The KLF14 transcription factor regulates hepatic gluconeogenesis in mice

J Biol Chem. 2017 Dec 29;292(52):21631-21642. doi: 10.1074/jbc.RA117.000184. Epub 2017 Nov 9.


Krüppel-like factor 14 (KLF14) is a member of the Cys2/His2 zinc-finger DNA-binding proteins. Despite strong evidence showing that a polymorphism in the Klf14 gene is closely linked to the development of type 2 diabetes, the physiological and metabolic functions of KLF14 still remain unclear. In the present study, we investigated the role of KLF14 in the regulation of hepatic gluconeogenesis. Adenoviruses expressing KLF14 (Ad-Klf14) or KLF14-specific shRNAs (Ad-shKlf14) were injected into normal C57BL/6J, db/db diabetic, or high-fat diet-induced obese (DIO) mice. Gene expression, hepatic glucose production, glucose tolerance, and insulin resistance were tested in C57BL/6J, db/db, and DIO mice and primary hepatocytes. Our results demonstrate that KLF14 expression is induced in the livers of normal C57BL/6J mice upon fasting and significantly up-regulated in the livers of db/db mice, suggesting a physiological link between KLF14 and gluconeogenesis. Adenovirus-mediated overexpression of KLF14 in primary hepatocytes increased both the mRNA and protein levels of peroxisome proliferator-activated receptor-γ coactivator 1α (Pgc-1α, also known as Ppargc1a), thereby stimulating cellular glucose production. Conversely, knockdown of KLF14 expression led to a reduction in PGC-1α, subsequently inhibiting glucose output in primary hepatocytes. Finally, forced expression of KLF14 in the livers of normal mice increased the plasma glucose levels and impaired glucose tolerance; in contrast, KLF14 knockdown in diabetic mouse livers improved glucose tolerance. Taken together, our data strongly indicate that KLF14 modulates hepatic gluconeogenesis.

Keywords: Krüppel-like factor 14 (KLF14); PGC-1α; diabetes; gluconeogenesis; glucose metabolism; hepatocyte; peroxisome proliferator–activated receptor γ coactivator 1α (PPARGC1α); type 2 diabetes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Diabetes Mellitus, Type 2 / metabolism
  • Diet, High-Fat
  • Gluconeogenesis / genetics
  • Gluconeogenesis / physiology*
  • Glucose / metabolism
  • Glucose Intolerance / metabolism
  • Hepatocytes / metabolism
  • Insulin Resistance / physiology
  • Kruppel-Like Transcription Factors / metabolism*
  • Kruppel-Like Transcription Factors / physiology
  • Liver / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / metabolism


  • Klf14 protein, mouse
  • Kruppel-Like Transcription Factors
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Ppargc1a protein, mouse
  • Glucose