College of Fisheries, Huazhong Agricultural University, Wuhan 430070, China.
Zoology Department, Faculty of Science, Zagazig University, Zagazig 44519, Egypt.
Int J Mol Sci. 2020 Feb 24;21(4):1533. doi: 10.3390/ijms21041533.
Hepatic disorders have been increasing in recent years because of high carbohydrate diets. Hepatocytes depend mainly on the basal autophagy to maintain hepatic glucose/lipid homeostasis in mammals. However, the regulatory mechanisms of autophagy in hepatic energy metabolism are still unknown in fish species. Accordingly, mutant zebrafish lines of autophagy-related genes and were generated by CRISPR/Cas9 gene-editing technology. Interestingly, unlike , male zebrafish displayed liver defects in the morphology and histology, including abnormal hepatocyte proliferation, hemorrhagic and inflammatory phenotypes. A significant decrease in hepatocyte glycogen and an increase in hepatocyte lipids were detected in the histological assay that coincidence with the hepatic gene expression. Meanwhile, loss of heterozygosity for creates a suitable microenvironment for hepatic tumorigenesis via phosphorylation of Akt kinase, which in turn affects liver autophagy. The reduction in autophagy activity in male liver leads to a disturbance in the glucose/lipid metabolism and negatively regulates apoptosis accompanied by the induction of cellular proliferation and acute inflammatory response. Our findings highlight an important role of in zebrafish liver development and energy metabolism, suggesting the crucial role of autophagy in maintaining homeostasis of the nutrient metabolism in fish species.
近年来，由于高碳水化合物饮食，肝脏疾病的发病率一直在上升。哺乳动物的肝细胞主要依赖基础自噬来维持肝脏的葡萄糖/脂质稳态。然而，鱼类中自噬在肝脏能量代谢中的调节机制尚不清楚。因此，本研究通过 CRISPR/Cas9 基因编辑技术生成了自噬相关基因 和 的突变斑马鱼品系。有趣的是，与 不同，雄性 斑马鱼的肝脏在形态和组织学上存在缺陷，包括异常的肝细胞增殖、出血和炎症表型。组织学检测显示，肝细胞糖原显著减少，肝细胞脂质增加，与肝脏基因表达一致。同时， 杂合性缺失通过 Akt 激酶的磷酸化为肝肿瘤发生创造了合适的微环境，进而影响肝脏自噬。雄性 肝脏中自噬活性的降低导致葡萄糖/脂质代谢紊乱，并负调控凋亡，同时伴随着细胞增殖和急性炎症反应的诱导。我们的研究结果强调了 在斑马鱼肝脏发育和能量代谢中的重要作用，表明自噬在维持鱼类营养代谢平衡方面起着关键作用。
