A novel HSF1 activator ameliorates non-alcoholic steatohepatitis by stimulating mitochondrial adaptive oxidation.

British journal of pharmacology 2022 Apr

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Non-alcoholic steatohepatitis (NASH) is the more severe form of metabolic associated fatty liver disease (MAFLD) and no pharmacological treatment as yet been approved. Identification of novel therapeutic targets and their agents is critical to overcome the current inadequacy of drug treatment for NASH. The correlation between heat shock factor 1 (HSF1) levels and the development of NASH and the target genes of HSF1 in hepatocyte were investigated by chromatin-immunoprecipitation sequencing. The effects and mechanisms of SYSU-3d in alleviating NASH were examined in relevant cell models and mouse models (the Ob/Ob mice, high-fat and high-cholesterol diet and the methionine-choline deficient diet-fed mice). The actions of SYSU-3d in vivo were evaluated. HSF1 is progressively reduced with mitochondrial dysfunction in NASH pathogenesis and activation of this transcription factor by its newly identified activator SYSU-3d effectively inhibited all manifestations of NASH in mice. When activated, the phosphorylated HSF1 (Ser326) translocated to nucleus and bound to the promoter of PPARγ coactivator-1α (PGC-1α) to induce mitochondrial biogenesis. Thus, increasing mitochondrial adaptive oxidation and inhibiting oxidative stress. The deletion of HSF1 and PGC-1α or recovery of HSF1 in HSF1-deficiency cells showed the HSF1/PGC-1α pathway was mainly responsible for the anti-NASH effects of SYSU-3d independent of AMP-activated protein kinase (AMPK). Activation of HSF1 is a practical therapeutic approach for NASH treatment via the HSF1/PGC-1α/mitochondrial pathway and SYSU-3d can be considered as a potential candidate for the treatment of NASH. © 2021 The British Pharmacological Society.

Citation

Yong Rao, Chan Li, Yu-Tao Hu, Yao-Hao Xu, Bing-Bing Song, Shi-Yao Guo, Zhi Jiang, Dan-Dan Zhao, Shuo-Bin Chen, Jia-Heng Tan, Shi-Liang Huang, Qing-Jiang Li, Xiao-Jun Wang, Ying-Jun Zhang, Ji-Ming Ye, Zhi-Shu Huang. A novel HSF1 activator ameliorates non-alcoholic steatohepatitis by stimulating mitochondrial adaptive oxidation. British journal of pharmacology. 2022 Apr;179(7):1411-1432