| Summary: | Lipophagy is a selective autophagy that regulates lipid metabolism and reduces hepatic lipid deposition. However, the underlying mechanism has not been understood in fish. In this study, we used micronutrient zinc (Zn) as a regulator of autophagy and lipid metabolism and found that Ras-related protein 7 (<i>rab7</i>) was involved in Zn-induced lipophagy in hepatocytes of yellow catfish <i>Pelteobagrus pelteobagrus</i>. We then characterized the <i>rab7</i> promoter and identified binding sites for a series of transcription factors, including Forkhead box O3 (FOXO3). Site mutation experiments showed that the −1358/−1369 bp FOXO3 binding site was responsible for Zn-induced transcriptional activation of <i>rab7</i>. Further studies showed that inhibition of <i>rab7</i> significantly inhibited Zn-induced lipid degradation by lipophagy. Moreover, <i>rab7</i> inhibitor also mitigated the Zn-induced increase of <i>cpt1α</i> and <i>acadm</i> expression. Our results suggested that Zn exerts its lipid-lowering effect partly through <i>rab7</i>-mediated lipophagy and FA β-oxidation in hepatocytes. Overall, our findings provide novel insights into the FOXO3/<i>rab7</i> axis in lipophagy regulation and enhance the understanding of lipid metabolism by micronutrient Zn, which may help to reduce excessive lipid accumulation in fish.
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