Dietary carbohydrate and control of hepatic gene expression: mechanistic links from ATP and phosphate ester homeostasis to the carbohydrate-response element-binding protein.
Type 2 diabetes and non-alcoholic fatty liver disease (NAFLD) are associated with elevated hepatic glucose production and fatty acid synthesis (de novo lipogenesis (DNL)). High carbohydrate diets also increase hepatic glucose production and lipogenesis. The carbohydrate-response element-binding protein (ChREBP, encoded by MLXIPL) 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 in G6PC and SLC37A4 and common variants of MLXIPL, GCKR and PKLR in 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.
Institutes of Cellular Medicine and Ageing and Health,Medical School,Newcastle University,Newcastle upon Tyne NE2 4HH,UK.
Loranne
L
Agius
 ChREBP carbohydrate-response element-binding protein;  DNL 
                  de novo lipogenesis;  F1P fructose 1-phosphate;  F2;  F6P fructose 6-phosphate;  G6P glucose 6-phosphate;  G6pc glucose 6-phosphatase;  Gckr glucokinase inhibitor protein;  KHK ketohexokinase;  NAFLD non-alcoholic fatty liver disease;  PE phosphate esters;  PKLR pyruvate kinase;  Pi inorganic phosphate;  T2D type 2 diabetes; 6-bisphosphate; 6P2
                fructose 2; ATP; Carbohydrate-response element-binding protein; Glucokinase: GCKR
            ; Glucose 6-phosphatase; Non-alcoholic fatty liver disease; Type 2 diabetes; Uric acid