title: 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.
  
  
  METHODS
  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 β cell dysfunction. SREBF-1c A allele carriers also had an impaired oral fat tolerance with a postprandial accumulation of large triglyceride-rich lipoproteins and oxidized LDLs, lower HDL cholesterol and adiponectin concentrations, and cytokeratin-18 fragment elevation.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Gradenigo Hospital, Turin, Italy, and the Department of Internal Medicine, University of Turin, Turin, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Musso
authors.forename: Simona
authors.initials: S
authors.lastname: Bo
authors.forename: Maurizio
authors.initials: M
authors.lastname: Cassader
authors.forename: Franco
authors.initials: F
authors.lastname: De Michieli
authors.forename: Roberto
authors.initials: R
authors.lastname: Gambino
mesh_terms: D052242:Adiponectin / Q000097:blood; D001786:Blood Glucose / Q000032:analysis; D015992:Body Mass Index; D002097:C-Reactive Protein / Q000032:analysis; D008076:Cholesterol, HDL / Q000097:blood; D019040:E-Selectin / Q000097:blood; D004730:Endothelium, Vascular / Q000503:physiopathology; D005234:Fatty Liver / Q000235:genetics* / Q000473:pathology; D005500:Follow-Up Studies; D018149:Glucose Intolerance / Q000235:genetics*; D006706:Homeostasis; D006801:Humans; D007333:Insulin Resistance / Q000235:genetics; D018799:Intercellular Adhesion Molecule-1 / Q000097:blood; D052439:Lipid Metabolism Disorders / Q000235:genetics*; D008077:Lipoproteins, LDL / Q000097:blood; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008875:Middle Aged; D065626:Non-alcoholic Fatty Liver Disease; D011110:Polymorphism, Genetic / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D052243:Resistin / Q000097:blood; D012720:Severity of Illness Index; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics*
chemical_list: D052242:Adiponectin; D001786:Blood Glucose; D008076:Cholesterol, HDL; D019040:E-Selectin; D008077:Lipoproteins, LDL; D052243:Resistin; D051780:Sterol Regulatory Element Binding Protein 1; C099252:oxidized low density lipoprotein; D018799:Intercellular Adhesion Molecule-1; D002097:C-Reactive Protein