PMID- 34603062 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20211005 IS - 1663-9812 (Print) IS - 1663-9812 (Electronic) IS - 1663-9812 (Linking) VI - 12 DP - 2021 TI - Alcohol Abstinence Rescues Hepatic Steatosis and Liver Injury via Improving Metabolic Reprogramming in Chronic Alcohol-Fed Mice. PG - 752148 LID - 10.3389/fphar.2021.752148 [doi] LID - 752148 AB - Background: Alcoholic liver disease (ALD) caused by chronic ethanol overconsumption is a common type of liver disease with a severe mortality burden throughout the world. The pathogenesis of ALD is complex, and no effective clinical treatment for the disease has advanced so far. Prolonged alcohol abstinence is the most effective therapy to attenuate the clinical course of ALD and even reverse liver damage. However, the molecular mechanisms involved in alcohol abstinence-improved recovery from alcoholic fatty liver remain unclear. This study aims to systematically evaluate the beneficial effect of alcohol abstinence on pathological changes in ALD. Methods: Using the Lieber-DeCarli mouse model of ALD, we analysed whether 1-week alcohol withdrawal reversed alcohol-induced detrimental alterations, including oxidative stress, liver injury, lipids metabolism, and hepatic inflammation, by detecting biomarkers and potential targets. Results: Alcohol withdrawal ameliorated alcohol-induced hepatic steatosis by improving liver lipid metabolism reprogramming via upregulating phosphorylated 5'-AMP -activated protein kinase (p-AMPK), peroxisome proliferator-activated receptor-alpha (PPAR-alpha), and carnitine palmitoyltransferase-1 (CPT-1), and downregulating fatty acid synthase (FAS) and diacylglycerol acyltransferase-2 (DGAT-2). The activities of antioxidant enzymes, including superoxide dismutase (SOD) and glutathione peroxidase (GSH-px), were significantly enhanced by alcohol withdrawal. Importantly, the abstinence recovered alcohol-fed induced liver injury, as evidenced by the improvements in haematoxylin and eosin (H&E) staining, plasma alanine aminotransferase (ALT) levels, and liver weight/body weight ratio. Alcohol-stimulated toll-like receptor 4/mitogen-activated protein kinases (TLR4/MAPKs) were significantly reversed by alcohol withdrawal, which might mechanistically contribute to the amelioration of liver injury. Accordingly, the hepatic inflammatory factor represented by tumour necrosis factor-alpha (TNF-alpha) was improved by alcohol abstinence. Conclusion: In summary, we reported that alcohol withdrawal effectively restored hepatic lipid metabolism and reversed liver injury and inflammation by improving metabolism reprogramming. These findings enhanced our understanding of the biological mechanisms involved in the beneficial role of alcohol abstinence as an effective treatment for ALD. CI - Copyright (c) 2021 Pi, Jiang, Ding, Lai, Yang, Zhu, Guo, Fan, Chi and Li. FAU - Pi, Aiwen AU - Pi A AD - School of Public Health, Zhejiang Chinese Medical University, Hangzhou, China. AD - School of Life Science, Zhejiang Chinese Medical University, Hangzhou, China. AD - Academy of Chinese Medical Science, Zhejiang Chinese Medical University, Hangzhou, China. FAU - Jiang, Kai AU - Jiang K AD - School of Life Science, Zhejiang Chinese Medical University, Hangzhou, China. AD - Molecular Medicine Institute, Zhejiang Chinese Medical University, Hangzhou, China. FAU - Ding, Qinchao AU - Ding Q AD - School of Public Health, Zhejiang Chinese Medical University, Hangzhou, China. AD - Academy of Chinese Medical Science, Zhejiang Chinese Medical University, Hangzhou, China. FAU - Lai, Shanglei AU - Lai S AD - School of Public Health, Zhejiang Chinese Medical University, Hangzhou, China. AD - School of Life Science, Zhejiang Chinese Medical University, Hangzhou, China. FAU - Yang, Wenwen AU - Yang W AD - School of Public Health, Zhejiang Chinese Medical University, Hangzhou, China. AD - School of Life Science, Zhejiang Chinese Medical University, Hangzhou, China. FAU - Zhu, Jinyan AU - Zhu J AD - School of Public Health, Zhejiang Chinese Medical University, Hangzhou, China. AD - Academy of Chinese Medical Science, Zhejiang Chinese Medical University, Hangzhou, China. FAU - Guo, Rui AU - Guo R AD - School of Public Health, Zhejiang Chinese Medical University, Hangzhou, China. AD - Academy of Chinese Medical Science, Zhejiang Chinese Medical University, Hangzhou, China. FAU - Fan, Yibin AU - Fan Y AD - Department of Dermatology, People's Hospital of Hangzhou Medical College, Zhejiang Provincial People's Hospital, Hangzhou, China. FAU - Chi, Linfeng AU - Chi L AD - School of Basic Medicine, Zhejiang Chinese Medical University, Hangzhou, China. FAU - Li, Songtao AU - Li S AD - School of Public Health, Zhejiang Chinese Medical University, Hangzhou, China. AD - Molecular Medicine Institute, Zhejiang Chinese Medical University, Hangzhou, China. AD - Academy of Chinese Medical Science, Zhejiang Chinese Medical University, Hangzhou, China. LA - eng PT - Journal Article DEP - 20210916 PL - Switzerland TA - Front Pharmacol JT - Frontiers in pharmacology JID - 101548923 PMC - PMC8481816 OTO - NOTNLM OT - alcohol abstinence OT - alcoholic liver disease OT - hepatic inflammation OT - hepatic steatosis OT - liver injury COIS- The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. EDAT- 2021/10/05 06:00 MHDA- 2021/10/05 06:01 PMCR- 2021/09/16 CRDT- 2021/10/04 05:56 PHST- 2021/08/02 00:00 [received] PHST- 2021/09/01 00:00 [accepted] PHST- 2021/10/04 05:56 [entrez] PHST- 2021/10/05 06:00 [pubmed] PHST- 2021/10/05 06:01 [medline] PHST- 2021/09/16 00:00 [pmc-release] AID - 752148 [pii] AID - 10.3389/fphar.2021.752148 [doi] PST - epublish SO - Front Pharmacol. 2021 Sep 16;12:752148. doi: 10.3389/fphar.2021.752148. eCollection 2021.