γ-鼠胆酸抑制非酒精性脂肪性肝炎：通过 FXR/SHP/LXRα/FASN 信号消除脂肪变性依赖性过氧化损伤,Nutrients

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γ-鼠胆酸抑制非酒精性脂肪性肝炎：通过 FXR/SHP/LXRα/FASN 信号消除脂肪变性依赖性过氧化损伤
Nutrients ( IF 4.8 ) Pub Date : 2023-03-02 , DOI: 10.3390/nu15051255
Yang Xie ₁ , Feng Shen ₂ , Yafang He ₃ , Canjie Guo ₄ , Ruixu Yang ₁ , Haixia Cao ₁ , Qin Pan ₅ , Jiangao Fan _{1,

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Affiliation

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。在此，根据γ-鼠胆酸（γ-MCA）在肝脂肪变性、脂质过氧化、过氧化损伤、肝细胞凋亡中的作用及其NAFLD活性评分（NAS），研究了γ-鼠胆酸（γ-MCA）对NASH的作用和机制。 γ-MCA 对法尼醇 X 受体 (FXR) 的激动作用上调肝细胞的小异二聚体伴侣 (SHP) 表达。 SHP 的增加减轻了以甘油三酯为主的肝脂肪变性，这种脂肪变性是由高脂肪高胆固醇 (HFHC) 饮食在体内和体外由游离脂肪酸诱导的，具体取决于肝脏 X 受体 α (LXRα) 和脂肪酸的抑制合酶（FASN）。相反，FXR 敲低消除了 γ-MCA 依赖性脂肪生成失活。与 HFHC 饮食诱导的啮齿动物 NASH 中的过量产生相比，脂质过氧化产物（MDA 和 4-HNE）在 γ-MCA 治疗后表现出显着减少。此外，血清丙氨酸转氨酶和天冬氨酸转氨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，损伤性改善可保护 γ-MCA 治疗的小鼠免受肝细胞凋亡。细胞凋亡的消除可以防止小叶炎症，从而通过降低 NAS 来降低 NASH 的发生率。总的来说，γ-MCA 通过靶向 FXR/SHP/LXRα/FASN 信号传导抑制脂肪变性诱导的过氧化损伤，从而改善 NASH。

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Gamma-Muricholic Acid Inhibits Nonalcoholic Steatohepatitis: Abolishment of Steatosis-Dependent Peroxidative Impairment by FXR/SHP/LXRα/FASN Signaling

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.

更新日期：2023-03-02

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