Imperatorin ameliorates metabolic dysfunction‐associated fatty liver disease through modulating Suv39h1/Fabps/Cept1 signalling pathway

BACKGROUND AND PURPOSE: Metabolic dysfunction associated fatty liver disease (MAFLD) is a leading cause of irreversible liver fibrosis and finally liver cancer. Imperatorin was reported to be effective for liver injury and fibrosis, but its effects and mechanisms on MAFLD remain unidentified. EXPERIMENTAL APPROACH: The high fat diet (HFD)-induced MAFLD model in the mice and palmitic acid-induced primary mouse hepatocytes were introduced to investigate the effects of imperatorin on lipid metabolism and inflammation. Molecular docking technique, cellular thermal shift assay and surface plasmon resonance (SPR) were performed to confirm the targeting of imperatorin on suppressor of variegation 3-9 homologue 1 (Suv39h1). RNA-sequencing was used to screen the downstream genes affected by Suv39h1 overexpression. The functional relationship between Suv39h1 and its downstream genes of fatty acid-binding proteins (Fabps) was elucidated by CHIP, DNA Pull Down and dual-luciferase reporter assays. Point mutation and knockdown of Set domain of Suv39h1 in palmitic acid-stimulated AML12 cells and HFD mice were adopted to confirm the function of Set domain in MAFLD. KEY RESULTS: Imperatorin could delay MAFLD by affecting lipid metabolism, inflammation and insulin resistance. Knockdown of Suv39h1, the target of imperatorin, weakened the therapeutic effects of imperatorin on MAFLD. Knockdown of Fabps and choline/ethanolamine phosphotransferase 1 (Cept1), the downstream of Suv39h1, could alleviate the disorder of lipid metabolism. Histone methylation modification of Fabp promoters was mediated by Suv39h1. Knockdown of Set domain of Suv39h1 could increase the protein expression of Fabps and aggravate the progression of MAFLD. CONCLUSIONS AND IMPLICATIONS: Imperatorin ameliorates MAFLD through modulating Suv39h1/Fabps/Cept1 signalling pathway.