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.: ThB and cholesterol biosynthesis in the liver

6533b826fe1ef96bd1283ca9

RESEARCH PRODUCT

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.: ThB and cholesterol biosynthesis in the liver

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

subject

Male MESH: Hepatomegaly Palmitates MESH : Pyrimidines MESH : Gene Deletion Biochemistry element-binding proteins MESH : Acetyl-CoA C-Acyltransferase Mice MESH: Up-Regulation MESH: Animals MESH : Up-Regulation MESH: Lipid Metabolism 0303 health sciences MESH : Gene Expression Regulation Thiolase 030302 biochemistry & molecular biology General Medicine MESH : Hepatomegaly Up-Regulation zellweger-syndrome Peroxisome Proliferators MESH: Peroxisome Proliferators Hepatomegaly Sterol Regulatory Element Binding Protein 2 peroxisomal 3-ketoacyl-CoA thiolase B MESH: Mitochondria 3-oxoacyl-coa thiolase Lathosterol fatty-acid oxidation rat-liver MESH: Sterol Regulatory Element Binding Protein 2 03 medical and health sciences MESH : Sterol Regulatory Element Binding Protein 2 Humans PPAR alpha MESH : Peroxisome Proliferators [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry Molecular Biology PPARa VLAG MESH : Oxidation-Reduction Fatty Acid Oxidation.MESH: Humans Cholesterol MESH : Humans cholesterol Lipid Metabolism MESH: Peroxisomes Sterol regulatory element-binding protein chemistry MESH: Pyrimidines Cholesterol; Micro-array analysis; Peroxisomal 3-ketoacyl-CoA thiolase B; PPARα and SREBP-2; Wy14 643 Fatty Acid Oxidation Gene Deletion MESH: Liver MESH: Oxidation-Reduction MESH: Signal Transduction MESH: Mice Knockout Voeding Metabolisme en Genomica chemistry.chemical_compound MESH: Cholesterol MESH : Lipid Metabolism Wy14 MESH : Palmitates MESH: PPAR alpha MESH : Cholesterol Mice Knockout neuronal migration 643 Peroxisome Acetyl-CoA C-Acyltransferase MESH: Gene Expression Regulation Metabolism and Genomics Mitochondria Liver Biochemistry Micro-array analysis Metabolisme en Genomica ACOX1 Nutrition Metabolism and Genomics MESH : Mitochondria Oxidation-Reduction Signal Transduction acyl-coa oxidase cholesterol-synthesis MESH : Male MESH : PPAR alpha Peroxisome Proliferation PPARα and SREBP-2 Biology beta-oxidation Voeding proliferator-activated receptors MESH : Mice Peroxisomes Animals [SDV.BBM]Life Sciences [q-bio]/Biochemistry Molecular Biology MESH: Mice 030304 developmental biology SCP2 Nutrition MESH : Signal Transduction MESH : Liver MESH: Palmitates MESH: Male Pyrimidines MESH: Acetyl-CoA C-Acyltransferase Gene Expression Regulation MESH: Gene Deletion MESH : Mice Knockout MESH : Animals MESH : Peroxisomes

description

International audience; 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.

year	journal	country	edition	language
2011-05-01

10.1016/j.biochi.2011.02.001 https://www.hal.inserm.fr/inserm-00573373