Rationale: An elevated level of plasma LDL (low-density lipoprotein) is an established risk factor for cardiovascular disease. Recently, we reported that the (pro)renin receptor ([P]RR) regulates LDL metabolism in vitro via the LDLR (LDL receptor) and SORT1 (sortilin-1), independently of the renin-angiotensin system. Objectives: To investigate the physiological role of (P)RR in lipid metabolism in vivo. Methods and Results: We used N-acetylgalactosamine modified antisense oligonucleotides to specifically inhibit hepatic (P)RR expression in C57BL/6 mice and studied the consequences this has on lipid metabolism. In line with our earlier report, hepatic (P)RR silencing increased plasma LDL-C (LDL cholesterol). Unexpectedly, this also resulted in markedly reduced plasma triglycerides in a SORT1-independent manner in C57BL/6 mice fed a normal-or high-fat diet. In LDLR-deficient mice, hepatic (P)RR inhibition reduced both plasma cholesterol and triglycerides, in a diet-independent manner. Mechanistically, we found that (P)RR inhibition decreased protein abundance of ACC (acetyl-CoA carboxylase) and PDH (pyruvate dehydrogenase). This alteration reprograms hepatic metabolism, leading to reduced lipid synthesis and increased fatty acid oxidation. As a result, hepatic (P) RR inhibition attenuated diet-induced obesity and hepatosteatosis. Conclusions: Collectively, our study suggests that (P)RR plays a key role in energy homeostasis and regulation of plasma lipids by integrating hepatic glucose and lipid metabolism. Integrative Physiology

Additional Metadata
Keywords Dyslipidemia, Hypercholesterolemia, Hypertriglyceridemia, Liver, Renin-angiotensin system, Vacuolar H+-ATPase
Persistent URL dx.doi.org/10.1161/CIRCRESAHA.117.312422, hdl.handle.net/1765/110136
Journal Circulation Research
Citation
Ren, L, Sun, Y. (Yuan), Lu, H. (Hong), Ye, D. (Dien), Han, L. (Lijuan), Wang, N. (Na), … Lu, X. (2018). (Pro)renin receptor inhibition reprograms hepatic lipid metabolism and protects mice from diet-induced obesity and hepatosteatosis. Circulation Research, 122(5), 730–741. doi:10.1161/CIRCRESAHA.117.312422