Liver ChREBP Protects Against Fructose-Induced Glycogenic Hepatotoxicity by Regulating L-Type Pyruvate Kinase
| Autor: | Jian-Hui Shi, Hai Zhang, Chun-Chun Wei, Dongmei Cao, Yu-Xia Chen, Fang-Zhen Xia, Yingli Lu, Ya-Nan Shi, Guanghou Shui, Sin Man Lam, Xia Yang, Xiongfei Xu, Heng-Yu Chen, Weiping J. Zhang, Jun-Yu Lu, Qiufang Bai, Hao Li, Liming Chen |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Male medicine.medical_specialty Endocrinology Diabetes and Metabolism Pyruvate Kinase 030209 endocrinology & metabolism Fructose Carbohydrate metabolism 03 medical and health sciences chemistry.chemical_compound Mice 0302 clinical medicine Adenosine Triphosphate Internal medicine Internal Medicine medicine Animals Glycolysis Carbohydrate-responsive element-binding protein Glycogen synthase Mice Knockout biology Glycogen Basic Helix-Loop-Helix Leucine Zipper Transcription Factors 030104 developmental biology Endocrinology Glucose chemistry Liver biology.protein Homeostasis Pyruvate kinase |
| Zdroj: | Diabetes. 69(4) |
| ISSN: | 1939-327X |
| Popis: | Excessive fructose consumption is closely linked to the pathogenesis of metabolic disease. Carbohydrate response element-binding protein (ChREBP) is a transcription factor essential for fructose tolerance in mice. However, the functional significance of liver ChREBP in fructose metabolism remains unclear. Here, we show that liver ChREBP protects mice against fructose-induced hepatotoxicity by regulating liver glycogen metabolism and ATP homeostasis. Liver-specific ablation of ChREBP did not compromise fructose tolerance, but rather caused severe transaminitis and hepatomegaly with massive glycogen overload in mice fed a high-fructose diet, while no obvious inflammation, cell death, or fibrosis was detected in the liver. In addition, liver ATP contents were significantly decreased by ChREBP deficiency in the fed state, which was rendered more pronounced by fructose feeding. Mechanistically, liver contents of glucose-6-phosphate (G6P), an allosteric activator of glycogen synthase, were markedly increased in the absence of liver ChREBP, while fasting-induced glycogen breakdown was not compromised. Furthermore, hepatic overexpression of LPK, a ChREBP target gene in glycolysis, could effectively rescue glycogen overload and ATP reduction, as well as mitigate fructose-induced hepatotoxicity in ChREBP-deficient mice. Taken together, our findings establish a critical role of liver ChREBP in coping with hepatic fructose stress and protecting from hepatotoxicity by regulating LPK. |
| Databáze: | OpenAIRE |
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