Mechanism Of Mitophagy In Chronic Intermittent Hypoxia Induced Hepatic Lipid Metabolism Disorder

Background and objective: Obstructive sleep apnea(OSA)is a condition in which the upper respiratory tract is completely or partially blocked during sleep,causing snoring and daytime sleepiness.Chronic intermittent hypoxia(CIH)has been a significant factor in the development of cardiovascular,nervous and systemic metabolic disorders.Mitochondria play an important role in our lives.Mitochondria have their own unique quality control system in the cell,namely mitochondrial dynamic change and Mitophagy.The normal structure and function of liver mitochondria are the cornerstone of maintaining normal lipid metabolism in liver.At present,the prevalence rate of hepatic steatosis is very high in patients with OSA,while related OSA treatment cannot improve lipid metabolism level in patients with hepatic steatosis.To this end,we further explored the mechanism of CIH-induced hepatic lipid metabolism disorder and sought possible therapeutic targets.Methods: 6-week-old C57BL/6 male mice were randomly divided into control group(NC group)and CIH group.The NC group was fed conventionally,and the CIH group underwent 8 hours of intermittent hypoxia modeling every day.After12 weeks of feeding,mice were weighed,liver weighed and serum samples were collected.Serum levels of ALT,AST,triglyceride(TG)and total cholesterol(TC)were detected.Liver H&E and oil red O were stained to determine the lipid deposition and damage status of liver.The changes of mitochondrial structure were observed by electron microscopy.The β-oxidation of fatty acids,the expression of pro-inflammatory factors in liver,mitochondrial fusion and division,and the expression of genes related to mitochondrial autophagy were detected by Western blot and q PCRResults: We found that after 12 weeks of intermittent hypoxia treatment,the levels of TC,TG,AST and ALT in serum of mice in CIH group increased,and liver lipid droplets deposition was obviously accompanied by inflammatory infiltration.In addition,we found that the fatty acid β-oxidation pathway in mouse liver was impaired(PPARα,cpt-1α,MCAD expression decreased),and further observed the accumulation of broken mitochondria by transmission electron microscopy,the number and size of lipid droplets in liver increased.It also activated liver pro-inflammatory factors(TNFα,IL-6,IL-1β increased)and inflammatory cascade(phosphorylated NFκB and JNK increased).Through transmission electron microscopy(TEM),mitochondrial division increased and autopolysosome decreased in hepatocytes.Abnormal mitochondrial division and fusion,mitochondrial autophagy level decreased.Conclusion: 12-week CIH can inhibit mitochondrial fatty acid-β oxidation,activate inflammatory response,and inhibit mitochondrial autophagy,which ultimately leads to the accumulation of damaged mitochondria in hepatocytes,leading to the disorder of liver lipid metabolism...