Methyltransferase SETD2 mediates hepatoprotection of berberine against steatosis

Background: Berberine (BBR) can alleviate nonalcoholic fatty liver (NAFL), but the mechanisms remain uncertain. Mounting evidence has underscored the roles of epigenetic modulation in the development of NAFL. Increased expression of histone methyltransferase SET domain-containing protein 2 (SETD2) is found in the livers of diabetic animals with BBR administration. Whether SETD2 contributes to the protective effects of BBR against NAFL remains to be elucidated. Methods: A C57BL/6 mouse model of NAFL induced by a high-fat high-sucrose diet (HFHS) and a palmitate-treated hepatocyte steatosis model were generated. The effects of BBR were evaluated by Oil Red O staining and the cell viability assay. Quantitative real-time polymerase chain reaction, Western blotting, and immunofluorescence staining were used to analyze the expression and activity of SETD2 and its downstream target trimethylation of lysine 36 on histone 3 (H3K36me3). Results: BBR treatment induced the reduction of lipid droplets in both HFHS mouse livers and HepG2 cells, coincident with the elevation of the mRNA and protein expression of SETD2 and H3K36me3. Knockdown of SETD2 compromised the BBR-mediated inhibition of the accumulation of lipid droplets in the HepG2 cell model of steatosis. Moreover, upregulated SETD2 and H3K36me3 expression was also observed in intact HepG2 cells treated with BBR. The promoter assay indicated that BBR treatment increased the transcriptional activity of SETD2 and H3K36me3. Conclusions: BBR confers hepatoprotection against steatosis through transcriptional regulation of SETD2 activity.