PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR-ALPHA CONTROLS THE HEPATICCYP4A INDUCTION ADAPTIVE RESPONSE TO STARVATION AND DIABETES

The hepatic CYP4A enzymes are important fatty acid and prostaglandin o mega-hydroxylases that are highly inducible by fibric acid hypolipidem ic agents and other peroxisome proliferators. Induction of the CYP4A e nzymes by peroxisome proliferators is mediated through the nuclear per oxisome proliferator-activated receptor alpha (PPAR alpha), Fatty acid s have recently been identified as endogenous ligands of PPAR alpha, a nd this receptor has been implicated in the regulation of lipid homeos tasis. In the present report we characterized the induction of the hep atic CYP4A genes in rats during the altered lipid metabolism associate d with starvation and diabetes. The mRNA levels of CYP4A1, CYP4A2, and CYP4A3 were induced 7-17-fold in the livers of fasted animals and 3-8 -fold in the livers of diabetic animals. This was accompanied by corre sponding changes in CYP4A protein levels and arachidonic and lauric ac id omega-hydroxylase activity. Interestingly, feeding animals after th e fasting period caused as much as an 80% suppression of CYP4A mRNA le vels, whereas CYP4A protein levels and functional activity returned to control values. A second PPAR alpha-responsive gene, acyl-CoA oxidase , was also induced in rat liver by diabetes and fasting. By using PPAR alpha-deficient mice, we unambiguously demonstrated that PPAR alpha i s strictly required for hepatic CYP4A induction by starvation and diab etes. Similarly, induction of hepatic thiolase and bifunctional enzyme also required expression of PPAR alpha. This represents the first evi dence for the pathophysiologically induced activation of a nuclear rec eptor.