Nectandrin B, a lignan isolated from nutmeg, inhibits liver X receptor-alpha-induced hepatic lipogenesis through AMP-activated protein kinase activation

Abstract

Nonalcoholic fatty liver disease is recognized as the most commonly occurring chronic liver disease. Liver X receptor alpha (LXR alpha) and sterol regulatory element-binding protein (SREBP)-1c play a central role in de novo fatty acid synthesis. This study investigated pharmacological effects of nectandrin B, a lignan isolated from nutmeg extract, on hepatic lipogenesis stimulated by LXR alpha -SREBP-1c-mediated pathway and the possible molecular basis. The reporter gene assay revealed that nectandrin B completely represses LXR alpha activity enhanced by a synthetic LXR alpha ligand (T0901317) in HepG2 cells. The inhibitory effect was further supported by the suppression of mRNA expression of LXR alpha target genes, SREBP-1c and LXR alpha itself. Nectandrin B also inhibited the increase in SREBP-1c expression promoted by insulin plus high glucose, major contributors to hepatic lipid accumulation. LXR alpha -SREBP-1c-mediated induction of acetylCoA carboxylase 1 and fatty acid synthase, major genes for de novo lipogenesis, was suppressed by nectandrin B. Moreover, Oil Red O staining showed that nectandrin B notably attenuates LXR alpha-induced lipid accumulation. AMP-activated protein kinase (AMPK) inhibits the activities of LXR alpha and SREBP-1c. Nectandrin B strongly activated AMPK signaling in HepG2 cells. Taken together, the suppressive effects of nectandrin B on lipogenic gene expression and lipid accumulation in hepatocytes may be due to its inhibitory effect on the LXR alpha-SREBP-1c pathway presumably via AMPK activation. These results suggest the potential of nectandrin B as a therapeutic candidate for fatty liver disease.