The KLF14 transcription factor regulates hepatic gluconeogenesis in mice

Abstract

Krüppel-like factor 14 (KLF14) is a member of the Cys/His zinc-finger DNA-binding proteins. Despite strong evidence showing that a polymorphism in the 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-) or KLF14-specific shRNAs (Ad-sh) were injected into normal C57BL/6J, diabetic, or high-fat diet-induced obese (DIO) mice. Gene expression, hepatic glucose production, glucose tolerance, and insulin resistance were tested in C57BL/6J,, 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 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 (α, 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.

Longitudinal Effects of Developmental Bisphenol A Exposure on Epigenome-Wide DNA Hydroxymethylation at Imprinted Loci in Mouse Blood

“…The first of these genes, Klf14 , encodes the maternally expressed Krüppel-like factor 14 (Klf14), a member of the Cys2/His2 zinc finger transcription factors ( Small et al. 2011 ; Wang et al. 2017 ).…”

“…2011 ), and may be involved in metabolic disease risk. In addition, recent results in mice suggest that Klf14 may interact with peroxisome proliferator-activated coactivator ( ), a transcription coactivator that regulates a number of metabolic pathways, including hepatic gluconeogenesis ( Wang et al. 2017 ).…”

Transcription Factor KLF14 and Metabolic Syndrome

“…However, Argmann et al showed that mice harboring whole-body germ-line deletion of Klf14 were resilient to HFD-induced insulin resistance (91). Their results were inconsistent with the previously reported role of KLF14 in regulating HDL-C levels in the liver (92,93). This is possibly due to the utilization of different mouse lines ( Table 2).…”

“…It has been shown that hepatic KLF14 regulates glucose production in fasted and re-fed mice as well as diet-induced and genetically obese mice (93). Several lines of evidence suggest that increased KLF14 expression facilitates gluconeogenesis (93).…”

Taking KLF9 to “Cort” for crimes against metabolism

“…promote gluconeogenesis through increasing the transcription of the rate-limiting enzyme for gluconeogenesis, PEPCK (10). Additionally, each of these factors does so via regulation of PGC1α transcription or activity ( Figure 1B): KLF9, KLF10, and KLF14 increase Pgc1a transcription, and KLF15 binds to and cooperates with PGC1α on the Pepck promoter (18)(19)(20).…”