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

Lilly Research Laboratories, Departments of Cardiovascular Research (T.H., P.F., J.V.F., M.C., G.C., P.E., L.F.M.), Endocrinology (A.S., M.D.M.), Toxicology (H.G., T.R.), Integrative Biology (S.L.), Eli Lilly & Co., Indianapolis, Indiana 46285

Address all correspondence and requests for reprints to: Dr. Laura F. Michael, Eli Lilly & Co., Cardiovascular Research, DC 0520, Indianapolis, Indiana 46285. E-mail: laura_michael{at}lilly.com.

Peroxisomes are the exclusive site for the ß-oxidation of very-long-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 ß-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 ß-oxidation in liver. The genes encoding the three enzymes of the classic peroxisomal ß-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 dose-dependent and greater than 2-fold increase in the rate of peroxisomal ß-oxidation in the liver. The LXR effect is independent of PPAR, because T0901317-induced peroxisomal ß-oxidation in the liver of PPAR-null mice. Interestingly, T0901317-induced peroxisomal ß-oxidation is dependent on the LXR isoform, but not the LXRß isoform. We propose that induction of peroxisomal ß-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.

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