Regulation of glucose metabolism from a liver-centric perspective

Abstract

Glucose homeostasis is tightly regulated to meet the energy requirements of the vital organs and maintain an individual's health. The liver has a major role in the control of glucose homeostasis by controlling various pathways of glucose metabolism, including glycogenesis, glycogenolysis, glycolysis and gluconeogenesis. Both the acute and chronic regulation of the enzymes involved in the pathways are required for the proper functioning of these complex interwoven systems. Allosteric control by various metabolic intermediates, as well as post-translational modifications of these metabolic enzymes constitute the acute control of these pathways, and the controlled expression of the genes encoding these enzymes is critical in mediating the longer-term regulation of these metabolic pathways. Notably, several key transcription factors are shown to be involved in the control of glucose metabolism including glycolysis and gluconeogenesis in the liver. In this review, we would like to illustrate the current understanding of glucose metabolism, with an emphasis on the transcription factors and their regulators that are involved in the chronic control of glucose homeostasis.

Figure 1

Regulation of hepatic glycogen metabolism. Under fasting conditions, glucagon and epinephrine induce cAMP-dependent signaling cascades, leading to the activation of glycogen phosphorylase and glycogenolysis while inhibiting glycogenesis. Conversely, feeding enhances insulin-mediated signaling in the liver, leading to the activation of both PP1 and Akt, thus promoting glycogen synthesis in response to increased glucose uptake in the liver. See the main text for more specific regulatory pathways. cAMP, cyclic AMP.

Figure 2

Regulation of hepatic glycolysis. Under feeding conditions, increased glucose uptake in hepatocytes promotes glycolysis and lipogenesis to generate triglycerides as storage forms of fuel. This process is transcriptionally regulated by two major transcription factors in the liver, SREBP-1c and ChREBP-Mlx heterodimer, which mediate the insulin and glucose response, respectively. See the main text for more specific regulatory pathways.

Figure 3

Regulation of hepatic gluconeogenesis. Under fasting conditions, hepatic gluconeogenesis is enhanced via a decreased concentration of insulin and an increased concentration of insulin counterregulatory hormones such as glucagon. CREB/CRTC2, FoxO1, and a family of nuclear receptors are critical in coordinating the fasting-mediated activation of gluconeogenesis in the liver. See the main text for more specific regulatory pathways. FoxO1, forkhead box O 1