University of Perugia, Department of Medicine and Surgery, Perugia, Italy.
University of Naples Federico II, Department of Pharmacy, Naples, Italy.
Biochim Biophys Acta Mol Cell Biol Lipids. 2022 Nov;1867(11):159218. doi: 10.1016/j.bbalip.2022.159218. Epub 2022 Aug 18.
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.
非酒精性脂肪性肝病（NAFLD）和脂肪性肝炎（NASH）是两种高度流行的人类疾病，其治疗方法仍不尽人意。胆汁酸在调节肝脏代谢中起着至关重要的作用，目前正在研究几种基于胆汁酸的疗法，以评估其在 NAFLD/NASH 中的潜在治疗效果。胆汁酸至少部分通过调节两种主要受体——法尼醇 X 受体（FXR）和 G 蛋白偶联受体，G 蛋白偶联受体 1（GPBAR1）来发挥其功能。在本研究中，我们比较了两种胆汁酸，熊去氧胆酸（UDCA）及其衍生物 norUDCA，在喂食小鼠西方饮食 12 周诱导的 NAFLD/NASH 模型中的药理作用。这些研究的结果表明，UDCA 和 norUDCA 均可预防脂肪变性和纤维化的发生，但不能减少肝细胞气球样变，也不能改善促动脉粥样硬化脂质谱的发展。两种药物均降低肝脏脂肪生成，并改善胰岛素敏感性和脂肪细胞信号转导，表现为脂联素表达增加。在机制上，UDCA 作为弱 GPBAR1 激动剂，而 norUDCA 对 GPBAR1 和 FXR 均无作用。UDCA 的体内给药可重置胆汁酸合成，并促进向作为 GPBAR1 激动剂的胆汁酸种类（UDCA、TUDCA 和去氧胆酸）的转变，并增加回肠中 GLP1 的表达。相反，norUDCA 代谢不良，对 GPBAR1 信号的影响最小。综上所述，这些数据强调了 UDCA 和 norUDCA 在治疗 NAFLD 中的潜在作用，尽管这些有益作用是由不同的机制支持的。
