title: A role for the peroxisomal 3-ketoacyl-CoA thiolase B enzyme in the control of PPARα-mediated upregulation of SREBP-2 target genes in the liver.
abstract: Peroxisomal 3-ketoacyl-CoA thiolase B (Thb) catalyzes the final step in the peroxisomal β-oxidation of straight-chain acyl-CoAs and is under the transcription control of the nuclear hormone receptor PPARα. PPARα binds to and is activated by the synthetic compound Wy14,643 (Wy). Here, we show that the magnitude of Wy-mediated induction of peroxisomal β-oxidation of radiolabeled (1-(14)C) palmitate was significantly reduced in mice deficient for Thb. In contrast, mitochondrial β-oxidation was unaltered in Thb(-/-) mice. Given that Wy-treatment induced Acox1 and MFP-1/-2 activity at a similar level in both genotypes, we concluded that the thiolase step alone was responsible for the reduced peroxisomal β-oxidation of fatty acids. Electron microscopic analysis and cytochemical localization of catalase indicated that peroxisome proliferation in the liver after Wy-treatment was normal in Thb(-/-) mice. Intriguingly, micro-array analysis revealed that mRNA levels of genes encoding cholesterol biosynthesis enzymes were upregulated by Wy in Wild-Type (WT) mice but not in Thb(-/-) mice, which was confirmed at the protein level for the selected genes. The non-induction of genes encoding cholesterol biosynthesis enzymes by Wy in Thb(-/-) mice appeared to be unrelated to defective SREBP-2 or PPARα signaling. No difference was observed in the plasma lathosterol/cholesterol ratio (a marker for de novo cholesterol biosynthesis) between Wy-treated WT and Thb(-/-) mice, suggesting functional compensation. Overall, we conclude that ThA and SCPx/SCP2 thiolases cannot fully compensate for the absence of ThB. In addition, our data indicate that ThB is involved in the regulation of genes encoding cholesterol biosynthesis enzymes in the liver, suggesting that the peroxisome could be a promising candidate for the correction of cholesterol imbalance in dyslipidemia.
authors.affiliation: Centre de recherche INSERM U866, Dijon F-21000, France; Université de Bourgogne, Faculté des Sciences Gabriel, Equipe Biochimie Métabolique et Nutritionnelle, Dijon F-21000, France.
authors.forename: Marco
authors.initials: M
authors.lastname: Fidaleo
authors.forename: Ségolène
authors.initials: S
authors.lastname: Arnauld
authors.forename: Marie-Claude
authors.initials: MC
authors.lastname: Clémencet
authors.forename: Grégory
authors.initials: G
authors.lastname: Chevillard
authors.forename: Marie-Charlotte
authors.initials: MC
authors.lastname: Royer
authors.forename: Melina
authors.initials: M
authors.lastname: De Bruycker
authors.forename: Ronald J A
authors.initials: RJ
authors.lastname: Wanders
authors.forename: Anne
authors.initials: A
authors.lastname: Athias
authors.forename: Joseph
authors.initials: J
authors.lastname: Gresti
authors.forename: Pierre
authors.initials: P
authors.lastname: Clouet
authors.forename: Pascal
authors.initials: P
authors.lastname: Degrace
authors.forename: Sander
authors.initials: S
authors.lastname: Kersten
authors.forename: Marc
authors.initials: M
authors.lastname: Espeel
authors.forename: Norbert
authors.initials: N
authors.lastname: Latruffe
authors.forename: Valérie
authors.initials: V
authors.lastname: Nicolas-Francès
authors.forename: Stéphane
authors.initials: S
authors.lastname: Mandard
mesh_terms: D000102:Acetyl-CoA C-Acyltransferase / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002784:Cholesterol / Q000235:genetics / Q000378:metabolism; D017353:Gene Deletion; D005786:Gene Expression Regulation; D006529:Hepatomegaly / Q000235:genetics / Q000473:pathology; D006801:Humans; D050356:Lipid Metabolism / Q000235:genetics; D008099:Liver / Q000201:enzymology* / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism; D010084:Oxidation-Reduction; D047493:PPAR alpha / Q000378:metabolism*; D010168:Palmitates / Q000378:metabolism; D020025:Peroxisome Proliferators / Q000494:pharmacology; D020675:Peroxisomes / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology; D015398:Signal Transduction; D051782:Sterol Regulatory Element Binding Protein 2 / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D047493:PPAR alpha; D010168:Palmitates; D020025:Peroxisome Proliferators; D011743:Pyrimidines; C497391:Srebf2 protein, mouse; D051782:Sterol Regulatory Element Binding Protein 2; C006253:pirinixic acid; D002784:Cholesterol; C486234:Acaa1b protein, mouse; D000102:Acetyl-CoA C-Acyltransferase