5 years ago

The KLF14 transcription factor regulates hepatic gluconeogenesis in mice.

Huabing Zhang, Xin Tong, Fang Gu, Xiaowen Cheng, Liwei Xie, Lu Wang, Lei Zhang, Yongsheng Chang, Wei Chen
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 (T2D), 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 upregulated 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.

Publisher URL: http://doi.org/10.1074/jbc.RA117.000184

DOI: 10.1074/jbc.RA117.000184

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