The Role And Mechansim Study Of KLF14 In The Regulation Of Hepatic Gluconeogenesis In Mice

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 sh RNAs(Ad-sh KLF14)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 m RNA and protein levels of peroxisome proliferator-activated receptor-coactivator 1(PGC-1?,also known as Ppargc1a),thereby stimulating cellular glucose production.Conversely,knockdown of KLF14 expression led to a reduction in PGC-1?,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.