesis through the reduced expression of NOX subunits.
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Affiliation(s)
- Hirotada Murayama
- 1 Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology, Fuchu-shi, Tokyo, Japan
| | - Ayumi Eguchi
- 1 Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology, Fuchu-shi, Tokyo, Japan
| | - Misato Nakamura
- 1 Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology, Fuchu-shi, Tokyo, Japan
| | - Masahi Kawashima
- 1 Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology, Fuchu-shi, Tokyo, Japan
| | - Rei Nagahara
- 1 Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology, Fuchu-shi, Tokyo, Japan
| | - Sayaka Mizukami
- 1 Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology, Fuchu-shi, Tokyo, Japan.,2 Pathogenetic Veterinary Science, United Graduate School of Veterinary Sciences, Gifu University, Gifu-shi, Gifu, Japan
| | - Masayuki Kimura
- 1 Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology, Fuchu-shi, Tokyo, Japan.,2 Pathogenetic Veterinary Science, United Graduate School of Veterinary Sciences, Gifu University, Gifu-shi, Gifu, Japan
| | - Emi Makino
- 3 Institute of Environmental Toxicology, Joso-shi, Ibaraki, Japan
| | | | - Ryoichi Ohtsuka
- 3 Institute of Environmental Toxicology, Joso-shi, Ibaraki, Japan
| | - Mihoko Koyanagi
- 4 Global Scientific and Regulatory Affairs, San-Ei Gen F. F. I., Inc., Toyonaka, Osaka, Japan
| | - Shim-Mo Hayashi
- 4 Global Scientific and Regulatory Affairs, San-Ei Gen F. F. I., Inc., Toyonaka, Osaka, Japan
| | | | - Makoto Shibutani
- 1 Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology, Fuchu-shi, Tokyo, Japan
| | - Toshinori Yoshida
- 1 Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology, Fuchu-shi, Tokyo, Japan
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Rajamoorthi A, Lee RG, Baldán Á. Therapeutic silencing of FSP27 reduces the progression of atherosclerosis in Ldlr -/- mice. Atherosclerosis 2018; 275:43-49. [PMID: 29859472 PMCID: PMC6113075 DOI: 10.1016/j.atherosclerosis.2018.05.045] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2018] [Revised: 05/08/2018] [Accepted: 05/23/2018] [Indexed: 11/22/2022]
Abstract
Background and aims Obesity, hepatosteatosis, and hypertriglyceridemia are components of the metabolic syndrome and independent risk factors for cardiovascular disease. The lipid droplet-associated protein CIDEC (cell death-inducing DFFA-like effector C), known in mice as FSP27 (fat-specific protein 27), plays a key role in maintaining triacylglyceride (TAG) homeostasis in adipose tissue and liver, and controls circulating TAG levels in mice. Importantly, mutations and SNPs in CIDEC are associated with dyslipidemia and altered metabolic function in humans. Here we tested whether systemic silencing of Fsp27 using antisense oligonucleotides (ASOs) was atheroprotective in LDL receptor knock-out (Ldlr−/−) mice. Methods Atheroprone Ldlr−/− mice were fed a high-fat, high-cholesterol diet for 12 weeks while simultaneously dosed with saline, ASO-ctrl, or ASO-Fsp27. Results Data show that, compared to control treatments, silencing Fsp27 significantly reduced body weight gain and visceral adiposity, prevented diet-induced hypertriglyceridemia, and reduced athero-sclerotic lesion size both in en face aortas and in the aortic root. Conclusions Our findings suggest that therapeutic silencing of Fsp27 with ASOs may be beneficial in the prevention and management of atherogenic disease in patients with metabolic syndrome.
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Affiliation(s)
- Ananthi Rajamoorthi
- Edward A. Doisy Department of Biochemistry & Molecular Biology, Saint Louis University, Saint Louis, MO, 63104, USA
| | - Richard G Lee
- Cardiovascular Group, Antisense Drug Discovery, Ionis Pharmaceuticals, Carlsbad, CA, 92010, USA
| | - Ángel Baldán
- Edward A. Doisy Department of Biochemistry & Molecular Biology, Saint Louis University, Saint Louis, MO, 63104, USA; Center for Cardiovascular Research, Saint Louis, MO, 63104, USA; Liver Center, Saint Louis University, Saint Louis, MO, 63104, USA.
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Animal models of binge drinking, current challenges to improve face validity. Neurosci Biobehav Rev 2018; 106:112-121. [PMID: 29738795 DOI: 10.1016/j.neubiorev.2018.05.002] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2018] [Revised: 03/29/2018] [Accepted: 05/01/2018] [Indexed: 01/08/2023]
Abstract
Binge drinking (BD), i.e., consuming a large amount of alcohol in a short period of time, is an increasing public health issue. Though no clear definition has been adopted worldwide the speed of drinking seems to be a keystone of this behavior. Developing relevant animal models of BD is a priority for gaining a better characterization of the neurobiological and psychobiological mechanisms underlying this dangerous and harmful behavior. Until recently, preclinical research on BD has been conducted mostly using forced administration of alcohol, but more recent studies used scheduled access to alcohol, to model more voluntary excessive intakes, and to achieve signs of intoxications that mimic the human behavior. The main challenges for future research are discussed regarding the need of good face validity, construct validity and predictive validity of animal models of BD.
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Linares I, Farrokhi K, Echeverri J, Kaths JM, Kollmann D, Hamar M, Urbanellis P, Ganesh S, Adeyi OA, Yip P, Selzner M, Selzner N. PPAR-gamma activation is associated with reduced liver ischemia-reperfusion injury and altered tissue-resident macrophages polarization in a mouse model. PLoS One 2018; 13:e0195212. [PMID: 29617419 PMCID: PMC5884549 DOI: 10.1371/journal.pone.0195212] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2017] [Accepted: 03/19/2018] [Indexed: 12/26/2022] Open
Abstract
BACKGROUND PPAR-gamma (γ) is highly expressed in macrophages and its activation affects their polarization. The effect of PPAR-γ activation on Kupffer cells (KCs) and liver ischemia-reperfusion injury (IRI) has not yet been evaluated. We investigated the effect of PPAR-γ activation on KC-polarization and IRI. MATERIALS AND METHODS Seventy percent (70%) liver ischemia was induced for 60mins. PPAR-γ-agonist or vehicle was administrated before reperfusion. PPAR-γ-antagonist was used to block PPAR-γ activation. Liver injury, necrosis, and apoptosis were assessed post-reperfusion. Flow-cytometry determined KC-phenotypes (pro-inflammatory Nitric Oxide +, anti-inflammatory CD206+ and anti-inflammatory IL-10+). RESULTS Liver injury assessed by serum AST was significantly decreased in PPAR-γ-agonist versus control group at all time points post reperfusion (1hr: 3092±105 vs 4469±551; p = 0.042; 6hr: 7041±1160 vs 12193±1143; p = 0.015; 12hr: 5746±328 vs 8608±1259; p = 0.049). Furthermore, liver apoptosis measured by TUNEL-staining was significantly reduced in PPAR-γ-agonist versus control group post reperfusion (1hr:2.46±0.49 vs 6.90±0.85%;p = 0.001; 6hr:26.40±2.93 vs 50.13±8.29%; p = 0.048). H&E staining demonstrated less necrosis in PPAR-γ-agonist versus control group (24hr:26.66±4.78 vs 45.62±4.57%; p = 0.032). The percentage of pro-inflammatory NO+ KCs was significantly lower at all post reperfusion time points in the PPAR-γ-agonist versus control group (1hr:28.49±4.99 vs 53.54±9.15%; p = 0.040; 6hr:5.51±0.54 vs 31.12±9.58%; p = 0.009; 24hr:4.15±1.50 vs 17.10±4.77%; p = 0.043). In contrast, percentage of anti-inflammatory CD206+ KCs was significantly higher in PPAR-γ-agonist versus control group prior to IRI (8.62±0.96 vs 4.88 ±0.50%; p = 0.04). Administration of PPAR-γ-antagonist reversed the beneficial effects on AST, apoptosis, and pro-inflammatory NO+ KCs. CONCLUSION PPAR-γ activation reduces IRI and decreases the pro-inflammatory NO+ Kupffer cells. PPAR-γ activation can become an important tool to improve outcomes in liver surgery through decreasing the pro-inflammatory phenotype of KCs and IRI.
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Affiliation(s)
- Ivan Linares
- Multi Organ Transplant Program, Toronto General Hospital, Toronto, ON, Canada
- Consejo Nacional de Ciencia y Tecnología, México City, México
- Institute of Medical Science, University of Toronto, Toronto, ON, Canada
| | - Kaveh Farrokhi
- Multi Organ Transplant Program, Toronto General Hospital, Toronto, ON, Canada
- Department of Immunology, University of Toronto, Toronto, ON, Canada
| | - Juan Echeverri
- Multi Organ Transplant Program, Toronto General Hospital, Toronto, ON, Canada
| | - Johan Moritz Kaths
- Multi Organ Transplant Program, Toronto General Hospital, Toronto, ON, Canada
- Institute of Medical Science, University of Toronto, Toronto, ON, Canada
| | - Dagmar Kollmann
- Multi Organ Transplant Program, Toronto General Hospital, Toronto, ON, Canada
| | - Matyas Hamar
- Multi Organ Transplant Program, Toronto General Hospital, Toronto, ON, Canada
| | - Peter Urbanellis
- Multi Organ Transplant Program, Toronto General Hospital, Toronto, ON, Canada
- Institute of Medical Science, University of Toronto, Toronto, ON, Canada
| | - Sujani Ganesh
- Multi Organ Transplant Program, Toronto General Hospital, Toronto, ON, Canada
| | - Oyedele A. Adeyi
- Department of Pathology, Toronto General Hospital, Toronto, ON, Canada
| | - Paul Yip
- Laboratory of Medicine and Pathobiology, Toronto General Hospital, Toronto, ON, Canada
| | - Markus Selzner
- Multi Organ Transplant Program, Toronto General Hospital, Toronto, ON, Canada
| | - Nazia Selzner
- Multi Organ Transplant Program, Toronto General Hospital, Toronto, ON, Canada
- * E-mail:
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