Suv39h1 contributes to activation of hepatic stellate cells in non-alcoholic fatty liver disease by enabling anaerobic glycolysis

Abstract

Aims: Non-alcoholic fatty liver disease (NAFLD) has become a global epidemic. Excessive fibrogenesis, characterized by activation of hepatic stellate cells (HSCs), is a hallmark event in late stages of NAFLD. HSC activation is metabolically programmed by anaerobic glycolysis. In the present study we investigated the involvement of suppressor of variegation 3-9 homolog 1 (Suv39h1), a lysine methyltransferase, in NAFLD-associated liver fibrosis.

Methods and materials: Liver fibrosis was induced by feeding the mice with a methionine-and-choline deficient (MCD) diet for 8 weeks.

Results: We report that germline deletion of Suv39h1 attenuated liver fibrosis in mice fed an MCD diet. In addition, HSC conditional deletion of Suv39h1 similarly ameliorated liver fibrosis in the NAFLD mice. Interestingly, co-culturing with hepatocytes exposed to palmitate promoted glycolysis in wild type HSCs but not in Suv39h1 deficient HSCs. Mechanistically, Suv39h1 facilitated the recruitment of hypoxia induced factor (HIF-1α) to stimulate the transcription of hexokinase 2 (HK2) in HSCs thereby enhancing glycolysis. Importantly, a positive correlation between Suv39h1, HK2, and myofibroblast markers was identified in liver specimens from NAFLD patients.

Significance: In conclusion, our data identify a novel pathway that contributes to the liver fibrosis and points to the possibility of targeting Suv39h1 for the intervention of liver fibrosis in NAFLD.

Keywords: Glycolysis; Hepatic stellate cell; Non-alcoholic fatty liver disease; Transcriptional regulation.