Regulatory cross-talk between drug metabolism and lipid homeostasis: constitutive androstane receptor and pregnane X receptor increase Insig-1 expression

Activation of pregnane X receptor (PXR) and constitutive an-drostane receptor (CAR) by xenobiotic inducers of cyto-chromes P450 is part of a pleiotropic response that includes liver hypertrophy, tumor promotion, effects on lipid homeosta-sis, and energy metabolism. Here, we describe an acute re-sponse to CAR and PXR activators that is associated with induction of Insig-1, a protein with antilipogenic properties. We first observed that activation of CAR and PXR in mouse liver results in activation of Insig-1 along with reduced protein levels of the active form of sterol regulatory element binding protein 1 (Srebp-1). Studies in mice deficient in CAR and PXR revealed that the effect on triglycerides involves these two nuclear re-ceptors. Finally, we identified a functional binding site for CAR and PXR in the Insig-1 gene by in vivo, in vitro, and in silic