title: Deregulated Lipid Sensing by Intestinal CD36 in Diet-Induced Hyperinsulinemic Obese Mouse Model.
abstract: The metabolic syndrome (MetS) greatly increases risk of cardiovascular disease and diabetes and is generally associated with abnormally elevated postprandial triglyceride levels. We evaluated intestinal synthesis of triglyceride-rich lipoproteins (TRL) in a mouse model of the MetS obtained by feeding a palm oil-rich high fat diet (HFD). By contrast to control mice, MetS mice secreted two populations of TRL. If the smaller size population represented 44% of total particles in the beginning of intestinal lipid absorption in MetS mice, it accounted for only 17% after 4 h due to the secretion of larger size TRL. The MetS mice displayed accentuated postprandial hypertriglyceridemia up to 3 h due to a defective TRL clearance. These alterations reflected a delay in lipid induction of genes for key proteins of TRL formation (MTP, L-FABP) and blood clearance (ApoC2). These abnormalities associated with blunted lipid sensing by CD36, which is normally required to optimize jejunal formation of large TRL. In MetS mice CD36 was not downregulated by lipid in contrast to control mice. Treatment of controls with the proteosomal inhibitor MG132, which prevented CD36 downregulation, resulted in blunted lipid-induction of MTP, L-FABP and ApoC2 gene expression, as in MetS mice. Absence of CD36 sensing was due to the hyperinsulinemia in MetS mice. Acute insulin treatment of controls before lipid administration abolished CD36 downregulation, lipid-induction of TRL genes and reduced postprandial triglycerides (TG), while streptozotocin-treatment of MetS mice restored lipid-induced CD36 degradation and TG secretion. In vitro, insulin treatment abolished CD36-mediated up-regulation of MTP in Caco-2 cells. In conclusion, HFD treatment impairs TRL formation in early stage of lipid absorption via insulin-mediated inhibition of CD36 lipid sensing. This impairment results in production of smaller TRL that are cleared slowly from the circulation, which might contribute to the reported association of CD36 variants with MetS risk.
authors.affiliation: Physiologie de la Nutrition et Toxicologie (NUTox), UMR U866 INSERM/Université de Bourgogne/AgroSup Dijon, F-21000, Dijon, France.
authors.forename: Marjorie
authors.initials: M
authors.lastname: Buttet
authors.affiliation: Physiologie de la Nutrition et Toxicologie (NUTox), UMR U866 INSERM/Université de Bourgogne/AgroSup Dijon, F-21000, Dijon, France.
authors.forename: Hélène
authors.initials: H
authors.lastname: Poirier
authors.affiliation: Physiologie de la Nutrition et Toxicologie (NUTox), UMR U866 INSERM/Université de Bourgogne/AgroSup Dijon, F-21000, Dijon, France.
authors.forename: Véronique
authors.initials: V
authors.lastname: Traynard
authors.affiliation: Physiologie de la Nutrition et Toxicologie (NUTox), UMR U866 INSERM/Université de Bourgogne/AgroSup Dijon, F-21000, Dijon, France.
authors.forename: Kévin
authors.initials: K
authors.lastname: Gaire
authors.affiliation: Physiologie de la Nutrition et Toxicologie (NUTox), UMR U866 INSERM/Université de Bourgogne/AgroSup Dijon, F-21000, Dijon, France.
authors.forename: Thi Thu Trang
authors.initials: TT
authors.lastname: Tran
authors.affiliation: Department of Medicine, Gastroenterology Division, University of Michigan, Ann Arbor, Michigan, 48109, United States of America.
authors.forename: Sinju
authors.initials: S
authors.lastname: Sundaresan
authors.affiliation: Physiologie de la Nutrition et Toxicologie (NUTox), UMR U866 INSERM/Université de Bourgogne/AgroSup Dijon, F-21000, Dijon, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Besnard
authors.affiliation: Department of Medicine, Center for Human Nutrition, and Department of Cell Biology & Physiology, Washington University School of Medicine, St. Louis, Missouri, 63110, United States of America.
authors.forename: Nada A
authors.initials: NA
authors.lastname: Abumrad
authors.affiliation: Physiologie de la Nutrition et Toxicologie (NUTox), UMR U866 INSERM/Université de Bourgogne/AgroSup Dijon, F-21000, Dijon, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Niot
mesh_terms: D000818:Animals; D018955:CD36 Antigens / Q000378:metabolism*; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D006946:Hyperinsulinism / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000378:metabolism*; D050356:Lipid Metabolism; D051379:Mice; D009765:Obesity / Q000378:metabolism*
chemical_list: D018955:CD36 Antigens