title: Mechanism of AMPK suppression of LXR-dependent Srebp-1c transcription.
abstract: Activation of AMP-activated protein kinase (AMPK) inhibits hepatic fatty acid synthesis by suppressing sterol regulatory element-binding protein (SREBP)-1c, a master regulator of hepatic lipogenic gene expression. Using a model cell line rat hepatoma McA-RH7777 (CRL-1601) that mimics the behavior of the intact liver by producing high levels of SREPB-1c mRNA and protein, we previously showed that AMPK suppresses hepatic Srebp-1c transcription by inhibiting endogenous liver X receptor (LXR) ligand production and SREBP-1c processing. However, whether AMPK directly inhibits ligand-induced LXR activity remained undetermined. In this study we used a series of mutant Srebp-1c promoter linked to a luciferase reporter to determine the inhibitory mechanism in rat hepatoma McA-RH7777 cells. AMPK activation by either AICAR or metformin decreases Srebp-1c promoter activity by about 75%. Normally, the synthetic LXR ligand T0901317 compound increases the wild-type Srebp-1c promoter activity by about 3-fold, which is similar to that observed in the presence of AICAR or metformin. When endogenous LXR ligand production was blocked by the potent HMG CoA reductase inhibitor compactin, T0901317-induced Srebp-1c promoter activity was decreased by AICAR or metformin treatment. In the mutant Srebp-1c promoter in which two LXR elements are intact but the sterol regulatory element (SRE) is disrupted, the fold inductions of the promoter activity by T0901317 without AMPK activators are significantly higher than those with AMPK activators. Furthermore, AMPK activation attenuates induction of endogenous SREBP-1c mRNA by T0901317. These results indicate that AMPK directly inhibits ligand-induced LXR activity in addition to blocking production of endogenous LXR ligands.
authors.affiliation: Department of Physiology, University of South Alabama College of Medicine, Mobile, Alabama 36688, USA.
authors.forename: Fuichi
authors.initials: F
authors.lastname: Yap
authors.forename: Lauren
authors.initials: L
authors.lastname: Craddock
authors.forename: Jian
authors.initials: J
authors.lastname: Yang
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D002460:Cell Line; D006845:Hydrocarbons, Fluorinated / Q000494:pharmacology; D008099:Liver / Q000378:metabolism*; D000071518:Liver X Receptors; D008687:Metformin / Q000494:pharmacology; D057093:Orphan Nuclear Receptors / Q000819:agonists / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic / Q000235:genetics; D051381:Rats; D012265:Ribonucleotides / Q000494:pharmacology; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics / Q000378:metabolism*; D013449:Sulfonamides / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects / Q000235:genetics; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
chemical_list: D055372:AMP-Activated Protein Kinases; D000620:Aminoimidazole Carboxamide; D006845:Hydrocarbons, Fluorinated; D000071518:Liver X Receptors; D008687:Metformin; D057093:Orphan Nuclear Receptors; D012265:Ribonucleotides; D051780:Sterol Regulatory Element Binding Protein 1; D013449:Sulfonamides; C423915:T0901317; D005466:Fluorocarbons; D000096926:Benzenesulfonamides; C031143:AICA ribonucleotide