title: Nectandrin B, a lignan isolated from nutmeg, inhibits liver X receptor-α-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 α (LXRα) 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 LXRα-SREBP-1c-mediated pathway and the possible molecular basis. The reporter gene assay revealed that nectandrin B completely represses LXRα activity enhanced by a synthetic LXRα ligand (T0901317) in HepG2 cells. The inhibitory effect was further supported by the suppression of mRNA expression of LXRα target genes, SREBP-1c and LXRα itself. Nectandrin B also inhibited the increase in SREBP-1c expression promoted by insulin plus high glucose, major contributors to hepatic lipid accumulation. LXRα-SREBP-1c-mediated induction of acetyl-CoA 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 LXRα-induced lipid accumulation. AMP-activated protein kinase (AMPK) inhibits the activities of LXRα 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 LXRα-SREBP-1c pathway presumably via AMPK activation. These results suggest the potential of nectandrin B as a therapeutic candidate for fatty liver disease.
authors.forename: Du Gon
authors.initials: du G
authors.lastname: Choi
authors.forename: Eun Kyung
authors.initials: EK
authors.lastname: Kim
authors.forename: Jin Won
authors.initials: JW
authors.lastname: Yang
authors.forename: Jae Sook
authors.initials: JS
authors.lastname: Song
authors.forename: Young-Mi
authors.initials: YM
authors.lastname: Kim
mesh_terms: D000103:Acetyl-CoA Carboxylase / Q000378:metabolism; D000818:Animals; D045744:Cell Line, Tumor; D017868:Cyclic AMP-Dependent Protein Kinases / Q000187:drug effects* / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D064429:Fatty Acid Synthases / Q000378:metabolism; D005234:Fatty Liver / Q000188:drug therapy; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D017705:Lignans / Q000494:pharmacology*; D050155:Lipogenesis / Q000187:drug effects*; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D000071518:Liver X Receptors / Q000037:antagonists & inhibitors* / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D026323:Myristica / Q000737:chemistry*
chemical_list: D017705:Lignans; D000071518:Liver X Receptors; C524653:nectandrin-B; D064429:Fatty Acid Synthases; D017868:Cyclic AMP-Dependent Protein Kinases; D000103:Acetyl-CoA Carboxylase