Fructose overconsumption impairs hepatic manganese homeostasis and ammonia disposal

Jian-Hui Shi, Yu-Xia Chen, Yingying Feng, Xiaohang Yang, Jie Lin, Ting Wang, Chun-Chun Wei, Xian-Hua Ma, Rui Yang, Dongmei Cao, Hai Zhang, Xiangyang Xie, Zhifang Xie and Weiping J. Zhang ()
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Jian-Hui Shi: Naval Medical University
Yu-Xia Chen: Naval Medical University
Yingying Feng: Naval Medical University
Xiaohang Yang: Tianjin Medical University
Jie Lin: Naval Medical University
Ting Wang: Tianjin Medical University
Chun-Chun Wei: Naval Medical University
Xian-Hua Ma: Naval Medical University
Rui Yang: Naval Medical University
Dongmei Cao: Naval Medical University
Hai Zhang: Naval Medical University
Xiangyang Xie: Tianjin Medical University
Zhifang Xie: Naval Medical University
Weiping J. Zhang: Naval Medical University

Nature Communications, 2023, vol. 14, issue 1, 1-12

Abstract: Abstract Arginase, a manganese (Mn)-dependent enzyme, is indispensable for urea generation and ammonia disposal in the liver. The potential role of fructose in Mn and ammonia metabolism is undefined. Here we demonstrate that fructose overconsumption impairs hepatic Mn homeostasis and ammonia disposal in male mice. Fructose overexposure reduces liver Mn content as well as its activity of arginase and Mn-SOD, and impairs the clearance of blood ammonia under liver dysfunction. Mechanistically, fructose activates the Mn exporter Slc30a10 gene transcription in the liver in a ChREBP-dependent manner. Hepatic overexpression of Slc30a10 can mimic the effect of fructose on liver Mn content and ammonia disposal. Hepatocyte-specific deletion of Slc30a10 or ChREBP increases liver Mn contents and arginase activity, and abolishes their responsiveness to fructose. Collectively, our data establish a role of fructose in hepatic Mn and ammonia metabolism through ChREBP/Slc30a10 pathway, and postulate fructose dietary restriction for the prevention and treatment of hyperammonemia.

Date: 2023
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DOI: 10.1038/s41467-023-43609-0

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