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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 ?-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.

SUBMITTER: Musso G

PROVIDER: S-EPMC5454511 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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TM6SF2 rs58542926 variant affects postprandial lipoprotein metabolism and glucose homeostasis in NAFLD.

Musso Giovanni G Cipolla Ugo U Cassader Maurizio M Pinach Silvia S Saba Francesca F De Michieli Franco F Paschetta Elena E Bongiovanni Daria D Framarin Luciana L Leone Nicola N Berrutti Mara M Rosina Floriano F Corvisieri Stefania S Molinaro Federica F Sircana Antonio A Gambino Roberto R

Journal of lipid research 20170227 6

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: ...[more]

PMID: 28242789

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Project description:Accumulating evidence identifies diet and inflammation as potential mechanisms contributing to cardiometabolic risk. However, inconsistent reports regarding dietary inflammatory potential, biomarkers of cardiometabolic health and metabolic syndrome (MetS) risk exist. Our objective was to examine the relationships between a food frequency questionnaire (FFQ)-derived dietary inflammatory index (DII®), biomarkers of lipoprotein metabolism, inflammation and glucose homeostasis and MetS risk in a cross-sectional sample of 1992 adults. Energy-adjusted DII (E-DII) scores derived from an FFQ were calculated. Lipoprotein particle size and subclass concentrations were measured using nuclear magnetic resonance (NMR) spectroscopy. Serum acute-phase reactants, adipocytokines, pro-inflammatory cytokines and white blood cell (WBC) counts were determined. Insulin resistance was calculated by homeostasis model assessment (HOMA-IR). Our data indicate that a more pro-inflammatory diet, reflected by higher E-DII scores, was associated with potentially pro-atherogenic lipoprotein profiles characterised by increased numbers of large very low density lipoprotein (VLDL), small dense low density lipoprotein (LDL) and high density lipoprotein (HDL) particles and less large LDL and HDL particles (all p < 0.001). Inflammatory profiling identified a range of adverse phenotypes among those with higher E-DII scores, including higher complement component C3 (C3), C-reactive protein (CRP), (both p < 0.05), interleukin 6 (IL-6) and tumour necrosis factor (TNF)-? concentrations, higher WBC counts and neutrophil to lymphocyte ratio (NLR) and lower adiponectin levels (all p < 0.001). MetS risk was increased among those with higher E-DII scores (OR 1.37, 95% CI (1.01, 1.88), p < 0.05), after adjusting for potential confounders. In conclusion, habitual intake of a more pro-inflammatory diet is associated with unfavourable lipoprotein and inflammatory profiles and increased MetS risk.

Dataset Information

TM6SF2 rs58542926 variant affects postprandial lipoprotein metabolism and glucose homeostasis in NAFLD.

Publications

TM6SF2 rs58542926 variant affects postprandial lipoprotein metabolism and glucose homeostasis in NAFLD.

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