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

Mechanisms underlying the opposite effects of TM6SF2 rs58542926 C>T polymorphism on liver injury and cardio-metabolic risk in 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, incretin GIP, and an OGTT with Minimal Model analysis of glucose homeostasis. TM6SF2 T-allele was associated with higher hepatic and adipose insulin resistance, with impaired pancreatic beta-cell function and incretin effect and with higher muscle insulin sensitivity and whole-body fat oxidation rate. Compared with TM6SF2 C-allele, T-allele entailed lower postprandial lipemia and nefaemia, a less atherogenic lipoprotein profile, a postprandial cholesterol redistribution from smaller, atherogenic lipoprotein subfractions to larger intestinal and hepatic VLDL1 subfration. Postprandial plasma VLDL1-cholesterol response independently predicted the severity of liver histology. In conclusion, 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 cardio-metabolic risk in NAFLD.