Peroxisomes are the exclusive site for the -oxidation of very-long-chain fatty acids of greater 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 PPAR. In this study, we provide evidence that the liver X receptor (LXR) regulates expression of the genetic program for peroxisomal -oxidation in liver. The genes encoding the three enzymes of the classic peroxisomal -oxidation cycle--acyl CoA oxidase, enoyl-CoA hydratase/liter-3-hydroxyacyl-CoA dehydrogenase, and 3-ketoacyl-CoA thiolase--are activated by the LXR ligand, T0901317. Accordingly, administration of T0901317 in mice promoted a dose-dependent and greater than 2-fold increase in the rate of peroxisomal -oxidation in the liver. The LXR effect is independent of PPAR since T0901317-induced peroxisomal -oxidation in 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 counter-regulatory mechanism for responding to hypertriglyceridemia and liver steatosis that is promoted by potent LXR agonists in vivo; however, further studies are warranted.