Natural small molecule hinokitone mitigates NASH fibrosis by targeting regulation of FXR-mediated hepatocyte apoptosis

作者：Ze-Jiang Ma, Ying‐Kun Qiu, Zhe-Wei Yu, Tiantian Song, Yitong Hu, Ankang Peng, Rong Qi · 发表于：Journal of Advanced Research · 年份：2024 · DOI：10.1016/j.jare.2024.12.016 · 被引用次数：8 · 研究领域：Synthesis of Organic Compounds、Quinazolinone synthesis and applications、Biological Activity of Diterpenoids and Biflavonoids

Hinokitone exerts an inhibitory effect on NASH fibrosis. Mechanistically, Hinokitone attenuates hepatocyte apoptosis by targeting the upregulation of hepatocyte FXR, which in turn indirectly inhibits HSC activation. • Natural small molecule HO inhibits liver fibrosis in a mouse NASH model. • Hepatocyte FXR mediates the effect of HO anti-liver fibrosis. • HO inhibits hepatocyte lipid deposition and hepatic inflammation by binding to and upregulating the protein level of FXR proteins in hepatocytes, thereby exerting an anti-apoptotic effect on hepatocytes. • HO indirectly preventing hepatic stellate cell activation through inhibiting hepatocyte apoptosis and thus inhibits liver fibrosis. Liver fibrosis is the common fate of NASH and poses a major health threat with very limited pharmacological treatments. This study aims to investigate the preventive effect of hinokitone (HO), an isolated compound from Agathis dammara , on NASH fibrosis and its underlying mechanism. To investigate the effect of HO on NASH fibrosis, C57BL/6 mice were either fed a high-fat diet (HFD) in conjunction with intraperitoneal injection of CCl 4 for 8 weeks or single CCl 4 for 14 days to establish mouse liver fibrosis model, and HO was administered by gavage simultaneously. To elucidate the underlying mechanisms, HepG2 cells were stimulated by palmitic acid (PA) or tumor necrosis factor α plus actinomycin-D (Act-D + TNFα) to induce hepatocyte apoptosis model. Furthermore, hepatocyte Farnesoid-X-receptor ...