Zinc reduces hepatic lipid deposition and activates lipophagy via Zn 2+ /MTF‐1/PPARα and Ca 2+ /CaMKKβ/AMPK pathways

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 in lipolysis. Given the potential role of lipophagy in lipid metabolism, the purpose of this study was to test the hypothesis that Zn attenuates hepatic lipid accumulation by modulating lipophagy. The present study indicated that Zn is 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 autophagy‐mediated lipophagy. Zn‐induced up‐regulation of autophagy and lipid depletion is free Zn 2+ ‐dependent in the cytosols. Zn‐induced autophagy and lipid turnover involved up‐regulation of the calcium/calmodulin‐dependent protein kinase kinase‐β (Ca 2+ /CaMKKβ)/AMPK pathway. Meanwhile, Zn 2+ ‐activated autophagy and lipid depletion were via enhancing metal response element‐binding transcription factor (MTF)‐1 DNA binding at PPARα promoter region, which in turn induced transcriptional activation of the key genes related to autophagy and lipolysis. Zn activated the pathways of Zn 2+ /MTF‐1/ Peroxisome proliferator‐activated receptor (PPAR)α and Ca 2+ /CaMKKβ/AMPK, resulting in the up‐regulation of lipophagy and accordingly reduced hepatic lipid accumulation. Our study, for the first time, provided innovative evidence of 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 Zn 2+ /MTF‐1/PPARα and Ca 2 +/CaMKKβ/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.—Wei, C.‐C., Luo, Z., Hogstrand, C., Xu, Y.‐H., Wu, L.‐X., Chen, G.‐H., Pan, Y.‐X., Song, Y.‐F. Zinc reduces hepatic lipid deposition and activates lipophagy via Zn 2+ /MTF‐1/PPARα and Ca 2+ /CaMKKβ/AMPK pathways. FASEB J. 32, 6666–6680 (2018). www.fasebj.org