title: Transcription factor 7-like 2 polymorphism modulates glucose and lipid homeostasis, adipokine profile, and hepatocyte apoptosis in NASH.
abstract: Genetic factors underlying the association of NAFLD with diabetes and atherosclerosis are unknown. Recent human studies suggest transcription factor 7-like 2 (TCF7L2) polymorphism predisposes to diabetes through modulation of beta-cell function and modulates lipid levels in familial dyslipidemia. Emerging experimental evidence connects TCF7L2 to adipocyte metabolism and lipid homeostasis, as well. We tested if TCF7L2 polymorphism is a risk factor for nonalcoholic fatty liver disease (NAFLD) and if it modulates liver injury, glucose homeostasis, lipoprotein, and adipokine profiles in NASH. TCF7L2 genotype and dietary habits of 78 nondiabetic normolipidemic NAFLD subjects and 156 age-, body mass index-, sex-matched healthy controls were assessed. In 39 biopsy-proven nonalcoholic steatohepatitis (NASH) and matched controls TCF7L2 polymorphism was correlated to liver histology and oral glucose tolerance test-derived parameters of glucose homeostasis. Patients with NASH and controls consumed a high-fat meal and TCF7L2 genotype was correlated to postprandial circulating lipoproteins, adipokines, and cytokeratin-18 fragments. The TCF7L2 CT/TT genotype was more frequent in NAFLD and predicted the presence and severity of liver disease, of beta-cell dysfunction, of reduced incretin effect and hepatic insulin resistance in NASH; it also modulated postprandial hepatocyte apoptosis, lipoproteins, and adipokine profiles in both groups.
  
  
  CONCLUSIONS
  TCF7L2 polymorphism predisposes to NAFLD and significantly impacts liver injury, glucose homeostasis, and postprandial lipoprotein and adipokine responses to fat ingestion. This polymorphism also modulates a fat-induced increase in circulating markers of hepatocyte apoptosis in NASH. Targeting postprandial lipemia, at least in at-risk TCF7L2 genotypes, may improve liver disease and glucose dysmetabolism in these patients.
authors.affiliation: Gradenigo Hospital, Turin, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Musso
authors.forename: Roberto
authors.initials: R
authors.lastname: Gambino
authors.forename: Giovanni
authors.initials: G
authors.lastname: Pacini
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Pagano
authors.forename: Marilena
authors.initials: M
authors.lastname: Durazzo
authors.forename: Maurizio
authors.initials: M
authors.lastname: Cassader
mesh_terms: D054392:Adipokines / Q000502:physiology*; D052242:Adiponectin / Q000097:blood; D000273:Adipose Tissue / Q000033:anatomy & histology; D017209:Apoptosis; D003920:Diabetes Mellitus / Q000235:genetics; D005234:Fatty Liver / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D005260:Female; D005947:Glucose / Q000378:metabolism*; D022781:Hepatocytes / Q000166:cytology*; D006801:Humans; D020738:Leptin / Q000097:blood; D008297:Male; D018579:Patient Selection; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D052243:Resistin / Q000097:blood; D051820:TCF Transcription Factors / Q000235:genetics*; D058118:Transcription Factor 7-Like 2 Protein; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
chemical_list: D054392:Adipokines; D052242:Adiponectin; D020738:Leptin; D052243:Resistin; D051820:TCF Transcription Factors; C544894:TCF7L2 protein, human; D058118:Transcription Factor 7-Like 2 Protein; D014409:Tumor Necrosis Factor-alpha; D005947:Glucose