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Hepatic peroxisomal fatty acid beta-oxidation is regulated by liver X receptor alpha.
Endocrinology. 2005 Dec; 146(12):5380-7.E

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+Show Affiliations

Lilly Research Laboratories, Department of Cardiovascular Research, Eli Lilly & Co., Indianapolis, Indiana 46285, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

16123164

Citation

Hu, Tonghuan, et al. "Hepatic Peroxisomal Fatty Acid Beta-oxidation Is Regulated By Liver X Receptor Alpha." Endocrinology, vol. 146, no. 12, 2005, pp. 5380-7.
Hu T, Foxworthy P, Siesky A, et al. Hepatic peroxisomal fatty acid beta-oxidation is regulated by liver X receptor alpha. Endocrinology. 2005;146(12):5380-7.
Hu, T., Foxworthy, P., Siesky, A., Ficorilli, J. V., Gao, H., Li, S., Christe, M., Ryan, T., Cao, G., Eacho, P., Michael, M. D., & Michael, L. F. (2005). Hepatic peroxisomal fatty acid beta-oxidation is regulated by liver X receptor alpha. Endocrinology, 146(12), 5380-7.
Hu T, et al. Hepatic Peroxisomal Fatty Acid Beta-oxidation Is Regulated By Liver X Receptor Alpha. Endocrinology. 2005;146(12):5380-7. PubMed PMID: 16123164.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Hepatic peroxisomal fatty acid beta-oxidation is regulated by liver X receptor alpha. AU - Hu,Tonghuan, AU - Foxworthy,Patricia, AU - Siesky,Angela, AU - Ficorilli,James V, AU - Gao,Hong, AU - Li,Shuyu, AU - Christe,Michael, AU - Ryan,Timothy, AU - Cao,Guoqing, AU - Eacho,Patrick, AU - Michael,M Dodson, AU - Michael,Laura F, Y1 - 2005/08/25/ PY - 2005/8/27/pubmed PY - 2006/1/6/medline PY - 2005/8/27/entrez SP - 5380 EP - 7 JF - Endocrinology JO - Endocrinology VL - 146 IS - 12 N2 - 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. SN - 0013-7227 UR - https://www.unboundmedicine.com/medline/citation/16123164/Hepatic_peroxisomal_fatty_acid_beta_oxidation_is_regulated_by_liver_X_receptor_alpha_ L2 - https://academic.oup.com/endo/article-lookup/doi/10.1210/en.2005-0591 DB - PRIME DP - Unbound Medicine ER -