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

Abstract

Type 2 diabetes and non-alcoholic fatty liver disease (NAFLD) are associated with elevated hepatic glucose production and fatty acid synthesis (de novolipogenesis (DNL)). High carbohydrate diets also increase hepatic glucose production and lipogenesis. The carbohydrate-response element-binding protein (ChREBP, encoded byMLXIPL) is a transcription factor with a major role in the hepatic response to excess dietary carbohydrate. Because its target genes include pyruvate kinase (PKLR) and enzymes of lipogenesis, it is regarded as a key regulator for conversion of dietary carbohydrate to lipid for energy storage. An alternative hypothesis for ChREBP function is to maintain hepatic ATP homeostasis by restraining the elevation of phosphate ester intermediates in response to elevated glucose. This is supported by the following evidence: (i) A key stimulus for ChREBP activation and induction of its target genes is elevation of phosphate esters; (ii) target genes of ChREBP include key negative regulators of the hexose phosphate ester pool (GCKR,G6PC,SLC37A4) and triose phosphate pool (PKLR); (iii) ChREBP knock-down models have elevated hepatic hexose phosphates and triose phosphates and compromised ATP phosphorylation potential; (iv) gene defects inG6PCandSLC37A4and common variants ofMLXIPL,GCKRandPKLRin man are associated with elevated hepatic uric acid production (a marker of ATP depletion) or raised plasma uric acid levels. It is proposed that compromised hepatic phosphate homeostasis is a contributing factor to the elevated hepatic glucose production and lipogenesis that associate with type 2 diabetes, NAFLD and excess carbohydrate in the diet.

Hepatocytes contribute to residual glucose production in a mouse model for glycogen storage disease type Ia

“…In the current study, almost no labeling of UDP‐glucose from 13 C‐glucose could be observed in L‐ G6pc −/− mice, reflected in a 95% decrease of the GCK flux, which may represent a response to maintain phosphate homeostasis in the liver . Thus, the hepatic phosphorylation of infused 13 C‐glucose and its subsequent intrahepatic metabolism are strongly reduced in L‐ G6pc −/− mice.…”

“…(38) In the current study, almost no labeling of UDPglucose from 13 C-glucose could be observed in L-G6pc 2/2 mice, reflected in a 95% decrease of the GCK flux, which may represent a response to maintain phosphate homeostasis in the liver. (41) Thus, the hepatic phosphorylation of infused 13 C-glucose and its subsequent intrahepatic metabolism are strongly reduced in L-G6pc 2/2 mice. Intrahepatic 13 C-glucose metabolism leads to "scrambling" of the label after the reentering of 13 C-labeled glycolytic intermediates into gluconeogenesis, a phenomenon referred to as "glucose carbon recycling."…”

Metformin lowers glucose 6-phosphate in hepatocytes by activation of glycolysis downstream of glucose phosphorylation

“…1E). The elevation in G6P by S4048 in hepatocytes and in vivo (24 -26) supports the role of glucose 6-phosphatase in maintaining G6P homeostasis (16,17). Metformin did not lower G6P in hepatocytes incubated with 5 mM glucose (Fig.…”

Opposite effects of a glucokinase activator and metformin on glucose‐regulated gene expression in hepatocytes

“…This effect of glucose is often described as glucotoxicity because induction in G6pc and, thereby, hepatic glucose production by hyperglycaemia is counter‐intuitive. However, repression of Gck and induction of G6pc by high glucose can be rationalized as a mechanism for preserving intracellular metabolite homeostasis at the expense of worsening hyperglycaemia . In this study we tested the hypothesis that treatment of hepatocytes with a GKA represses the Gck gene by a mechanism linked to raised cell metabolites.…”

“…However, repression of Gck and induction of G6pc by high glucose can be rationalized as a mechanism for preserving intracellular metabolite homeostasis at the expense of worsening hyperglycaemia. 16 In this study we tested the hypothesis that treatment of hepatocytes with a GKA represses the Gck gene by a mechanism linked to raised cell metabolites. We also tested whether metformin, which has effects on glucokinase translocation opposite to those of GKAs, [17][18][19] also has effects on cell metabolites and gene regulation at high glucose that are converse to those of the GKA.…”