A novel HSF1 activator ameliorates non-alcoholic steatohepatitis by stimulating mitochondrial adaptive oxidation
| Autor: | Zhi-Shu Huang, Shi-Liang Huang, Zhi Jiang, Qingjiang Li, Dan-Dan Zhao, Jia-Heng Tan, Xiao-Jun Wang, Bing-Bing Song, Shi-Yao Guo, Chan Li, Ji-Ming Ye, Shuo-Bin Chen, Yu-Tao Hu, Ying-Jun Zhang, Yao-Hao Xu, Yong Rao |
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| Rok vydání: | 2021 |
| Předmět: |
Pharmacology
Activator (genetics) Chemistry fungi Fatty liver AMPK AMP-Activated Protein Kinases medicine.disease Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha digestive system diseases Mitochondria Mice Inbred C57BL Mice Mitochondrial biogenesis Heat Shock Transcription Factors Liver Non-alcoholic Fatty Liver Disease medicine Cancer research Animals HSF1 Receptor Protein kinase A Transcription factor |
| Zdroj: | British journal of pharmacologyREFERENCES. 179(7) |
| ISSN: | 1476-5381 |
| Popis: | Background and purpose Nonalcoholic steatohepatitis (NASH) is the more severe form of metabolic associated fatty liver disease (MAFLD), and no pharmacologic treatment approved as yet. Identification of novel therapeutic targets and their agents are critical to overcome the current inadequacy of drug treatment for NASH. Experimental approach The correlation between heat shock factor 1 (HSF1) levels and the development of NASH and the target genes of HSF1 in hepatocyte were revealed 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, the methionine-choline deficient diet fed mice). The drug-like properties of SYSU-3d in vivo were evaluated. Key results HSF1 is progressively reduced with mitochondrial dysfunction in NASH pathogenesis and activation of this transcription factor by its newly-identified activator SYSU-3d efficiently ameliorated all manifestations of NASH in mice. When activated, the phosphorylated HSF1 (Ser326) translocated to nucleus and bound to the promoter of peroxisome proliferator-activated receptor γ 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 revealed the HSF1/PGC-1α metabolic axis mainly responsible for the anti-NASH effects of SYSU-3d independent of adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK). Conclusion and implications Activation of HSF1 is a practicable therapeutic approach for NASH treatment via the HSF1/PGC-1α/mitochondrial axis, and SYSU-3d would take into consideration as a potential candidate for the treatment of NASH. |
| Databáze: | OpenAIRE |
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