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

Marco Fidaleo, Ségolène Arnauld, Marie Claude Clémencet, Grégory Chevillard, Marie Charlotte Royer, Melina De Bruycker, Ronald J A Wanders, Anne Athias, Joseph Gresti, Pierre Clouet, Pascal Degrace, Sander Kersten, Marc Espeel, Norbert Latruffe, Valérie Nicolas-Francès, Stéphane Mandard

Research output: Contribution to journalArticle

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 (1-14C) 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.

Original languageEnglish
Pages (from-to)876-891
Number of pages16
JournalBiochimie
Volume93
Issue number5
DOIs
Publication statusPublished - May 2011

Keywords

  • Cholesterol
  • Micro-array analysis
  • Peroxisomal 3-ketoacyl-CoA thiolase B
  • PPARα and SREBP-2
  • Wy14,643

ASJC Scopus subject areas

  • Biochemistry

Fingerprint Dive into the research topics of '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'. Together they form a unique fingerprint.

  • Cite this

    Fidaleo, M., Arnauld, S., Clémencet, M. C., Chevillard, G., Royer, M. C., De Bruycker, M., Wanders, R. J. A., Athias, A., Gresti, J., Clouet, P., Degrace, P., Kersten, S., Espeel, M., Latruffe, N., Nicolas-Francès, V., & Mandard, S. (2011). 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. Biochimie, 93(5), 876-891. https://doi.org/10.1016/j.biochi.2011.02.001