法尼甾体X受体
熊去氧胆酸
脂肪性肝炎
脂肪变性
胆汁酸
G蛋白偶联胆汁酸受体
内科学
内分泌学
脂肪肝
脂肪生成
生物
化学
脂质代谢
生物化学
核受体
医学
基因
转录因子
疾病
作者
Silvia Marchianò,Michele Biagioli,Rosalinda Roselli,Angela Zampella,Cristina Di Giorgio,Martina Bordoni,Rachele Bellini,Ginevra Urbani,Elva Morretta,Maria Chiara Monti,Eleonora Distrutti,Stefano Fiorucci
标识
DOI:10.1016/j.bbalip.2022.159218
摘要
Non-alcoholic steatosis (NAFLD) and steatohepatitis (NASH) are two highly prevalent human disorders for which therapy remains suboptimal. Bile acids play an essential role in regulating liver metabolism, and several bile acids-based therapy are currently investigated for their potential therapeutic efficacy in NAFLD/NASH. Bile acids exert their functions, at least in part, by modulating two main receptors the Farnesoid-x-receptor (FXR) and the G protein-coupled receptor, GPBAR1. In the present study we have compared the pharmacological effects of two bile acids, the ursodeoxycholic acid (UDCA) and its derivative norUDCA, in a model of NAFLD/NASH induced by feeding mice with a Western diet for 12 weeks. The results of these studies demonstrated that both UDCA and norUDCA protected against development of steatosis and fibrosis, but did not reduce the hepatocytes ballooning nor the development of a pro-atherogenic lipid profile. Both agents reduced liver lipogenesis and ameliorated insulin sensitivity and adipocytes signaling as shown by increased expression of adiponectin. Mechanistically, UDCA acts as weak GPBAR1 agonist, while norUDCA exerted no effect on both GPBAR1 and FXR. In vivo administration of UDCA resets bile acid synthesis and promotes a shift toward bile acids species that are GPBAR1 agonists, UDCA, TUDCA and hyodeoxycholic acid, and increases GLP1 expression in the ileum. In contrast norUDCA is poorly metabolized exerting a minimal impact on GPBAR1 signaling. Together, these data, highlight the potential role of UDCA and norUDCA in treating of NAFLD, though these beneficial effects are supported by different mechanisms.
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