Cross-regulation of hepatic glucose metabolism via ChREBP and nuclear receptors

There is a worldwide epidemic of obesity and type 2 diabetes, two major public health concerns associated with alterations in both insulin and glucose signaling pathways. Glucose is not only an energy source but also controls the expression of key genes involved in energetic metabolism, through the glucose-signaling transcription factor, Carbohydrate Responsive Element Binding Protein (ChREBP). ChREBP has emerged as a central regulator of de novo fatty acid synthesis (lipogenesis) in response to glucose under both physiological and physiopathological conditions. Glucose activates ChREBP by regulating its entry from the cytosol to the nucleus, thereby promoting its binding to carbohydrate responsive element (ChoRE) in the promoter regions of glycolytic (L-PK) and lipogenic genes (ACC and FAS). We have previously reported that the inhibition of ChREBP in liver of obese ob/ob mice improves the metabolic alterations linked to obesity, fatty liver and insulin-resistance. Therefore, regulating ChREBP activity could be an attractive target for lipid-lowering therapies in obesity and diabetes. However, before this is possible, a better understanding of the mechanism(s) regulating its activity is needed. In this review, we summarize recent findings on the role and regulation of ChREBP and particularly emphasize on the cross-regulations that may exist between key nuclear receptors (LXR, TR, HNF4α) and ChREBP for the control of hepatic glucose metabolism. These novel molecular cross-talks may open the way to new pharmacological opportunities. This article is part of a Special Issue entitled: Translating nuclear receptors from health to disease.

Research highlights
► ChREBP is a central transcriptional regulator of hepatic de novo fatty acid synthesis.
► ChREBP inhibition in liver of obese ob/ob mice improves hepatic steatosis and insulin-resistance.
► ChREBP represents an attractive target for lipid-lowering therapies in obesity and diabetes.
► Cross-regulations exist between ChREBP and liver nuclear receptors for the control of hepatic glucose and lipid metabolism.
► Identification of novel molecular cross-talks between ChREBP and nuclear receptors may open the way to new pharmacological opportunities.