title: Hepatic peroxisomal fatty acid beta-oxidation is regulated by liver X receptor alpha.
abstract: Peroxisomes are the exclusive site for the beta-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 beta-oxidation. The regulation of peroxisomal, mitochondrial, and microsomal fatty acid oxidation systems in liver is mediated principally by peroxisome proliferator-activated receptor alpha (PPARalpha). In this study we provide evidence that the liver X receptor (LXR) regulates the expression of the genetic program for peroxisomal beta-oxidation in liver. The genes encoding the three enzymes of the classic peroxisomal beta-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 beta-oxidation in the liver. The LXR effect is independent of PPARalpha, because T0901317-induced peroxisomal beta-oxidation in the liver of PPARalpha-null mice. Interestingly, T0901317-induced peroxisomal beta-oxidation is dependent on the LXRalpha isoform, but not the LXRbeta isoform. We propose that induction of peroxisomal beta-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.
authors.affiliation: Lilly Research Laboratories, Department of Cardiovascular Research, Eli Lilly & Co., Indianapolis, Indiana 46285, USA.
authors.forename: Tonghuan
authors.initials: T
authors.lastname: Hu
authors.forename: Patricia
authors.initials: P
authors.lastname: Foxworthy
authors.forename: Angela
authors.initials: A
authors.lastname: Siesky
authors.forename: James V
authors.initials: JV
authors.lastname: Ficorilli
authors.forename: Hong
authors.initials: H
authors.lastname: Gao
authors.forename: Shuyu
authors.initials: S
authors.lastname: Li
authors.forename: Michael
authors.initials: M
authors.lastname: Christe
authors.forename: Timothy
authors.initials: T
authors.lastname: Ryan
authors.forename: Guoqing
authors.initials: G
authors.lastname: Cao
authors.forename: Patrick
authors.initials: P
authors.lastname: Eacho
authors.forename: M Dodson
authors.initials: MD
authors.lastname: Michael
authors.forename: Laura F
authors.initials: LF
authors.lastname: Michael
mesh_terms: D000102:Acetyl-CoA C-Acyltransferase / Q000235:genetics; D000214:Acyl Coenzyme A / Q000235:genetics; D000818:Animals; D004268:DNA-Binding Proteins / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D004746:Enoyl-CoA Hydratase / Q000235:genetics; D005227:Fatty Acids / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D006845:Hydrocarbons, Fluorinated; D008024:Ligands; D008099:Liver / Q000378:metabolism*; D000071518:Liver X Receptors; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D057093:Orphan Nuclear Receptors; D010084:Oxidation-Reduction / Q000187:drug effects; D047493:PPAR alpha / Q000172:deficiency / Q000502:physiology; D020675:Peroxisomes / Q000378:metabolism*; D018160:Receptors, Cytoplasmic and Nuclear / Q000502:physiology*; D013449:Sulfonamides / Q000008:administration & dosage / Q000494:pharmacology; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
chemical_list: D000102:Acetyl-CoA C-Acyltransferase; D000214:Acyl Coenzyme A; D004268:DNA-Binding Proteins; D004746:Enoyl-CoA Hydratase; D005227:Fatty Acids; D006845:Hydrocarbons, Fluorinated; D008024:Ligands; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D047493:PPAR alpha; D018160:Receptors, Cytoplasmic and Nuclear; D013449:Sulfonamides; C000605214:Nr1h3 protein, mouse; C423915:T0901317; D005466:Fluorocarbons; D000096926:Benzenesulfonamides