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

Lookup NU author(s): Professor Loranne Agius, Dr Shruti Chachra, Dr Brian FordORCiD



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


The Carbohydrate response element binding protein, ChREBP encoded by the MLXIPLgene, is a transcription factor that is expressed at high levels in the liver and has aprominent function during consumption of high-carbohydrate diets. ChREBP is activatedby raised cellular levels of phosphate ester intermediates of glycolysis, gluconeogenesisand the pentose phosphate pathway. Its target genes include a wide range of enzymesand regulatory proteins, including G6pc, Gckr, Pklr, Prkaa1,2, and enzymes oflipogenesis. ChREBP activation cumulatively promotes increased disposal of phosphateester intermediates to glucose, via glucose 6-phosphatase or to pyruvate via glycolysiswith further metabolism by lipogenesis. Dietary fructose is metabolized in both theintestine and the liver and is more lipogenic than glucose. It also induces greaterelevation in phosphate ester intermediates than glucose, and at high concentrationscauses transient depletion of inorganic phosphate, compromised ATP homeostasis anddegradation of adenine nucleotides to uric acid. ChREBP deficiency predisposes tofructose intolerance and compromised cellular phosphate ester and ATP homeostasisand thereby markedly aggravates the changes in metabolite levels caused by dietaryfructose. The recent evidence that high fructose intake causes more severe hepatocytedamage in ChREBP-deficient models confirms the crucial protective role for ChREBP inmaintaining intracellular phosphate homeostasis. The improved ATP homeostasis inhepatocytes isolated from mice after chronic activation of ChREBP with a glucokinaseactivator supports the role of ChREBP in the control of intracellular homeostasis. It ishypothesized that drugs that activate ChREBP confer a protective role in the liverparticularly in compromised metabolic states.

Publication metadata

Author(s): Agius L, Chachra SS, Ford BE

Publication type: Review

Publication status: Published

Journal: Frontiers in Endocrinology

Year: 2020

Volume: 11

Online publication date: 17/11/2020

Acceptance date: 16/10/2020

ISSN (electronic): 1664-2392


DOI: 10.3389/fendo.2020.594041