Prorenin receptor regulates lipid metabolism via distinct actions on PPARγ and SREBP‐2 in liver of male mice

Abstract

Introduction and objectivesThe epidemic of obesity is currently affecting more than 35% of the population in the United States. Non‐alcoholic fatty liver disease (NAFLD) is strongly associated with obesity and metabolic syndrome. Our laboratory previously demonstrated that adipose prorenin receptor (PRR) KO mice developed lipodystrophy and liver steatosis associated with elevated hepatic triglycerides (TG) levels. Interestingly, hepatic PRR and PPARγ expression were up‐regulated in HF‐fed adipose PRR KO mice. Since body of evidence indicated that PPARγ becomes elevated in fatty livers and since we showed that PRR regulated PPARγ in adipose, we sought to investigate whether PRR regulated TG contents in liver through a PPARγ‐dependent mechanism.Methods and resultsPRR floxed male mice fed a standard diet were injected with a single dose of an adeno‐associated virus thyroxine‐binding globulin Cre (Liver PRR KO, n=5) or saline (Veh, n=6). Body weights were measured weekly for 3 weeks. The deletion of PRR in liver did not change body weight curves. Hepatic levels of TG were significantly decreased in liver PRR KO mice compared with control mice injected with saline (Veh, 53.22 ± 15.4 mg/g liver; AAV, 10.79 ± 1.61 mg/g liver, P<0.05). The deletion of PRR induced a significant decrease of PPARγ gene expression whereas SREBP‐1c expression was unchanged suggesting that PRR regulated TG contents through a PPARγ‐dependent mechanism. Surprisingly, liver weights were significantly higher in liver PRR KO mice compared to control mice injected with saline (Veh, 1.82 ± 0.12 g; Liver PRR KO, 2.37 ± 0.08g, P<0.05). Plasma cholesterol levels (Veh, 143 ± 10 mg/dL; Liver PRR KO, 383 ± 14g mg/dL, P<0.05) and hepatic total cholesterol levels (Veh, 3.64 ± 0.09 mg/g liver; Liver PRR KO, 10.47 ± 0.55 mg/g liver) were elevated in liver PRR KO mice. Interestingly, the increase in total cholesterol content in liver was associated with an increase in SREBP‐2 and HMGCoA‐reductase gene expression suggesting that the deletion of PRR stimulated cholesterol synthesis. Additionally, ABCG5 gene expression was increased, reflecting an increased cholesterol efflux.ConclusionTaken together our results demonstrated for the first time that PRR is an important modulator of lipid metabolism in liver. In agreement with our hypothesis, hepatic PRR positively regulated TG contents through a PPARγ‐dependent mechanism. Interestingly, the deletion of hepatic PRR stimulates cholesterol synthesis via SREBP‐2 up‐regulation indicating that PRR acts at the crossroad between triglycerides and cholesterol metabolism.Support or Funding Information COBRE ‐ P20 GM103527 American Heart Association ‐ 13SDG17230008 University of Kentucky, Center for Clinical and Translational Sciences, CCTS pilot grant, CCTS small grant, NIH T32HL091812 This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.