Objective: Sterol regulatory element binding protein 1 (SREBP-1) is a lipogenic transcription factor of the basic helix-loop-helix family. SREBP-1 binds to sterol regulatory elements (SREs) in the promoter of lipogenic genes and induces fatty acid and triglyceride synthesis. Decreased drug clearance has been observed in obese and other dyslipidemic rodents as well as in diabetic, obese or overfed rodents. A hallmark of these conditions is increased expression of SREBP-1 in the liver. We therefore searched for a possible link between regulation of cytochromes P450 (CYPs) and SREBP-1.
Methods: We combined gene expression analysis, lipid analysis, effects of high levels of SREBP-1 in hepatocyte cultures to characterize the effects and protein interaction and chromatin immunoprecipitation assays to define the underlying mechanism. Finally, mice were fed a diet enriched in cholesterol to demonstrate the relevance of our data in vivo. By analyzing gene expression and lipids in cholesterol-fed mice or transfection of recombinant SREBP-1 in hepatocyte cultures the effect on CYPs was characterized. By use of protein interaction assays and chromatin immunoprecipitation the underlying mechanism was defined.
Results: We observed that SREBP-1 represses drug-mediated induction of hepatic CYPs, mainly members of the 2B and the 3A subfamilies. These drugs induce transcription of CYPs and other drug metabolizing enzymes via activation of the nuclear receptors pregnane X receptor (PXR) and constitutive androstane receptor (CAR). Here we report that the activation of SREBP-1 by insulin or cholesterol in mouse liver and primary human hepatocytes inhibits the transcriptional effects in PXR and CAR. Our results suggest that SREBP-1 functions as a non-DNA binding inhibitor and blocks the interaction of PXR and CAR with cofactors such as steroid receptor coactivator 1. Consequently, mRNA induction of CYPs by drugs and other xenochemicals is impaired.
Conclusion: We conclude that PXR and CAR respond to lipid accumulation by direct interaction with SREBP-1 and show that drug metabolism and lipid metabolism are interconnected within a complex network of transcriptional regulators.