title: Glucokinase links Krüppel-like factor 6 to the regulation of hepatic insulin sensitivity in nonalcoholic fatty liver disease.
abstract: The polymorphism, KLF6-IVS1-27A, in the Krüppel-like factor 6 (KLF6) transcription factor gene enhances its splicing into antagonistic isoforms and is associated with delayed histological progression of nonalcoholic fatty liver disease (NAFLD). To explore a potential role for KLF6 in the development of insulin resistance, central to NAFLD pathogenesis, we genotyped KLF6-IVS1-27 in healthy subjects and assayed fasting plasma glucose (FPG) and insulin sensitivities. Furthermore, we quantified messenger RNA (mRNA) expression of KLF6 and glucokinase (GCK), as an important mediator of insulin sensitivity, in human livers and in liver tissues derived from a murine Klf6 knockdown model (DeltaKlf6). Klf6 overexpression studies in a mouse hepatocyte line were utilized to mechanistically link KLF6 with Gck promoter activity. KLF6-IVS1-27Gwt (i.e., less KLF6 splicing) was associated with stepwise increases in FPG and insulin and reduced hepatic insulin sensitivity. KLF6 binds to the liver-specific Gck promoter and activates a GCK promoter-reporter, identifying GCK as a KLF6 direct transcriptional target. Accordingly, in DeltaKlf6 hepatocytes Gck expression was reduced and stable transfection of Klf6 led to up-regulation of Gck. GCK and KLF6 mRNAs correlate directly in human NAFLD tissues and immunohistochemistry studies confirm falling levels of both KLF6 and GCK in fat-laden hepatocytes. In contrast to full-length KLF6, splice variant KLF6-SV1 increases in NAFLD hepatocytes and inversely correlates with glucokinase regulatory protein, which negatively regulates GCK activity.
  
  
  CONCLUSIONS
  KLF6 regulation of GCK contributes to the development of hepatic insulin resistance. The KLF6-IVS1-27A polymorphism, which generates more KLF6-SV1, combats this, lowering hepatic insulin resistance and blood glucose.
authors.affiliation: Division of Liver Diseases, Mount Sinai School of Medicine, New York, NY, USA.
authors.forename: Lars P
authors.initials: LP
authors.lastname: Bechmann
authors.forename: Amalia
authors.initials: A
authors.lastname: Gastaldelli
authors.forename: Diana
authors.initials: D
authors.lastname: Vetter
authors.forename: Gillian L
authors.initials: GL
authors.lastname: Patman
authors.forename: Laura
authors.initials: L
authors.lastname: Pascoe
authors.forename: Rebekka A
authors.initials: RA
authors.lastname: Hannivoort
authors.forename: Ursula E
authors.initials: UE
authors.lastname: Lee
authors.forename: Isabel
authors.initials: I
authors.lastname: Fiel
authors.forename: Ursula
authors.initials: U
authors.lastname: Muñoz
authors.forename: Demetrio
authors.initials: D
authors.lastname: Ciociaro
authors.forename: Young-Min
authors.initials: YM
authors.lastname: Lee
authors.forename: Emma
authors.initials: E
authors.lastname: Buzzigoli
authors.forename: Luca
authors.initials: L
authors.lastname: Miele
authors.forename: Kei Y
authors.initials: KY
authors.lastname: Hui
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Bugianesi
authors.forename: Alastair D
authors.initials: AD
authors.lastname: Burt
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Day
authors.forename: Andrea
authors.initials: A
authors.lastname: Mari
authors.forename: Loranne
authors.initials: L
authors.lastname: Agius
authors.forename: Mark
authors.initials: M
authors.lastname: Walker
authors.forename: Scott L
authors.initials: SL
authors.lastname: Friedman
authors.forename: Helen L
authors.initials: HL
authors.lastname: Reeves
mesh_terms: D000328:Adult; D000818:Animals; D001706:Biopsy; D001786:Blood Glucose / Q000378:metabolism; D015331:Cohort Studies; D004195:Disease Models, Animal; D005234:Fatty Liver / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology*; D005260:Female; D005838:Genotype; D005941:Glucokinase / Q000378:metabolism*; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007333:Insulin Resistance / Q000502:physiology*; D000075723:Kruppel-Like Factor 6; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism*; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D065626:Non-alcoholic Fatty Liver Disease; D011110:Polymorphism, Genetic / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism
chemical_list: D001786:Blood Glucose; C105465:KLF6 protein, human; C491358:Klf6 protein, mouse; D000075723:Kruppel-Like Factor 6; D051741:Kruppel-Like Transcription Factors; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D005941:Glucokinase
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