Liver ChREBP Protects Against Fructose-Induced Glycogenic Hepatotoxicity by Regulating L-Type Pyruvate Kinase

被引:37
作者
Shi, Jian-Hui [1 ]
Lu, Jun-Yu [1 ]
Chen, Heng-Yu [2 ,3 ]
Wei, Chun-Chun [1 ]
Xu, Xiongfei [1 ]
Li, Hao [1 ]
Bai, Qiufang [1 ,2 ,3 ]
Xia, Fang-Zhen [4 ]
Lam, Sin Man [5 ]
Zhang, Hai [1 ]
Shi, Ya-Nan [2 ,3 ]
Cao, Dongmei [1 ]
Chen, Liming [2 ,3 ]
Shui, Guanghou [5 ]
Yang, Xia [6 ]
Lu, Yingli [4 ]
Chen, Yu-Xia [1 ]
Zhang, Weiping J. [1 ,2 ,3 ]
机构
[1] Navy Med Univ, Dept Pathophysiol, Obes & Diabet Res Ctr, Shanghai, Peoples R China
[2] Tianjin Med Univ, NHC Key Lab Hormones & Dev, Tianjin Key Lab Metab Dis, Chu Hsien I Mem Hosp, Tianjin, Peoples R China
[3] Tianjin Inst Endocrinol, Tianjin, Peoples R China
[4] Shanghai Jiao Tong Univ, Inst & Dept Endocrinol & Metab, Shanghai Ninth Peoples Hosp, Sch Med, Shanghai, Peoples R China
[5] Chinese Acad Sci, Inst Genet & Dev Biol, State Key Lab Mol Dev Biol, Beijing, Peoples R China
[6] Univ Calif Los Angeles, Dept Integrat Biol & Physiol, Los Angeles, CA USA
基金
上海市自然科学基金; 中国国家自然科学基金;
关键词
TRANSCRIPTION FACTOR; CELL-DEATH; GLUCOSE; LIPOGENESIS; METABOLISM; ZBTB20; GENE; DYSFUNCTION; SREBP-1C; DELETION;
D O I
10.2337/db19-0388
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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.
引用
收藏
页码:591 / 602
页数:12
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