(+)-Dehydrovomifoliol Alleviates Oleic Acid-Induced Lipid Accumulation in HepG2 Cells via the PPARα–FGF21 Pathway

Abstract

An overload of hepatic fatty acids, such as oleic acid is a key trigger of non-alcoholic fatty liver disease (NAFLD). Here, we investigated whether <i>Artemisia frigida</i>, a valuable traditional medicine used to treat various diseases, could mitigate OA-induced lipid accumulation in HepG2 cells. Then, to identify the active substances in <i>A. frigida</i>, a phytochemistry investigation was conducted using a bioassay-guided isolation method. Consequently, one terpene (<b>1</b>) and one flavone (<b>2</b>) were identified. Compound <b>1</b> ((+)-dehydrovomifoliol) exhibited potent effects against lipid accumulation in OA-induced HepG2 cells, without causing cyto-toxicity. Notably, treatment with (+)-dehydrovomifoliol decreased the expression levels of three genes related to lipogenesis (<i>SREBP1, ACC,</i> and <i>FASN</i>) and increased those of three genes related to fatty acid oxidation (<i>PPARα, ACOX1,</i> and <i>FGF21</i>). In addition, similar results were observed for SREBP1, PPARα, and FGF21 protein levels. The effects of (+)-dehydrovomifoliol were partially reversed by treatment with the PPARα antagonist GW6471, indicating the important role of the PPARα-FGF21 axis in the effects of (+)-dehydrovomifoliol. Based on its effects on hepatic lipogenesis and fatty acid oxidation signaling via the PPARα-FGF21 axis, (+)-dehydrovomifoliol isolated from <i>A. frigida</i> could be a useful early lead compound for developing new drugs for NAFLD prevention.