CREB and FoxO1: two transcription factors for the regulation of hepatic gluconeogenesis

Abstract

Liver plays a major role in maintaining glucose homeostasis in mammals. Under fasting conditions, hepatic glucose production is critical as a source of fuel to maintain the basic functions in other tissues, including skeletal muscle, red blood cells, and the brain. Fasting hormones glucagon and cortisol play major roles during the process, in part by activating the transcription of key enzyme genes in the gluconeogenesis such as phosphoenol pyruvate carboxykinase (PEPCK) and glucose 6 phosphatase catalytic subunit (G6Pase). Conversely, gluconeogenic transcription is repressed by pancreatic insulin under feeding conditions, which effectively inhibits transcriptional activator complexes by either promoting post-translational modifications or activating transcriptional inhibitors in the liver, resulting in the reduction of hepatic glucose output. The transcriptional regulatory machineries have been highlighted as targets for type 2 diabetes drugs to control glycemia, so understanding of the complex regulatory mechanisms for transcription circuits for hepatic gluconeogenesis is critical in the potential development of therapeutic tools for the treatment of this disease. In this review, the current understanding regarding the roles of two key transcriptional activators, CREB and FoxO1, in the regulation of hepatic gluconeogenic program is discussed. [BMB Reports 2013; 46(12): 567-574]

Hyperglycemia-induced changes in miRNA expression patterns in epicardial adipose tissue of piglets

“…Gluconeogenesis is controlled through the transcriptional modulation of PCK and glucose-6-phosphatase (G6P), the rate-limiting enzymes in the process, which have been shown to be regulated by glucagon and insulin (Ramnanan et al 2011, Oh et al 2013. In our study, miR-675-5p was significantly upregulated in EAT during hyperglycemia.…”

MicroRNA-214 Suppresses Gluconeogenesis by Targeting Activating Transcriptional Factor 4

“…Phosphatase and tensin homolog-mediated Akt/␤-catenin-Foxo1 axis is a key regulator of innate inflammatory response in the mouse liver (24). Furthermore, FOXO1 is a key regulator of hepatic gluconeogenesis (25). FGFR1 is involved in the effect of fibroblast growth factor-21 (FGF21) on gluconeogenesis (26).…”

A decrease in hepatic microRNA-9 expression impairs gluconeogenesis by targeting FOXO1 in obese mice

“…We found that a miR-9 mimic significantly inhibited the activity of the 3′-untranslated region of Foxo1 mRNA and FOXO1 expression in mouse liver cells (data not shown). Given that FOXO1 is an important regulator of hepatic gluconeogenesis [6,7], we further speculated that FOXO1 mediates miR-9 function in the regulation of gluconeogenesis and HGP in hepatocytes. This speculation was supported by the observation that silencing of FOXO1 expression could almost completely reverse the increase in gluconeogenic enzyme expression and the glucose output in hepatocytes induced by miR-9 deletion.…”

“…The transcription factor forkhead box O1 (FOXO1) is implicated in multiple metabolic pathways [5]. In the liver, FOXO1 promotes HGP and activates the transcription of gluconeogenic enzymes, such as glucose-6-phosphatase (G6Pase) and PEPCK [6,7]. Increased FOXO1 expression was observed in patients with hepatic IR and nuclear FOXO1 was significantly accumulated in the livers of highfat diet (HFD) mice and db/db mice [8,9].…”