1. Modulation of the hepatic fatty acid pool in peroxisomal 3-ketoacyl-CoA thiolase B-null mice exposed to the selective PPARalpha agonist Wy14,643
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Ronald J.A. Wanders, Marie Claude Clémencet, Valérie Nicolas-Francès, Joseph Gresti, Grégory Chevillard, Stéphane Mandard, Norbert Latruffe, Ségolène Arnauld, Anne Athias, Marco Fidaleo, Mandard, Stéphane, ‘‘Peroxisomes' LSHG-CT-2004-512018 - INCOMING, Lipides - Nutrition - Cancer (U866) (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA), Plateforme Lipidomique [Dijon] (LAP), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA)-Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA)-IFR100 - Structure fédérative de recherche Santé-STIC-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Laboratory Genetic Metabolic Diseases, Academic Medical Center at the University of Amsterdam, (AMC), Universiteit van Amsterdam (UvA), The European Union project ‘‘Peroxisomes' LSHG-CT-2004-512018, the Regional Council of Burgundy, the INSERM U866 center (Dijon) and the Italian Ministero della Ricerca Scientifica e Tecnologica., European Project, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, Laboratory Genetic Metabolic Diseases, Lipides - Nutrition - Cancer (U866) ( LNC ), Université de Bourgogne ( UB ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon ( ENSBANA ), Plateforme Lipidomique [Dijon] ( LAP ), Université de Bourgogne ( UB ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon ( ENSBANA ) -Université de Bourgogne ( UB ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon ( ENSBANA ) -IFR100 - Structure fédérative de recherche Santé-STIC-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Laboratory Genetic Metabolic Diseases, Academic Medical Center at the University of Amsterdam, ( AMC ), and Université d'Amsterdam
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MESH : RNA, Messenger ,MESH: Microsomes, Liver ,MESH : Pyrimidines ,Mono-unsaturated fatty acids n-7 and n-9 ,MESH : Hepatocytes ,[SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology ,MESH: Mice, Knockout ,PPARα ,Biochemistry ,MESH: Acetyl-CoA C-Acetyltransferase ,Stearoyl-CoA desaturase-1 ,MESH: Hepatocytes ,Mice ,chemistry.chemical_compound ,MESH : Lipid Metabolism ,Wy14 ,MESH: Animals ,Peroxisomal 3-ketoacyl-CoA thiolase B ,Acetyl-CoA C-Acetyltransferase ,MESH: PPAR alpha ,MESH : Fatty Acids ,MESH: Lipid Metabolism ,Mice, Knockout ,chemistry.chemical_classification ,Thiolase ,Fatty Acids ,General Medicine ,Peroxisome ,MESH : Stearoyl-CoA Desaturase ,MESH: Fatty Acids ,MESH : Microsomes, Liver ,MESH : Acetyl-CoA C-Acetyltransferase ,Microsomes, Liver ,Wy14,643 ,lipids (amino acids, peptides, and proteins) ,Stearoyl-CoA Desaturase ,Polyunsaturated fatty acid ,medicine.medical_specialty ,MESH : PPAR alpha ,MESH : Mice, Inbred C57BL ,[ SDV.BBM.BM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology ,Biology ,MESH: Mice, Inbred C57BL ,Internal medicine ,MESH : Mice ,Peroxisomes ,medicine ,Animals ,Humans ,PPAR alpha ,RNA, Messenger ,MESH: Mice ,MESH: RNA, Messenger ,SCP2 ,MESH: Humans ,MESH : Humans ,Fatty acid ,[SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology ,Stearoyl-CoA ,Lipid Metabolism ,MESH: Peroxisomes ,Sterol regulatory element-binding protein ,Mice, Inbred C57BL ,Pyrimidines ,Endocrinology ,chemistry ,MESH: Pyrimidines ,MESH: Stearoyl-CoA Desaturase ,Hepatocytes ,MESH : Mice, Knockout ,MESH : Animals ,MESH : Peroxisomes - Abstract
10 pages; International audience; The peroxisomal 3-ketoacyl-CoA thiolase B (Thb) gene was previously identified as a direct target gene of PPARalpha, a nuclear hormone receptor activated by hypolipidemic fibrate drugs. To better understand the role of ThB in hepatic lipid metabolism in mice, Sv129 wild-type and Thb null mice were fed or not the selective PPARalpha agonist Wy14,643 (Wy). Here, it is shown that in contrast to some other mouse models deficient for peroxisomal enzymes, the hepatic PPARalpha signaling cascade in Thb null mice was normal under regular conditions. It is of interest that the hypotriglyceridemic action of Wy was reduced in Thb null mice underlining the conclusion that neither thiolase A nor SCPx/SCP2 thiolase can fully substitute for ThB in vivo. Moreover, a significant increased in the expression of lipogenic genes such as Stearoyl CoA Desaturase-1 (SCD1) was observed in Thb null mice fed Wy. Elevation of Scd1 mRNA and protein levels led to higher SCD1 activity, through a molecular mechanism that is probably SREBP1 independent. In agreement with higher SCD1, enrichment of liver mono-unsaturated fatty acids of the n-7 and n-9 series was found in Thb null mice fed Wy. Overall, we show that the reduced peroxisomal beta-oxidation of fat observed in Thb null mice fed Wy is associated with enhanced hepatic lipogenesis, through the combined elevation of microsomal SCD1 protein and activity. Ultimately, not only the amount but also the quality of the hepatic fatty acid pool is modulated upon the deletion of Thb.
- Published
- 2009
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