title: TM6SF2 rs58542926 variant affects postprandial lipoprotein metabolism and glucose homeostasis in NAFLD.
abstract: Mechanisms underlying the opposite effects of transmembrane 6 superfamily member 2 (TM6SF2) rs58542926 C>T polymorphism on liver injury and cardiometabolic risk in nonalcoholic fatty liver disease (NAFLD) are unclear. We assessed the impact of this polymorphism on postprandial lipoprotein metabolism, glucose homeostasis, and nutrient oxidation in NAFLD. Sixty nonobese nondiabetic normolipidemic biopsy-proven NAFLD patients and 60 matched controls genotyped for TM6SF2 C>T polymorphism underwent: indirect calorimetry; an oral fat tolerance test with measurement of plasma lipoprotein subfractions, adipokines, and incretin glucose-dependent insulinotropic polypeptide (GIP); and an oral glucose tolerance test with minimal model analysis of glucose homeostasis. The TM6SF2 T-allele was associated with higher hepatic and adipose insulin resistance, impaired pancreatic β-cell function and incretin effect, and higher muscle insulin sensitivity and whole-body fat oxidation rate. Compared with the TM6SF2 C-allele, the T-allele entailed lower postprandial lipemia and nefaemia, a less atherogenic lipoprotein profile, and a postprandial cholesterol (Chol) redistribution from smaller atherogenic lipoprotein subfractions to larger intestinal and hepatic VLDL1 subfractions. Postprandial plasma VLDL1-Chol response independently predicted the severity of liver histology. In conclusion, the TM6SF2 C>T polymorphism affects nutrient oxidation, glucose homeostasis, and postprandial lipoprotein, adipokine, and GIP responses to fat ingestion independently of fasting values. These differences may contribute to the dual and opposite effect of this polymorphism on liver injury and cardiometabolic risk in NAFLD.
authors.affiliation: HUMANITAS Gradenigo, Turin, Italy giovanni_musso@yahoo.it.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Musso
authors.affiliation: HUMANITAS Gradenigo, Turin, Italy.
authors.forename: Ugo
authors.initials: U
authors.lastname: Cipolla
authors.affiliation: Department of Medical Sciences, University of Turin, Turin, Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Cassader
authors.affiliation: HUMANITAS Gradenigo, Turin, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Pinach
authors.affiliation: HUMANITAS Gradenigo, Turin, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Saba
authors.affiliation: Department of Medical Sciences, University of Turin, Turin, Italy.
authors.forename: Franco
authors.initials: F
authors.lastname: De Michieli
authors.affiliation: HUMANITAS Gradenigo, Turin, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Paschetta
authors.affiliation: HUMANITAS Gradenigo, Turin, Italy.
authors.forename: Daria
authors.initials: D
authors.lastname: Bongiovanni
authors.affiliation: HUMANITAS Gradenigo, Turin, Italy.
authors.forename: Luciana
authors.initials: L
authors.lastname: Framarin
authors.affiliation: HUMANITAS Gradenigo, Turin, Italy.
authors.forename: Nicola
authors.initials: N
authors.lastname: Leone
authors.affiliation: HUMANITAS Gradenigo, Turin, Italy.
authors.forename: Mara
authors.initials: M
authors.lastname: Berrutti
authors.affiliation: Medical Team, Turin, Italy.
authors.forename: Floriano
authors.initials: F
authors.lastname: Rosina
authors.affiliation: HUMANITAS Gradenigo, Turin, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Corvisieri
authors.affiliation: HUMANITAS Gradenigo, Turin, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Molinaro
authors.affiliation: Emergency Medicine Department, Sassari Hospital, Sassari, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Sircana
authors.affiliation: Department of Medical Sciences, University of Turin, Turin, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Gambino
mesh_terms: D000328:Adult; D005260:Female; D005947:Glucose / Q000378:metabolism*; D006706:Homeostasis / Q000235:genetics*; D006801:Humans; D008074:Lipoproteins / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D065626:Non-alcoholic Fatty Liver Disease / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D020641:Polymorphism, Single Nucleotide; D019518:Postprandial Period
chemical_list: D008074:Lipoproteins; D008565:Membrane Proteins; C419195:TM6SF2 protein, human; D005947:Glucose
keywords: cholesterol; lipemia; lipoprotein subfractions; nonalcoholic fatty liver disease; nonalcoholic steatohepatitis; transmembrane 6 superfamily member 2