Nuclear Pregnane X Receptor Cross-talk with FoxA2 to Mediate Drug-induced Regulation of Lipid Metabolism in Fasting Mouse Liver

摘要

Upon drug activation, the nuclear pregnane X receptor (PXR) regulates not only hepatic drug but also energy metabolism. Using Pxr^-/- mice, we have now investigated the PXR-mediated repression of lipid metabolism in the fasting livers. Treatment with PXR activator pregnenolone 16α-carbonitrile (PCN) down-regulated the mRNA levels of carnitine palmitoyltransferase 1 A (CPT1A, in β-oxidation) and mitochondrial 3-hydroxy-3-methylglutarate CoA synthase 2 (HMGCS2, in ketogenesis) in the wild type (Pxr^+/+) mice only. In contrast, the stearoyl-Coenzyme A desaturase 1 (SCD1, in lipogenesis) mRNA was up-regulated in the PCN-treated Pxr^+/+ mice. Reflecting these up-and down regulations and consistent with decreased energy metabolism, the levels of hepatic triglycerides and of serum 3-hydroxybutylate were increased and decreased, respectively in the PCN-treated Pxr^+/+ mice. Using gel shift, GST pull down and cell-based reporter assays, we then examined whether PXR could cross talk with the insulin response forkhead factor FoxA2 to repress the transcription of the Cpt1a and Hmgcs2 genes, since FoxA2 activates these genes in fasting liver. PXR directly bound to FoxA2 and repressed its activation of the Cpt1a and Hmgcs2 promoters. Moreover, ChIP assays showed that PCN treatment attenuated the binding of FoxA2 to these promoters in fasting Pxr^+/+ but not Pxr^-/- mice. These results are consistent with the conclusion that PCN-activated PXR represses FoxA2-mediated transcription of Ctp1a and Hmgcs2 genes in fasting liver.