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Alcohol Abstinence Rescues Hepatic Steatosis and Liver Injury via Improving Metabolic Reprogramming in Chronic Alcohol-Fed Mice.

ABSTRACT: 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-α (PPAR-α), 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-α) 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.

SUBMITTER: Pi A

PROVIDER: S-EPMC8481816 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Hepatic steatosis develops after liver transplantation (LT) in 30% of adults, and nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in nontransplanted children. However, posttransplant steatosis has been minimally studied in pediatric LT recipients. We explored the prevalence, persistence, and association with chronic liver damage of hepatic steatosis in these children. In this single-center study of pediatric patients transplanted 1988-2015 (n?=?318), 31% of those with any posttransplant biopsy (n?=?271) had???1 biopsy with steatosis. Median time from transplant to first biopsy with steatosis was 0.8 months (interquartile range [IQR], 0.3-6.5 months) and to last biopsy with steatosis was 5.5 months (IQR, 1.0-24.5 months); 85% of patients with steatosis also had for-cause biopsies without steatosis. All available for-cause biopsies were re-evaluated (n?=?104). Of 9 biopsies that could be interpreted as nonalcoholic steatohepatitis (NASH)/borderline NASH, with steatosis plus inflammation or ballooning, 8 also had features of cholestasis or rejection. Among 70 patients with surveillance biopsies 3.6-20.0 years after transplant, only 1 overweight adolescent had a biopsy with NAFLD (grade 1 steatosis, mild inflammation, no ballooning or fibrosis)-despite a 30% prevalence of overweight/obesity in the cohort and 27% with steatosis on previous for-cause biopsy. Steatosis on preceding for-cause biopsy was not associated with portal (P?=?0.49) or perivenular fibrosis (P?=?0.85) on surveillance biopsy. Hepatic steatosis commonly develops early after transplant in children and adolescents, but it rarely persists. Biopsies that did have steatosis with NASH characteristics were all for-cause, mostly in patients with NAFLD risk factors and/or confounding causes of liver damage. Prospective studies that follow children into adulthood will be needed to evaluate if and when hepatic steatosis presents a longterm risk for pediatric LT recipients. Liver Transplantation 23 957-967 2017 AASLD.

Project description:BackgroundIn patients with metabolic-associated fatty liver disease (MAFLD), hepatic steatosis is the first step of diagnosis, and it is a risk predictor that independently predicts insulin resistance, cardiovascular risk, and mortality. Urine biomarkers have the advantage of being less complex, with a lower dynamic range and fewer technical challenges, in comparison to blood biomarkers.MethodsHepatic steatosis was measured by magnetic resonance imaging (MRI), which measured the proton density fat fraction (MRI-PDFF). Mild hepatic steatosis was defined as MRI-PDFF 5-10% and severe hepatic steatosis was defined as MRI-PDFF > 10%.ResultsMAFLD patients with any kidney diseases were excluded. There were 53 proteins identified by mass spectrometry with significantly different expressions among the healthy control, mild steatosis, and severe steatosis patients. Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses of these significantly changed urinary molecular features correlated with the liver, resulting in the dysregulation of carbohydrate derivative/catabolic/glycosaminoglycan/metabolic processes, insulin-like growth factor receptor levels, inflammatory responses, the PI3K-Akt signaling pathway, and cholesterol metabolism. Urine alpha-1-acid glycoprotein 1 (ORM1) and ceruloplasmin showed the most significant correlation with the clinical parameters of MAFLD status, including liver fat content, fibrosis, ALT, triglycerides, glucose, HOMA-IR, and C-reactive protein. According to ELISA and western blot (30 urine samples, normalized to urine creatinine), ceruloplasmin (ROC 0.78, p = 0.034) and ORM1 (ROC 0.87, p = 0.005) showed moderate diagnostic accuracy in distinguishing mild steatosis from healthy controls. Ceruloplasmin (ROC 0.79, p = 0.028) and ORM1 (ROC 0.81, p = 0.019) also showed moderate diagnostic accuracy in distinguishing severe steatosis from mild steatosis.ConclusionsCeruloplasmin and ORM1 are potential biomarkers in distinguishing mild and severe steatosis in MAFLD patients.

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Alcohol Abstinence Rescues Hepatic Steatosis and Liver Injury via Improving Metabolic Reprogramming in Chronic Alcohol-Fed Mice.

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