Liver-specific glucocorticoid action in alcoholic liver disease:Study of glucocorticoid receptor knockout and knockin mice
作者机构：Department of PharmacologySUNY Upstate Medical UniversitySyracuseNYUSA
出 版 物：《肝脏研究（英文）》 (Liver Research)
年 卷 期：2024年第8卷第2期
页 面：91-104页
核心收录：
基 金：National Institutes of Health, NIH, (R21AA027349) National Institutes of Health, NIH
主 题：Glucocorticoid receptor (GR) Alcohol-associated steatosis (AS) Alcoholic hepatitis (AH) Heterozygote Liver-specific knockout Liver-specific knockin Hepatic protection
摘 要：Background and aim:Glucocorticoids are the only first-line drugs for severe alcoholic hepatitis(AH),with limited efficacy and various side effects on extrahepatic ***-targeting glucocorticoid therapy may have multiple advantages over systemic glucocorticoid for *** aim of this study was to determine the role of hepatocellular glucocorticoid receptor(GR)in alcohol-associated steatosis(AS)and AH. Materials and methods:AS was induced by a high-fat diet plus binge alcohol in adult male and female mice with liver-specific knockout(LKO)and heterozygote of *** was induced by chronic-plus-binge in middle-aged male mice with liver-specific knockin of *** in hepatic mRNA and protein expression were determined by quantitative real-time polymerase chain reaction and Western blot. Results:GR-LKO aggravated steatosis and decreased hepatic expression and circulating levels of albumin in both genders of AS mice but only increased markers of liver injury in male AS *** steatosis in GR-LKO mice was associated with induction of lipogenic genes and down-regulation of bile acid synthetic *** protein levels of GR,hepatocyte nuclear factor 4 alpha,and phosphorylated signal transducer and activator of transcription 3 were gene-dosage-dependently decreased,whereas that of lipogenic ATP citrate lyase was increased in male GR heterozygote and LKO ***,hepatic expression of estrogen receptor alpha(ERα)was induced,and the essential estrogen-inactivating enzyme sulfotransferase 1e1 was gene-dosage-dependently down-regulated in GR heterozygote and knockout AS mice,which was associated with induction of ERα-target ***-specific knockin of GR protected against liver injury and steatohepatitis in middle-aged AH mice. Conclusions:Hepatic GR deficiency plays a crucial role in the pathogenesis of AS induced by high-fat diet plus binge,and liver-specific overexpression/activation of GR protects against chronic-plus-binge-induced AH in middl