Angiotensinogen In Hepatocytes Contributes To Western Diet-induced Liver Steatosis

Background:Non-alcoholic fatty liver disease(NAFLD)is considered as the liver manifestation of metabolic disorders.Previous studies hinted that renin-angiotensin system(RAS)played a multi-faceted role in development of NAFLD.Angiotensinogen(AGT)is the first precursor of RAS,whose deficiency profoundly impacts RAS bioactivity and regulates metabolic disorders.Here,in this study,we investigated the role AGT acted in diet-induced hepatosteatosis.Methods & Results:Mice with AGT floxed alleles or hepatocyte-specific AGT deficiency(hep AGT-/-)in C57BL/6 background were fed with western diet or normal laboratory diet.Mouse body weight and diet consumption were weighed weekly.Glucose and insulin tolerance tests were carried out to access insulin resistance.Adipose tissues,liver,and plasma were collected at termination.Experiments including triglyceride measurement,histological analysis,quantitative PCR,western blot of liver tissues were performed to study changes in hepatic lipid metabolism.Hepatocyte-specific AGT knockout mice resisted to western diet-induced body weight gain,liver steatosis with preserved insulin sensitivity.Liver expressions of genes related to de novo lipogenesis and lipid storage were remarkably decreased in hep AGT-/-mice.Besides,administration of losartan,an AT1 R antagonist,failed to protect hep AGT f/f mice from western diet-induced body weight gain and liver steatosis.Conclusions:Hepatocyte-specific AGT contributes to fat-enriched diet-induced liver steatosis via regulating liver de novo lipogenesis mediated by Srebp1 c pathway and lipid storage related proteins.