Abstract
Activation of AMP‐activated protein kinase (AMPK) inhibits hepatic fatty acid synthesis by suppressing sterol regulatory element‐binding protein (SREBP)‐1c via inhibition of 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%. 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.
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