Coactivator PGC-1α regulates the fasting inducible xenobiotic-metabolizing enzyme CYP2A5 in mouse primary hepatocytes

The nutritional state of organisms and energy balance related diseases such as diabetes regulate the metabolism of xenobiotics such as drugs, toxins and carcinogens. However, the mechanisms behind this regulation are mostly unknown. The xenobiotic-metabolizing cytochrome P450 (CYP) 2A5 enzyme has been shown to be induced by fasting and by glucagon and cyclic AMP (cAMP), which mediate numerous fasting responses. Peroxisome proliferator-activated receptor gamma coactivator (PGC)-1 alpha triggers many of the important hepatic fasting effects in response to elevated cAMP levels. In the present study, we were able to show that cAMP causes a coordinated induction of PGC-1 alpha expression level by adenovirus mediated gene transfer increased CYP2A5 transcription, Co-transfection of Cyp2a5' promoter constructs with PGC-1 alpha expression vector demonstrated that PGC-1 alpha is able to activate Cyp2a5 transcription through the hepatocyte nuclear factor (HNF)-4 alpha response element in the proximal promoter of the Cyp2a5 gene. Chromartin immunoprecipitation assays showed that PGC-1 alpha binds, together with HNF-4 alpha, to the same region at the Cyp2a5 proximal promoter. In conclusion, PGC-1 alpha mediates the expression of Cyp2A5 induced by cAMP in mouise hepatocytes throuch coactivation of transcription factor HNF-4 alpha. This strongly suggests that PGC-1 alpha is the major factor mediating the fasting response of CYP2A5. (C) 2008 Elsevier Inc. All rights reserved.