Angiotensinogen in Hepatocytes Contributes to Western Diet-induced Liver Steatosis.J Lipid Res 2019JL
Non-alcoholic fatty liver disease (NAFLD) is considered as a liver manifestation of metabolic disorders. Previous studies indicate that renin-angiotensin system (RAS) plays a complex role in NAFLD. As the only precursor of RAS, decreased angiotensinogen (AGT) profoundly impacts RAS bioactivity. Here we investigated the role of hepatocyte-derived AGT in liver steatosis. AGT floxed mice (hepAGT+/+) and hepatocyte-specific AGT deficient mice (hepAGT-/-) were fed on western diet and normal laboratory diet for 12 weeks, respectively. Compared with hepAGT+/+ mice, western diet-fed hepAGT-/- mice gained less body weight with improved insulin sensitivity. The attenuated severity of liver steatosis in hepAGT-/- mice was evidenced by histologic changes and reduced intrahepatic triglycerides. The abundance of SREBP1 and its down-stream molecules ACC, FASN was suppressed in hepAGT-/- mice. Furthermore, serum derived from hepAGT+/+ mice stimulated hepatocyte SREBP1 expression, which could be diminished by Akt/mTOR inhibition in vitro. Administration of losartan did not affect diet-induced body weight gain, liver steatosis severity, and hepatic p-Akt, p-mTOR, and SREBP1 protein abundance in hepAGT+/+ mice. These data suggest that attenuation of western diet-induced liver steatosis in hepAGT-/- mice is associated with the alternation of Akt/mTOR/SREBP-1c pathway.