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

作者：Chuan‐Chuan Wei, Zhi Luo, Christer Högstrand, Yi‐Huan Xu, Li‐Xiang Wu, Guang‐Hui Chen, Ya‐Xiong Pan, Yu–Feng Song · 发表于：The FASEB Journal · 年份：2018 · DOI：10.1096/fj.201800463 · 被引用次数：180 · 研究领域：Trace Elements in Health、Autophagy in Disease and Therapy、Drug Transport and Resistance Mechanisms

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, res...