The Protective Role of the Carbohydrate Response Element Binding Protein in the Liver: The Metabolite Perspective

Abstract

The Carbohydrate response element binding protein, ChREBP encoded by the MLXIPL gene, is a transcription factor that is expressed at high levels in the liver and has a prominent function during consumption of high-carbohydrate diets. ChREBP is activated by raised cellular levels of phosphate ester intermediates of glycolysis, gluconeogenesis and the pentose phosphate pathway. Its target genes include a wide range of enzymes and regulatory proteins, including G6pc , Gckr , Pklr, Prkaa1,2 , and enzymes of lipogenesis. ChREBP activation cumulatively promotes increased disposal of phosphate ester intermediates to glucose, via glucose 6-phosphatase or to pyruvate via glycolysis with further metabolism by lipogenesis. Dietary fructose is metabolized in both the intestine and the liver and is more lipogenic than glucose. It also induces greater elevation in phosphate ester intermediates than glucose, and at high concentrations causes transient depletion of inorganic phosphate, compromised ATP homeostasis and degradation of adenine nucleotides to uric acid. ChREBP deficiency predisposes to fructose intolerance and compromised cellular phosphate ester and ATP homeostasis and thereby markedly aggravates the changes in metabolite levels caused by dietary fructose. The recent evidence that high fructose intake causes more severe hepatocyte damage in ChREBP-deficient models confirms the crucial protective role for ChREBP in maintaining intracellular phosphate homeostasis. The improved ATP homeostasis in hepatocytes isolated from mice after chronic activation of ChREBP with a glucokinase activator supports the role of ChREBP in the control of intracellular homeostasis. It is hypothesized that drugs that activate ChREBP confer a protective role in the liver particularly in compromised metabolic states.

Maladaptive positive feedback production of ChREBPβ underlies glucotoxic β-cell failure

“…While transcriptional regulation and localization of the two splice isoforms, as demonstrated in this study seem to be of high importance for the regulation of ChREBP and activity, there are additional mechanisms that have been previously shown to tightly regulate ChREBP location and activity. ChREBP is regulated by carbohydrate metabolites and other metabolic signals 19 , 38 , including Ca ++ flux, which dissociates its binding to sorcin allowing nuclear translocation in beta cells 18 , and several posttranslational modifications [reviewed in 39 ], which may affect its stability and the binding of co-factors and co-activators 40 , 41 . Additionally, nuclear retention of ChREBP’s mRNA 42 , and sequestration of ChREBP’s heterodimer partner, Mlx, in lipid droplets play important roles in regulating ChREBP activity 43 .…”

Gene Variants of the SLC2A5 Gene Encoding GLUT5, the Major Fructose Transporter, Do Not Contribute to Clinical Presentation of Acquired Fructose Malabsorption.

“…In humans, several studies highlighted the role of the transcription factor ChREBP encoded by the MLXIPL gene for the predisposition concerning fructose intolerance malabsorption (21,43) and diarrheapredominant IBS patients with impaired intestinal fructose transport (44). The association between ChREBP and fructose malabsorption was further supported by animal models (45,46).…”

Gene variants of the SLC2A5 gene encoding GLUT5, the major fructose transporter, do not contribute to clinical presentation of acquired fructose malabsorption

“…In humans, several studies highlighted the role of the transcription factor ChREBP encoded by the MLXIPL gene for the predisposition concerning fructose intolerance malabsorption [ 21 , 42 ] and diarrhea—predominant IBS patients with impaired intestinal fructose transport [ 43 ]. The association between ChREBP and fructose malabsorption was further supported by animal models [ 44 , 45 ].…”