PDF(Pubmed)
Abstract：
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 (rab7) was involved in Zn-induced lipophagy in hepatocytes of yellow catfish Pelteobagrus pelteobagrus. We then characterized the rab7 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 rab7. Further studies showed that inhibition of rab7 significantly inhibited Zn-induced lipid degradation by lipophagy. Moreover, rab7 inhibitor also mitigated the Zn-induced increase of cpt1α and acadm expression. Our results suggested that Zn exerts its lipid-lowering effect partly through rab7-mediated lipophagy and FA β-oxidation in hepatocytes. Overall, our findings provide novel insights into the FOXO3/rab7 axis in lipophagy regulation and enhance the understanding of lipid metabolism by micronutrient Zn, which may help to reduce excessive lipid accumulation in fish.
摘要：
脂质吞噬是一种选择性自噬，可调节脂质代谢并减少肝脏脂质沉积。然而,潜在的机制在鱼类中尚未被理解。在这项研究中,我们使用微量营养素锌（Zn）作为自噬和脂质代谢的调节剂，发现Ras相关蛋白7（rab7）参与Zn诱导的黄of鱼Pelteobagruspelteobagruspatters肝细胞的吞噬。然后我们对rab7启动子进行了表征，并确定了一系列转录因子的结合位点，包括叉头盒O3（FOXO3）。位点突变实验表明，-1358/-1369bpFOXO3结合位点负责Zn诱导的rab7转录激活。进一步的研究表明，抑制rab7可显着抑制Zn诱导的脂质降解。此外，rab7抑制剂还减轻了Zn诱导的cpt1α和acadm表达的增加。我们的结果表明，Zn部分通过rab7介导的肝细胞脂质吞噬和FAβ氧化发挥其降脂作用。总的来说,我们的研究结果提供了新的见解FOXO3/rab7轴在脂质吞噬调节和加强了解通过微量营养素锌脂质代谢，这可能有助于减少鱼中过度的脂质积累。
