Impact of sterol regulatory element-binding factor-1c polymorphism on incidence of nonalcoholic fatty liver disease and on the severity of liver disease and of glucose and lipid dysmetabolism

Abstract

Background: Genetic factors that predispose individuals to nonalcoholic fatty liver disease (NAFLD) and associated diabetes and cardiovascular disease are unclear. The transcription factor sterol regulatory element-binding protein-1c (SREBP-1c) modulates lipogenesis and insulin sensitivity and was experimentally connected to NAFLD Objective: We assessed the impact of a common SREBF-1c polymorphism on the incidence and severity of NAFLD and on associated glucose and lipoprotein dysmetabolism Design: We followed up 212 randomly selected, nonobese, nondiabetic, insulin-sensitive participants in a population-based study without NAFLD or metabolic syndrome at baseline who were characterized for the common SREBF-1c gene rs11868035 A/G polymorphism, dietary habits, physical activity, adipokine profile, C-reactive protein (CRP), and circulating markers of endothelial dysfunction. A comparable cohort of NAFLD patients underwent a liver biopsy, an oral-glucose-tolerance test with minimal model analysis of glucose homeostasis variables, and an oral-fat-tolerance test with measurement of plasma lipoproteins, adipokines, and cytokeratin-18 fragments Results: SREBF-1c predicted the 7-y incidence of NAFLD (OR: 1.71; 95% CI: 1.15, 2.53) and diabetes and the 7-y elevation in CRP and endothelial dysfunction markers. In biopsy-proven NAFLD patients, the SREBF-1c A allele conferred increased risk of severe steatosis and nonalcoholic steatohepatitis; more-severe hepatic, muscle, and adipose tissue insulin resistance; and pancreatic b cell dysfunction. SREBF-1c A allele carriers also had an impaired oral fat tolerance with a postprandial accumulation of large triglyceriderich lipoproteins and oxidized LDLs, lower HDL cholesterol and adiponectin concentrations, and cytokeratin-18 fragment elevation Conclusion: SREBF-1c polymorphism is associated with increased risk of developing NAFLD with more severe liver histology and derangement in glucose and lipoprotein metabolism, which contribute to the presentation and natural history of NAFLD. © 2013 American Society for Nutrition.