Hypoxia-inducible factor-1α inhibitor promotes non-alcoholic steatohepatitis development and increases hepatocellular lipid accumulation via TSKU upregulation

Non-alcoholic steatohepatitis (NASH) is the progressive form of non-alcoholic fatty liver disease (NAFLD) which is the most common chronic liver disease worldwide. Hypoxia-inducible factor-1α (HIF1α) inhibitor is emerging as a promising therapeutic strategy for diseases. However, the role of HIF1α inhibitor in NASH is still unclear. A choline-deficient, l-amino acid-defined, high-fat diet (CDAHFD) -induced NASH mouse model was established to identify the impacts of HIF1α inhibitor KC7F2 on the development of NASH. We found that KC7F2 treatment substantially aggravated lipid accumulation, inflammation, and fibrosis in the liver of NASH mice presumably via increasing Tsukushi (TSKU) expression in the liver. Mechanistically, KC7F2 up-regulated expression of TSKU in hepatocyte in vitro, which led to increased hepatocellular lipid accumulation and was reversed when TSKU was knockdown in hepatocyte. Our findings indicated that HIF1α inhibitor promotes the development of NASH presumably via increasing TSKU expression in the liver, suggesting that HIF1α attenuates NASH, and that we should assess the potential liver toxicity when use HIF1α inhibitor or medicines that can decrease the expression of HIF1α to therapy other diseases.