Abstract

The pathogenesis of nonalcoholic fatty liver disease (NAFLD) is closely linked to the imbalance of lipid and glucose metabolism, in which peroxisome proliferator-activated receptors (PPARs) play essential roles. The clinical trials have shown the beneficial effects of the PPARs’ ligands on NAFLD. In this study, we screen the extracts from the marine fungus Acremonium citrinum and identify the natural compounds dihydrotrichodimerol (L1A) and trichodimerol (L1B) as the ligands of PPARs, of which L1A is a dual PPARα/γ agonist, whereas L1B is a selective PPARγ agonist. L1A but not L1B significantly prevents hepatic lipid accumulation in an oleic acid-induced NAFLD cell model as well as in a high-fat-diet-induced NAFLD mouse model. Moreover, L1A potently inhibits hepatic steatosis in a PPARα-dependent manner in another NAFLD mouse model constructed by using a choline-deficient and amino acid-defined diet. Mechanistically, L1A transcriptionally up-regulates the expression of SIRT1 in a PPARα-dependent manner, followed by the activation of AMPK and inactivation of ACC, resulting in the inhibition of lipid anabolism and the increase of lipid catabolism. Taken together, our study reveals a dual ligand of PPARα/γ with a distinct structure and therapeutic effect on NAFLD, providing a potential drug candidate bridging the currently urgent need for the management of NAFLD.