Hyperacmotone A alleviates Non-alcoholic Steatohepatitis via regulating PPARα signaling.

BACKGROUND

Non-alcoholic steatohepatitis (NASH) is a progressive form of non-alcoholic fatty liver disease (NAFLD), which is often accompanied by lipid metabolism disorders and mitochondrial dysfunction. Peroxisome proliferator-activated receptor α (PPARα) plays a crucial role in the oxidative metabolism of fatty acids, and its agonists are of great significance for the treatment of NASH.

PURPOSE: This study mainly explored the anti-NASH effect of the natural product hyperacmotone A (HA) by targeting PPARα.

METHOD: In this study, free fatty acids (FFA) were used in vitro to induce lipid deposition in hepatocytes, and a methionine and choline-deficient (MCD) diet was used in vivo to establish a NASH model in mice. The anti-NASH activity of HA and its therapeutic effect by targeting PPARα were comprehensively revealed through biochemical indices, pathological analysis, Western blotting, PCR, transcriptome sequencing analysis, DARTS, CETSA, molecular docking, molecular dynamics simulation, bio-layer interferometry assay, etc.

RESULTS

The results of the study showed that HA reduced the lipid accumulation in L02, HepG2, AML12, and primary mouse hepatocytes (PMHs) induced by FFA. In the mouse model induced by the MCD diet, HA improved the histological lesions of NASH, including hepatic steatosis, liver injury, and fibrosis. The transcriptomic results indicated that the PPAR signaling pathway was one of the key pathways through which HA exerted its effects. The experiments further verified that HA directly bound to PPARα and activated downstream signaling, regulated lipid metabolism, and improved mitochondrial damage. Finally, it was confirmed that the anti-NASH effect of HA was dependent on the expression of PPARα.

CONCLUSION

This study demonstrated that HA is a potential PPARα agonist and a therapeutic agent for NASH.