Department of Gastroenterology, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200092, China.
Endoscopy Center, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200092, China.
Nutrients. 2023 Mar 2;15(5):1255. doi: 10.3390/nu15051255.
Nonalcoholic steatohepatitis (NASH) reflects the outcome of steatosis-based peroxidative impairment. Here, the effect and mechanism of γ-muricholic acid (γ-MCA) on NASH were investigated on the basis of its actions in hepatic steatosis, lipid peroxidation, peroxidative injury, hepatocyte apoptosis, and its NAFLD activity score (NAS). The agonist action of γ-MCA on farnesoid X receptor (FXR) upregulated the small heterodimer partner (SHP) expression of hepatocytes. An increase in SHP attenuated the triglyceride-dominated hepatic steatosis which was induced in vivo by a high-fat high-cholesterol (HFHC) diet and in vitro by free fatty acids depending on the inhibition of liver X receptor α (LXRα) and fatty acid synthase (FASN). In contrast, FXR knockdown abrogated the γ-MCA-dependent lipogenic inactivation. When compared to their excessive production in HFHC diet-induced rodent NASH, products of lipid peroxidation (MDA and 4-HNE) exhibited significant reductions upon γ-MCA treatment. Moreover, the decreased levels of serum alanine aminotransferases and aspartate aminotransferases demonstrated an improvement in the peroxidative injury of hepatocytes. By TUNEL assay, injurious amelioration protected the γ-MCA-treated mice against hepatic apoptosis. The abolishment of apoptosis prevented lobular inflammation, which downregulated the incidence of NASH by lowering NAS. Collectively, γ-MCA inhibits steatosis-induced peroxidative injury to ameliorate NASH by targeting FXR/SHP/LXRα/FASN signaling.
非酒精性脂肪性肝炎（NASH）反映了基于脂肪变性的过氧化损伤的结果。本研究基于 γ-熊去氧胆酸（γ-MCA）在肝脂肪变性、脂质过氧化、过氧化损伤、肝细胞凋亡和其非酒精性脂肪性肝病活动评分（NAS）中的作用，研究了其在 NASH 中的作用和机制。γ-MCA 对法尼醇 X 受体（FXR）的激动作用上调了肝细胞的小异二聚体伴侣（SHP）表达。SHP 的增加减弱了高脂肪高胆固醇（HFHC）饮食体内诱导和游离脂肪酸体外诱导的以甘油三酯为主的肝脂肪变性，这取决于肝 X 受体 α（LXRα）和脂肪酸合酶（FASN）的抑制。相比之下，FXR 敲低消除了 γ-MCA 依赖性的生脂失活。与 HFHC 饮食诱导的啮齿动物 NASH 中过度产生的情况相比，脂质过氧化产物（MDA 和 4-HNE）在 γ-MCA 处理后显著减少。此外，血清丙氨酸氨基转移酶和天冬氨酸氨基转移酶水平的降低表明肝细胞过氧化损伤得到改善。通过 TUNEL 测定，损伤的改善保护了 γ-MCA 处理的小鼠免受肝凋亡。凋亡的消除阻止了小叶炎症，从而通过降低 NAS 降低 NASH 的发生率。综上所述，γ-MCA 通过靶向 FXR/SHP/LXRα/FASN 信号抑制脂肪变性诱导的过氧化损伤来改善 NASH。
