(Pro)renin Receptor Inhibition Reprograms Hepatic Lipid Metabolism and Protects Mice From Diet-Induced Obesity and Hepatosteatosis. Issue 5 (2nd March 2018)

• Record Type: Journal Article
• Authors: Ren, Liwei; Sun, Yuan; Lu, Hong; Ye, Dien; Han, Lijuan; Wang, Na; Daugherty, Alan; Li, Furong; Wang, Miaomiao; Su, Fengting; Tao, Wenjun; Sun, Jie; Zelcer, Noam; Mullick, Adam E.; Danser, A.H. Jan; Jiang, Yizhou; He, Yongcheng; Ruan, Xiongzhong; Lu, Xifeng
• Is Part Of: Circulation research. Volume 122:Issue 5(2018)
• Publication Date: 2018-03-02
• Subjects: dyslipidemia -- hypercholesterolemia -- hypertriglyceridemia -- liver -- renin–angiotensin system -- vacuolar H+-ATPase; Cardiovascular system -- Periodicals; Blood -- Circulation -- Periodicals; Blood Circulation; Cardiovascular System; Vascular Diseases; Sang -- Circulation -- Périodiques; Appareil cardiovasculaire -- Périodiques; 612.1
• DOI: 10.1161/CIRCRESAHA.117.312422
• Languages: English
• ISSNs: 0009-7330

Abstract

Abstract : 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. Abstract : Supplemental Digital Content is available in the text.