MicroRNA-148a Participates In Regulating Lipid Metabolism By Targeting (P) RR In The Liver

BackgroundWith the rapid development of China’s economy,China has the largest number of obese people in the world,surpassing the United States.Obesity can lead to various diseases,such as nonalcoholic fatty liver,atherosclerosis and hyperlipidemia.Hepatic lipid metabolism disorder plays crucial role in the development of obesity,nonalcoholic fatty liver and atherosclerosis.Increased hepatic lipid synthesis results in increasing VLDL secretion,accelerating fat storage and causing weight gain.In addition,an increased secretion of VLDL also increases LDL level and the rate of atherosclerosis.In recent years,we have discovered a new regulator in lipid metabolism,(pro)renin receptor [(P)RR].(P)RR is an important member of the blood pressure regulation system(renin-angiotensin-aldosterone system).We found that inhibition of(P)RR expression can regulate LDLR protein levels post-transcriptionally as well as LDL uptake.Through computational analysis and experimental evidence,we found that(P)RR is a target gene of miR-148 a,and previous studies reported that miR-148 a can regulate LDL metabolism.Based on this,we hypothesized that miR-148 a may regulate hepatic lipid metabolism by targeting on(P)RR.ObjectiveTo investigate how hepatic(P)RR regulates lipid metabolism in vivo,and to determine whether miR-148 a participates in the regulation of lipid metabolism by regulating(P)RR expression and function.Methods and ResultsWe specifically inhibited the expression of hepatic(P)RR using glycosylation-modified antisense oligonucleotides(GalNAc modified antisense oligos,GalNAc-ASO)and investigated its effects on VLDL secretion,LDL clearance and hepatic lipid synthesis.We also investigate the effects of inhibition of hepatic(P)RR on high-fat diet-induced dyslipidemia and nonalcoholic fatty liver.Moreover,we used hepatic cell lines to investigate whether miR-148 a specifically regulates(P)RR expression and its effects on cellular uptake of LDL in vitro using a luciferase reporter system.We found that inhibition of mouse liver(P)RR decreases LDLR protein levels and increases blood cholesterol and LDL levels.However,inhibition of(P)RR also reduced hepatic VLDL secretion rate and blood triglyceride levels.These results suggest that(P)RR can reduce VLDL secretion as well as LDL clearance.Through further research,we found that inhibition of hepatic(P)RR can reduce ACC and PDH protein levels,thereby inhibiting fatty acid synthesis and promoting fatty acid degradation,which helps to block high-fat diet-induced obesity and nonalcoholic fatty liver disease in mice.We clarified miR-148 a can inhibit(P)RR expression by acting on the 3’-UTR region of(P)RR,and reduce LDLR protein levels and LDL uptake by(P)RR through in vitro cell experiments.ConclusionsHepatic(P)RR is an important regulator in lipid metabolism and miR-148 a can regulate(P)RR expression and function.Therefore,miR-148 a may be involved in the regulation of hepatic lipid metabolism through(P)RR.