Abstract P189: The Prorenin Receptor and its Soluble From Stimulate Hepatic Triglyceride and Cholesterol Metabolism in Male Mice

Abstract

Non-alcoholic fatty liver disease is strongly associated with obesity and metabolic syndrome. Our laboratory previously demonstrated that mice lacking adipose prorenin receptor (PRR) have elevated hepatic triglycerides and cholesterol contents. In addition, lack of adipose PRR induced a counter regulatory increase of hepatic PRR and plasma soluble PRR (sPRR). Therefore, our study aimed to determine whether PRR and sPRR stimulated endogenous hepatic triglycerides and cholesterol synthesis. PRR floxed male mice fed a standard diet were injected with a single dose of an adeno-associated virus thyroxine-binding globulin Cre (KO, n=5) or saline (CTL, n=6). Body weight 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 (CTL, 615 ± 196 mg/g prot; KO, 114 ± 18 mg/g prot; P=0.047). PRR KO decreased significantly PPARγ gene expression suggesting that PRR positively regulates TG contents through PPARγ pathway. Surprisingly, similar to adipose PRR KO, liver PRR KO increased significantly plasma sPRR (CTL, 5942 ± 199 pg/ml; KO, 8903 ± 559 pg/ml; P=0.001) and hepatic total cholesterol levels (CTL, 40 ± 3 mg/g prot; KO, 102 ± 6 mg/g prot; P<0.0001). This elevation was associated with an increase in SREBP-2 and HMGCoA-reductase gene expression. To determine whether sPRR stimulated cholesterol synthesis, HepG2 cells were treated with sPRR and sPRR was infused in C57BL/6J mice (n=7 to 8 mice/group). Results showed that sPRR significantly up-regulated hepatic SREPB2 mRNA expression in HepG2 cells (Veh, 1.00 ± 0.04; sPRR, 1.36 ± 0.08; P=0.009) and in the liver of mice (Veh, 1.01 ± 0.07; sPRR, 1.23 ± 0.07; P=0.04). In conclusion, our results demonstrated that hepatic PRR positively regulated TG contents through a PPARγ-dependent mechanism and that sPRR stimulated cholesterol synthesis via SREBP-2 pathway. Futures studies will investigate the mechanism by which PRR and sPRR modulate lipid metabolism.