Shi 2020 Diabetes
|Shi JH, Lu JY, Chen HY, Wei CC, Xu X, Li H, Bai Q, Xia FZ, Lam SM, Zhang H, Shi YN, Cao D, Chen L, Shui G, Yang X, Lu Y, Chen YX, Zhang WJ (2020) Liver ChREBP protects against fructose-induced glycogenic hepatotoxicity by regulating L-type pyruvate kinase. Diabetes 120:29.|
Shi Jian-Hui, Lu Jun-Yu, Chen Heng-Yu, Wei Chun-Chun, Xu Xiongfei, Li Hao, Bai Qiufang, Xia Fang-Zhen, Lam Sin M, Zhang Hai, Shi Ya-Nan, Cao Dongmei, Chen Liming, Shui Guanghou, Yang Xia, Lu Yingli, Chen Yu-Xia, Zhang Weiping J (2020) Diabetes
Abstract: 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 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, and this was rendered more pronounced by fructose feeding. Mechanistically, liver contents of glucose-6-phosphate (G-6-P), 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.
© 2020 by the American Diabetes Association.
• Keywords: Fructose metabolism, ChREBP, Glycogen storage disease, Liver injury, Transcriptional regulation, Transcription factor • Bioblast editor: Plangger M
Labels: MiParea: Respiration, Genetic knockout;overexpression, Exercise physiology;nutrition;life style, Pharmacology;toxicology
Organism: Mouse Tissue;cell: Liver Preparation: Intact cells
Regulation: Substrate Coupling state: LEAK, ROUTINE, ET
Labels, 2020, CN