期刊
NUTRIENTS
卷 15, 期 5, 页码 -出版社
MDPI
DOI: 10.3390/nu15051255
关键词
nonalcoholic steatohepatitis; muricholic acid; farnesoid X receptor; steatosis; lipid peroxidation; apoptosis
The effect and mechanism of gamma-muricholic acid (gamma-MCA) in improving nonalcoholic steatohepatitis (NASH) were investigated. It was found that gamma-MCA targeted the FXR/SHP/LXR alpha/FASN signaling pathway to inhibit steatosis-induced peroxidative injury and ameliorate NASH. The treatment with gamma-MCA resulted in decreases in hepatic steatosis, lipid peroxidation, peroxidative injury, hepatocyte apoptosis, and NAFLD activity score (NAS).
Nonalcoholic steatohepatitis (NASH) reflects the outcome of steatosis-based peroxidative impairment. Here, the effect and mechanism of gamma-muricholic acid (gamma-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 gamma-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 alpha (LXR alpha) and fatty acid synthase (FASN). In contrast, FXR knockdown abrogated the gamma-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 gamma-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 gamma-MCA-treated mice against hepatic apoptosis. The abolishment of apoptosis prevented lobular inflammation, which downregulated the incidence of NASH by lowering NAS. Collectively, gamma-MCA inhibits steatosis-induced peroxidative injury to ameliorate NASH by targeting FXR/SHP/LXR alpha/FASN signaling.
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