title: Sar1b transgenic male mice are more susceptible to high-fat diet-induced obesity, insulin insensitivity and intestinal chylomicron overproduction.
abstract: In the intracellular secretory network, nascent proteins are shuttled from the endoplasmic reticulum to the Golgi by transport vesicles requiring Sar1b, a small GTPase. Mutations in this key enzyme impair intestinal lipid transport and cause chylomicron retention disease. The main aim of this study was to assess whether Sar1b overexpression under a hypercaloric diet accelerated lipid production and chylomicron (CM) secretion, thereby inducing cardiometabolic abnormalities. To this end, we generated transgenic mice overexpressing human Sar1b (Sar1b(+/+)) using pBROAD3-mcs that features the ubiquitous mouse ROSA26 promoter. In response to a high-fat diet (HFD), Sar1b(+/+) mice displayed significantly increased body weight and adiposity compared with Sar1b(+/+) mice under the same regimen or with wild-type (WT) mice exposed to chow diet or HFD. Furthermore, Sar1b(+/+) mice were prone to liver steatosis as revealed by significantly elevated hepatic triglycerides (TG) and cholesterol in comparison with WT animals. They also exhibited augmented levels of plasma TG along with alterations in fatty acid composition. Concomitantly, they showed susceptibility to develop insulin insensitivity and they responded abnormally to oral glucose tolerance test. Finally, Sar1b(+/+) mice that have been treated with Triton WR-1330 (to inhibit TG catabolism) and orotic acid (to block secretion of very low-density lipoprotein by the liver) responded more efficiently to fat meal tests as reflected by the rise in plasma TG and CM concentrations, indicating exaggerated intestinal fat absorption. These results suggest that Sar1b(+/+) under HFD can elicit cardiometabolic traits as revealed by incremental weight gain, fat deposition, dyslipidemia, hepatic steatosis, insulin insensitivity and intestinal fat absorption.
authors.affiliation: Research Center, Sainte-Justine UHC, Montreal, Quebec, Canada, H3T 1C5; Department of Nutrition, Université de Montréal, Montreal, Quebec, Canada, H3T 1J4; Canadian Institutes for Health Research Team on the Digestive Epithelium, Department of Anatomy and Cellular Biology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, Quebec, Canada, J1H 5N4. Electronic address: emile.levy@recherche-ste-Justine.qc.ca.
authors.forename: Emile
authors.initials: E
authors.lastname: Levy
authors.affiliation: Research Center, Sainte-Justine UHC, Montreal, Quebec, Canada, H3T 1C5; Department of Nutrition, Université de Montréal, Montreal, Quebec, Canada, H3T 1J4.
authors.forename: Schohraya
authors.initials: S
authors.lastname: Spahis
authors.affiliation: Research Center, Sainte-Justine UHC, Montreal, Quebec, Canada, H3T 1C5.
authors.forename: Carole
authors.initials: C
authors.lastname: Garofalo
authors.affiliation: Research Institute, McGill University, Montreal, Quebec, Canada, H3G 1A4.
authors.forename: Valérie
authors.initials: V
authors.lastname: Marcil
authors.affiliation: Research Center, Sainte-Justine UHC, Montreal, Quebec, Canada, H3T 1C5.
authors.forename: Alain
authors.initials: A
authors.lastname: Montoudis
authors.affiliation: Department of Pediatrics, Université de Montréal, Montreal, Quebec, Canada, H3T 1C5.
authors.forename: Daniel
authors.initials: D
authors.lastname: Sinnet
authors.affiliation: Research Center, Sainte-Justine UHC, Montreal, Quebec, Canada, H3T 1C5.
authors.forename: Rocio
authors.initials: R
authors.lastname: Sanchez
authors.affiliation: Centre de recherche Rhône-Alpes en nutrition humaine, Hôpital Edouard-Herriot, Faculté de Médicine, Université de Lyon-1, France.
authors.forename: Noel
authors.initials: N
authors.lastname: Peretti
authors.affiliation: Canadian Institutes for Health Research Team on the Digestive Epithelium, Department of Anatomy and Cellular Biology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, Quebec, Canada, J1H 5N4.
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Beaulieu
authors.affiliation: Research Center, Sainte-Justine UHC, Montreal, Quebec, Canada, H3T 1C5.
authors.forename: Alain
authors.initials: A
authors.lastname: Sane
mesh_terms: D000818:Animals; D001835:Body Weight / Q000235:genetics; D002914:Chylomicrons / Q000378:metabolism*; D059305:Diet, High-Fat / Q000009:adverse effects*; D004435:Eating / Q000235:genetics; D005227:Fatty Acids / Q000032:analysis / Q000097:blood; D005786:Gene Expression Regulation; D007333:Insulin Resistance; D007408:Intestinal Absorption; D007413:Intestinal Mucosa / Q000378:metabolism*; D050356:Lipid Metabolism / Q000235:genetics; D008055:Lipids / Q000097:blood; D008297:Male; D008822:Mice, Transgenic; D020559:Monomeric GTP-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D009765:Obesity / Q000209:etiology*; D009929:Organ Size / Q000235:genetics; D014280:Triglycerides / Q000097:blood
chemical_list: D002914:Chylomicrons; D005227:Fatty Acids; D008055:Lipids; D014280:Triglycerides; C513282:SAR1B protein, human; D020559:Monomeric GTP-Binding Proteins
keywords: Chylomicron production; Fat absorption; Fatty acids; Insulin resistance; Lipids; Sar1B GTPase