Hepatic glucose sensing: does flux matter?

Abstract

In this issue of the JCI, Denechaud et al. report studies investigating the role of the liver X receptors (LXRs) LXRalpha and LXRbeta in carbohydrate sensing by the liver (see the related article beginning on page 956). The results of this study, which utilized LXRalpha/beta double-KO mice, strongly contradict a recent Nature report that proposed that LXRalpha/beta sense glucose independent of metabolic flux. The reported findings further support a key role for the carbohydrate-responsive element-binding protein (ChREBP) in the regulation of lipogenic genes by glucose and dietary carbohydrates.

Figure 1. Transcriptional regulation of hepatic lipogenesis by glucose and insulin.

In this issue, Denechaud et al. (4) describe a series of studies that strongly challenge a recent report by Mitro et al. (3) suggesting that LXRα/β has a direct glucose-sensing function in liver. Denechaud et al. provide strong evidence for ChREBP, not the LXRs, in mediating the effect of glucose on genes in the liver (4). The regulation of hepatic lipogenesis involves several transcriptional regulatory networks. Three transcription factors, ChREBP, LXRα/β, and SREBP-1c, contribute to this regulation, but in an often incestuous manner. For instance, LXRα/β has been found to regulate the transcription of both ChREBP and SREBP-1c. ChREBP, LXRα/β, and SREBP-1c bind to ChOREs, LXR response elements (LXREs), and sterol response elements (SREs), respectively. Moreover, DNA binding by ChREBP and LXRα/β requires heterodimerization with Max-like protein (Mlx) and retinoid X receptor (RXR), respectively. Genes that regulate hepatic lipogenesis have been found to contain 1 or more ChOREs, LXREs, and/or SREs. Some genes, such as for FAS, are regulated by all 3 transcription factors. The authors demonstrate that glucose flux is necessary for regulation of hepatic genes by glucose and that phosphorylation of ChREBP at Ser196 is reciprocally regulated by glucose flux. ChREBP is located in the cytoplasm under low plasma glucose concentration due to the phosphorylation of Ser196. As the plasma glucose level rises, glucose enters hepatocytes and is rapidly equilibrated due to the low-K_m glucose transporter GLUT2. Glucose phosphorylation is then initiated by GK, leading to the formation of xyulose-5-phosphate (X-5-P) by the hexose monophosphate shunt pathway. Increased xyulose-5-phosphate in turn appears to cause dephosphorylation of Ser196 on ChREBP (probably through activation of PP2A), thereby allowing ChREBP to enter the nucleus and affect gene expression. Insulin appears to affect hepatic lipogenesis principally by increasing transcription of both ChREBP and SREBP-1c.