Regulation of peroxisome proliferator activated receptor α-mediated pathways in alcohol fed cytochrome P450 2E1 deficient mice

Fatty acids are substrates and inducers for cytochrome P450 2E1 (CYP7E1) and peroxisome proliferator activated receptor alpha (PPAR alpha). Previously, we have shown that the ethanol-induced CYP2E1 expression in rat is accompanied by the inhibition of the expression of the PPAR alpha gene and the reduction in polyunsaturated fatty acid content. To further analyze the effect of CYP2E1 and ethanol in PPAR alpha -mediated fatty acid homeostasis, the expression of PPAR alpha and retinoid x receptor alpha (RXR alpha) and their target genes was examined in ethanol fed CYP2E1 deficient mice. Our data demonstrated that the expression of PPAR alpha and RXR alpha genes was activated in the livers of CYP2E1-null mice suggesting a compensatory effect for the absence of CYP2E1. In addition, the expression of PPAR alpha target genes, which included the liver fatty acid-binding protein, malic enzyme, and CYP4A1 genes, was induced indicating the activation of PPAR alpha -mediated pathways in CYP2E1 deficient mice. Ethanol inhibited the expression of some of the PPAR alpha target genes in wild-type mouse livers, and the inhibitory effect of ethanol was particularly prominent in the CYP2E1-null mice. Morphologically, centrilobular fat accumulation was detected in the ethanol fed CYP2E1-null mouse livers suggesting that inhibition of PPAR alpha -mediated pathways might be responsible for the ethanol-induced fatty liver in CYP2E1-null mice. In addition, the expression of CYP2E1 was not changed in the PPAR alpha -null mice. These data suggest that CYP2E1 and ethanol can regulate PPAR alpha -mediated fatty acid homeostasis. CYP2E1-induced lipid peroxidation might play a major role in lipid metabolism. PPAR I only becomes important when the CYP2E1 level is low and polyunsaturated fatty acids increase. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved.