Hepatic glucose sensing and integrative pathways in the liver

Abstract

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.

Liver X receptor regulates hepatic nuclear O-GlcNAc signaling and carbohydrate responsive element-binding protein activity

“…of hepatic DNL, glucose also plays a role in this process ( 2 ). The liver X receptors (LXRs) [LXR ␣ (NR1H3) and LXR ␤ (NR1H2)] are oxysterol-activated nuclear receptors with important roles in cholesterol, glucose, and lipid metabolism ( 3,4 ).…”

Dietary carbohydrate and control of hepatic gene expression: mechanistic links from ATP and phosphate ester homeostasis to the carbohydrate-response element-binding protein

“…Two transcription factors involved are sterol regulatory element binding protein 1c that is induced by insulin and targets predominantly enzymes of DNL and ChREBP that is induced by high glucose and targets enzymes of DNL but also several additional genes, including pyruvate kinase (7)(8)(9) . Because ChREBP is induced by dietary carbohydrate, the generally held explanation for ChREBP function is that it represents a mechanism for efficient conversion of dietary carbohydrate to fat as a 'thrifty gene' (8)(9)(10)(11) . The decrease in DNL (37)(38)(39) and in steatosis (38,39) in ChREBP knock-down models (37) is consistent with such a hypothesis but it does not exclude the alternative explanation (25) that the role of DNL is regulatory for fuel selection because it is not a quantitative route of carbohydrate disposal (25,28) .…”

“…High-carbohydrate diets and particularly dietary sugars are a risk factor for both T2D and NAFLD (4)(5)(6) . The transcription factor carbohydrate-response elementbinding protein (ChREBP, encoded by MLXIPL), is a major mediator of the hepatic changes induced by highcarbohydrate diets and is conventionally regarded as a key mechanism for promoting conversion of dietary carbohydrate to fat for energy storage (7)(8)(9)(10)(11) . This review…”

The Hypolipidemic and Hypoglycemic Activities of Fermented Brown Rice Fibers by Regulating PPARα and ChREBP in the Livers of C57BL/6J Mice

“…The plasma concentrations of adipokine represent the status of metabolic syndrome. Especially, the plasma leptin and adiponectin concentrations are correlated with insulin resistance [28,29]. The plasma leptin levels of the FBRF, FBRP, and FBR groups were significantly reduced compared to the control group by 91.3%, 65.0%, and 71.7%, respectively ( Figure 4C), and the plasma adiponectin concentrations of the FBRF group were significantly increased compared to the control by 70.1%.…”