The Protective Role of the Carbohydrate Response Element Binding Protein in the Liver: The Metabolite Perspective
Autor: | Shruti S. Chachra, Brian E. Ford, Loranne Agius |
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Jazyk: | angličtina |
Rok vydání: | 2020 |
Předmět: |
0301 basic medicine
AMPK ChREBP Endocrinology Diabetes and Metabolism 030209 endocrinology & metabolism Review Pentose phosphate pathway Protective Agents Response Elements lcsh:Diseases of the endocrine glands. Clinical endocrinology fructose 03 medical and health sciences chemistry.chemical_compound Endocrinology 0302 clinical medicine Metabolic Diseases Animals Humans Glycolysis Carbohydrate-responsive element-binding protein Pklr Gckr lcsh:RC648-665 Basic Helix-Loop-Helix Leucine Zipper Transcription Factors Lipogenesis Gluconeogenesis Fructose Intolerance Fructose Metabolism ATP 030104 developmental biology Gene Expression Regulation Liver Biochemistry chemistry G6pc glucokinase activator |
Zdroj: | Frontiers in Endocrinology, Vol 11 (2020) Frontiers in Endocrinology |
ISSN: | 1664-2392 |
Popis: | 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. |
Databáze: | OpenAIRE |
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