Hepatic glucose sensing and integrative pathways in the liver

The hepatic glucose-sensing system is a functional network of enzymes and transcription factors that is critical for the maintenance of energy homeostasis and systemic glycemia. Here we review the recent literature on its components and metabolic actions. Glucokinase (GCK) is generally considered as the initial postprandial glucose-sensing component, which acts as the gatekeeper for hepatic glucose metabolism and provides metabolites that activate the transcription factor carbohydrate response element binding protein (ChREBP). Recently, liver receptor homolog 1 (LRH-1) has emerged as an upstream regulator of the central GCK–ChREBP axis, with a critical role in the integration of hepatic intermediary metabolism in response to glucose. Evidence is also accumulating that O-linked β-N-acetylglucosaminylation (O-GlcNAcylation) and acetylation can act as glucose-sensitive modifications that may contribute to hepatic glucose sensing by targeting regulatory proteins and the epigenome. Further elucidation of the components and functional roles of the hepatic glucose-sensing system may contribute to the future treatment of liver diseases associated with deregulated glucose sensors.