Trimetazidine improves hepatic lipogenesis and steatosis in non-alcoholic fatty liver disease via AMPK-ChREBP pathway

Clinical studies have demonstrated that trimetazidine (TMZ) possesses a synergistic hypolipidemic effect together with statins, but the underlying mechanism remains to be elucidated. The present study aimed to investigate the role of TMZ in non-alcoholic fatty liver disease (NAFLD). By investigating the TMZ treatment of NAFLD, it was identified that high-fat diet (HFD) mice exhibit significant changes in several physiologic indices, including body weight, plasma lipids and glucose tolerance. Notably, hepatocyte bullous steatosis and fibrosis in HFD mice are greatly attenuated by 8 weeks of TMZ treatments. The results of the present study also indicated that the expression of carbohydrate-responsive element-binding protein (ChREBP), fatty acid synthase and acetyl-CoA carboxylase were all significantly reduced in the HFD + TMZ group compared with the HFD group. In order to confirm the hypothesis in vitro, the palmitate-treated liver cancer cell line (HepG2) was employed and similar results were obtained in TMZ-treated HepG2 cells. Furthermore, TMZ markedly upregulated the AMP-activated protein kinase (AMPK) signaling pathway and reduced the expression of forkhead box O1 (FOXO1) in the cells, while these effects controlled by TMZ were abolished by the AMPK inhibitor Compound C. The present study reported that knockdown of FOXO1 expression by FOXO1 small interfering RNA resulted in a reduction of ChREBP protein expression and post-transcriptional activity. In summary, for the first time, to the best of the authors' knowledge, the present study revealed a novel role of TMZ in hepatic steatosis; TMZ ameliorated ChREBP-induced de novo lipogenesis by activating the AMPK-FOXO1 pathway.