Hepatic peroxisomal fatty acid β-oxidation is regulated by liver X receptor α

Tonghuan Hu, Patricia Foxworthy, Angela Siesky, James V. Ficorilli, Hong Gao, Shuyu Li, Michael Christe, Timothy Ryan, Guoqing Cao, Patrick Eacho, M. Dodson Michael, Laura F. Michael

Research output: Contribution to journalArticlepeer-review

40 Scopus citations

Abstract

Peroxisomes are the exclusive site for the β-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 β-oxidation. The regulation of peroxisomal, mitochondrial, and microsomal fatty acid oxidation systems in liver is mediated principally by peroxisome proliferator-activated receptor α(PPARα). In this study we provide evidence that the liver X receptor (LXR) regulates the expression of the genetic program for peroxisomal β-oxidation in liver. The genes encoding the three enzymes of the classic peroxisomal β-oxidation cycle, acyl-coenzymeA(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 β-oxidation in the liver. The LXR effect is independent of PPARα, because T0901317-induced peroxisomal β-oxidation in the liver of PPARα-null mice. Interestingly, T0901317-induced peroxisomal β-oxidation is dependent on the LXRα isoform, but not the LXRβ isoform. We propose that induction of peroxisomal β-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.

Original languageEnglish
Pages (from-to)5380-5387
Number of pages8
JournalEndocrinology
Volume146
Issue number12
DOIs
StatePublished - Dec 2005
Externally publishedYes

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