title: Disturbances in cholesterol, bile acid and glucose metabolism in peroxisomal 3-ketoacylCoA thiolase B deficient mice fed diets containing high or low fat contents.
abstract: The peroxisomal 3-ketoacyl-CoA thiolase B (ThB) catalyzes the thiolytic cleavage of straight chain 3-ketoacyl-CoAs. Up to now, the ability of ThB to interfere with lipid metabolism was studied in mice fed a laboratory chow enriched or not with the synthetic agonist Wy14,643, a pharmacological activator of the nuclear hormone receptor PPARα. The aim of the present study was therefore to determine whether ThB could play a role in obesity and lipid metabolism when mice are chronically fed a synthetic High Fat Diet (HFD) or a Low Fat Diet (LFD) as a control diet. To investigate this possibility, wild-type (WT) mice and mice deficient for Thb (Thb(-/-)) were subjected to either a synthetic LFD or a HFD for 25 weeks, and their responses were compared. First, when fed a normal regulatory laboratory chow, Thb(-/-) mice displayed growth retardation as well as a severe reduction in the plasma level of Growth Hormone (GH) and Insulin Growth Factor-I (IGF-I), suggesting alterations in the GH/IGF-1 pathway. When fed the synthetic diets, the corrected energy intake to body mass was significantly higher in Thb(-/-) mice, yet those mice were protected from HFD-induced adiposity. Importantly, Thb(-/-) mice also suffered from hypoglycemia, exhibited reduction in liver glycogen stores and circulating insulin levels under the LFD and the HFD. Thb deficiency was also associated with higher levels of plasma HDL (High Density Lipoproteins) cholesterol and increased liver content of cholesterol under both the LFD and the HFD. As shown by the plasma lathosterol to cholesterol ratio, a surrogate marker for cholesterol biosynthesis, whole body cholesterol de novo synthesis was increased in Thb(-/-) mice. By comparing liver RNA from WT mice and Thb(-/-) mice using oligonucleotide microarray and RT-qPCR, a coordinated decrease in the expression of critical cholesterol synthesizing genes and an increased expression of genes involved in bile acid synthesis (Cyp7a1, Cyp17a1, Akr1d1) were observed in Thb(-/-) mice. In parallel, the elevation of the lathosterol to cholesterol ratio as well as the increased expression of cholesterol synthesizing genes were observed in the kidney of Thb(-/-) mice fed the LFD and the HFD. Overall, the data indicate that ThB is not fully interchangeable with the thiolase A isoform. The present study also reveals that modulating the expression of the peroxisomal ThB enzyme can largely reverberate not only throughout fatty acid metabolism but also cholesterol, bile acid and glucose metabolism.
authors.affiliation: INSERM-UMR866, Dijon 21000, France; Université de Bourgogne, Faculté des Sciences Gabriel, Equipe 'Biochimie du peroxysome, inflammation et métabolisme lipidique', EA 7270, 21000 Dijon, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Nicolas-Francès
authors.affiliation: INSERM-UMR866, Dijon 21000, France; Université de Bourgogne, Faculté des Sciences Gabriel, Equipe 'Biochimie du peroxysome, inflammation et métabolisme lipidique', EA 7270, 21000 Dijon, France.
authors.forename: Ségolène
authors.initials: S
authors.lastname: Arnauld
authors.affiliation: INSERM-UMR866, Dijon 21000, France; Université de Bourgogne, Faculté des Sciences Gabriel, Equipe 'Biochimie du peroxysome, inflammation et métabolisme lipidique', EA 7270, 21000 Dijon, France.
authors.forename: Jacques
authors.initials: J
authors.lastname: Kaminski
authors.affiliation: Max Planck Institute for Plant Breeding Research Carl-von-Linné-Weg 10, 50829 Köln, Germany.
authors.forename: Emiel
authors.initials: E
authors.lastname: Ver Loren van Themaat
authors.affiliation: INSERM-UMR866, Dijon 21000, France; Université de Bourgogne, Faculté des Sciences Gabriel, Equipe 'Biochimie du peroxysome, inflammation et métabolisme lipidique', EA 7270, 21000 Dijon, France.
authors.forename: Marie-Claude
authors.initials: MC
authors.lastname: Clémencet
authors.affiliation: INSERM-UMR866, Dijon 21000, France; Université de Bourgogne, Faculté des Sciences Gabriel, Equipe 'Biochimie du peroxysome, inflammation et métabolisme lipidique', EA 7270, 21000 Dijon, France.
authors.forename: Julie
authors.initials: J
authors.lastname: Chamouton
authors.affiliation: Structure Fédérative de Recherche Santé-STIC, Université de Bourgogne, 21000 Dijon, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Athias
authors.affiliation: Centre de Recherche INSERM UMR 866 "Lipides, Nutrition, Cancer", Université de Bourgogne, Equipe "Protéines de transfert des lipides et métabolisme des lipoprotéines", Faculté de Médecine, 21079 Dijon Cedex, France.
authors.forename: Jacques
authors.initials: J
authors.lastname: Grober
authors.affiliation: INSERM-UMR866, Dijon 21000, France; Université de Bourgogne, Faculté des Sciences Gabriel, Equipe "Physiopathologies des dyslipidémies", 21000 Dijon, France.
authors.forename: Joseph
authors.initials: J
authors.lastname: Gresti
authors.affiliation: INSERM-UMR866, Dijon 21000, France; Université de Bourgogne, Faculté des Sciences Gabriel, Equipe "Physiopathologies des dyslipidémies", 21000 Dijon, France.
authors.forename: Pascal
authors.initials: P
authors.lastname: Degrace
authors.affiliation: Centre de Recherche INSERM UMR 866 "Lipides, Nutrition, Cancer", Université de Bourgogne, Equipe "Protéines de transfert des lipides et métabolisme des lipoprotéines", Faculté de Médecine, 21079 Dijon Cedex, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Lagrost
authors.affiliation: INSERM-UMR866, Dijon 21000, France; Université de Bourgogne, Faculté des Sciences Gabriel, Equipe 'Biochimie du peroxysome, inflammation et métabolisme lipidique', EA 7270, 21000 Dijon, France.
authors.forename: Norbert
authors.initials: N
authors.lastname: Latruffe
authors.affiliation: INSERM-UMR866, Dijon 21000, France; Université de Bourgogne, Faculté des Sciences Gabriel, Equipe 'Biochimie du peroxysome, inflammation et métabolisme lipidique', EA 7270, 21000 Dijon, France; Centre de Recherche INSERM UMR 866 "Lipides, Nutrition, Cancer", Université de Bourgogne, Equipe "Protéines de transfert des lipides et métabolisme des lipoprotéines", Faculté de Médecine, 21079 Dijon Cedex, France. Electronic address: stephane.mandard@u-bourgogne.fr.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Mandard
mesh_terms: D000102:Acetyl-CoA C-Acyltransferase / Q000172:deficiency*; D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism; D008076:Cholesterol, HDL / Q000097:blood; D059305:Diet, High-Fat; D004041:Dietary Fats / Q000008:administration & dosage; D005947:Glucose / Q000378:metabolism; D013006:Growth Hormone / Q000097:blood; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D007421:Intestine, Small / Q000378:metabolism; D008112:Liver Glycogen / Q000378:metabolism; D051379:Mice
chemical_list: D001647:Bile Acids and Salts; D008076:Cholesterol, HDL; D004041:Dietary Fats; D008112:Liver Glycogen; D007334:Insulin-Like Growth Factor I; D013006:Growth Hormone; D002784:Cholesterol; D000102:Acetyl-CoA C-Acyltransferase; D005947:Glucose
keywords: Bile acids; De novo biosynthesis of cholesterol; Hypoglycemia; Lathosterol; Peroxisomal 3-ketoacyl-CoA thiolase B