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Glucokinase links Krüppel-like factor 6 to the regulation of hepatic insulin sensitivity in nonalcoholic fatty liver disease
Lookup NU author(s)
Dr Gillian Patman
Dr Luca Miele
Professor Alastair Burt
Professor Chris Day
Professor Loranne Agius
Professor Mark Walker
Dr Helen Reeves
Bechmann LP, Gastaldelli A, Vetter D, Patman GL, Pascoe L, Hannivoort RA, Lee UE, Fiel I, Muñoz U, Ciociaro D, Buzzigoli E, Miele L, Hui KY, Bugianesi E, Burt AD, Day CP, Mari A, Agius L, Walker M, Friedman SL, Reeves HL
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, 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
in healthy subjects and assayed fasting plasma glucose (FPG) and insulin sensitivities. Furthermore, we quantified messenger RNA (mRNA) expression of
and glucokinase (
), as an important mediator of insulin sensitivity, in human livers and in liver tissues derived from a murine
knockdown model (DeltaKlf6).
overexpression studies in a mouse hepatocyte line were utilized to mechanistically link KLF6 with
wt (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
promoter and activates a GCK promoter-reporter, identifying GCK as a KLF6 direct transcriptional target. Accordingly, in DeltaKlf6 hepatocytes
expression was reduced and stable transfection of
led to up-regulation of
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
, splice variant
increases in NAFLD hepatocytes and inversely correlates with glucokinase regulatory protein, which negatively regulates GCK activity.
: KLF6 regulation of GCK contributes to the development of hepatic insulin resistance. The
polymorphism, which generates more KLF6-SV1, combats this, lowering hepatic insulin resistance and blood glucose.
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