Hepatic Peroxisomal Fatty Acid -Oxidation Is Regulated by Liver X Receptor

Peroxisomes are the exclusive site for the -oxidation of verylong-chain fatty acids of more than 20 carbons in length (VLCFAs). Although the bulk of dietary long-chain fatty acids are oxidized in the mitochondria, VLCFAs cannot be catabolized in mitochondria and must be shortened first by peroxisomal -oxidation. The regulation of peroxisomal, mitochondrial, and microsomal fatty acid oxidation systems in liver is mediated principally by peroxisome proliferator-activated receptor (PPAR ). In this study we provide evidence that the liver X receptor (LXR) regulates the expression of the genetic program for peroxisomal -oxidation in liver. The genes encoding the three enzymes of the classic peroxisomal -oxidation cycle, acyl-coenzyme A (acyl-CoA) oxidase, enoyl-CoA hydratase/ L-3-hydroxyacyl-CoA dehydrogenase, and 3-ketoacyl-CoA thiolase, are activated by the LXR ligand, T0901317. Accordingly, administration of T0901317 in mice promoted a dosedependent and greater than 2-fold increase in the rate of peroxisomal -oxidation in the liver. The LXR effect is independent of PPAR , because T0901317-induced peroxisomal -oxidation in the liver of PPAR -null mice. Interestingly, T0901317-induced peroxisomal -oxidation is dependent on the LXR isoform, but not the LXR isoform. We propose that induction of peroxisomal -oxidation by LXR agonists may serve as a counterregulatory mechanism for responding to the hypertriglyceridemia and liver steatosis that is promoted by potent LXR agonists in vivo; however, additional studies are warranted. (Endocrinology 146: 5380–5387, 2005)