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Zinc reduces hepatic lipid deposition and activates lipophagy via Zn2+/MTF-1/PPARalpha and Ca2+ /CaMKKbeta/AMPK pathways

Research output: Contribution to journalArticle

Chuan-Chuan Wei, Zhi Luo, Jan Lennart Christer Hogstrand, Yi-Huan Xu, Li-Xiang Wu, Guang-Hui Chen, Ya-Xiong Pan, Yu–Feng Song

Original languageEnglish
JournalTHE FASEB JOURNAL : OFFICIAL PUBLICATION OF THE FEDERATION OF AMERICAN SOCIETIES FOR EXPERIMENTAL BIOLOGY
Publication statusAccepted/In press - May 2018

King's Authors

Abstract

Zinc (Zn) deficiency is the most consistently discovered nutritional manifestations of fatty liver disease. Although Zn is known to stimulate hepatic lipid oxidation, little is known about its underlying mechanism of action on lipolysis. Given the lipophagy's potential role in lipid metabolism, the purpose of this study is to test the hypothesis that Zn attenuates hepatic lipid accumulation by modulating lipophagy. The present study indicated that Zn was a potent promoter of lipophagy. Zn administration significantly alleviated hepatocellular lipid accumulation, and increased the release of free fatty acids in association with enhanced fatty acid oxidation and inhibited lipogenesis, which was accompanied by activation of autophagy. Moreover, Zn reduced lipid accumulation and stimulated lipolysis by the autophagy-mediated lipophagy; Zn-induced up-regulation of autophagy and lipid depletion is free
Zn2+ -dependent in the cytosols. Zn-induced autophagy and lipid turnover involved up-regulation of Ca2+/CaMKKbeta/AMPK pathway. Meanwhile, Zn2+ -activated autophagy and lipid depletion were via enhancing MTF-1 DNA binding at PPARalpha promoter region, which in turn induced transcriptional activation of the key genes related to autophagy and lipolysis.

Conclusion: Zn activated the pathways of Zn2+/MTF-1/PPARapha and
Ca2+ /CaMKKbeta/AMPK, resulted in the up-regulation of lipophagy, and accordingly reduced hepatic lipid accumulation. Our study, for the first time, provided the innovative evidence for the direct relationship between metal elements (Zn) and lipid metabolism. The present study also indicated the novel mechanism for Zn-induced lipolysis by the activation of Zn2+/MTF-1/PPARalpha and Ca2+/CaMKKbeta/AMPK pathways, which induced the occurrence of lipophagy. These results provide new insight into Zn nutrition and its potential beneficial effects on the prevention of fatty liver disease in vertebrates.

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