Abstract
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 beclin1 and atg7 were generated by CRISPR/Cas9 gene-editing technology. Interestingly, unlike atg7+/−, male beclin1+/− 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 beclin1 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 beclin1+/− 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 beclin1 in zebrafish liver development and energy metabolism, suggesting the crucial role of autophagy in maintaining homeostasis of the nutrient metabolism in fish species.
Highlights
The liver plays a crucial role in governing body energy, especially in glucose and fatty acid metabolism
The phosphoinositide 3-kinase (PI3K)/AKT/mTOR pathway is an intracellular signaling pathway mediating cell growth, proliferation, quiescence metabolism, survival, autophagy, and angiogenesis, and it has been reported to be involved in human cancer initiation [20,49,50]
The constitutive deletion of atg7 is lethal at birth and conditional deletion of atg7 in hepatocytes leads to benign liver tumors [51,52], these did not appear in our autophagy-defect model atg7+/− mutant zebrafish
Summary
The liver plays a crucial role in governing body energy, especially in glucose and fatty acid metabolism. Glucose is synthesized into glycogen or converted into fatty acids or amino acids in the liver. Fatty acids generate triacylglycerol (TAG) that can be stored in the hepatocytes. TAG is released from the liver into the circulation, and it is metabolized into non-esterified fatty acids (NEFAs) and glycerol via lipolysis. Both gluconeogenesis and fatty acid β-oxidation processes take place in the liver to release energy [1]. Liver dysfunction usually leads to the disturbance of glucose and lipid metabolism, which affects the whole body’s energy and causes abnormal development
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