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Circ Res. 2018 Mar 2;122(5):730-741. doi: 10.1161/CIRCRESAHA.117.312422. Epub 2018 Jan 4.

(Pro)renin Receptor Inhibition Reprograms Hepatic Lipid Metabolism and Protects Mice From Diet-Induced Obesity and Hepatosteatosis.

Author information

1
From the AstraZeneca-Shenzhen University Joint Institute of Nephrology, Department of Physiology, Shenzhen University Health Science Center, Shenzhen University, China (L.R., Y.S., D.Y., L.H., N.W., M.W., F.S., W.T., J.S., X.R., X.L.); Translational Medicine Collaborative Innovation Center, The Second Clinical Medical College (Shenzhen People's Hospital) of Jinan University, Shenzhen, China (L.R., Y.S., F.L., X.L.); Division of Pharmacology and Vascular Medicine, Department of Internal Medicine, Erasmus Medical Center, Rotterdam University, The Netherlands (L.R., Y.S., A.H.J.D.); Saha Cardiovascular Research Center and Department of Physiology, University of Kentucky, Lexington (H.L., A.D.); Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, The Netherlands (N.Z.); Ionis Pharmaceuticals, Inc, Carlsbad, CA (A.E.M.); Institute for Advanced Study, Shenzhen University, China (Y.J.); The First Affiliated Hospital of Shenzhen University, China (Y.H.); and John Moorhead Laboratory, Center for Nephrology, University College London, United Kingdom (X.R.).
2
From the AstraZeneca-Shenzhen University Joint Institute of Nephrology, Department of Physiology, Shenzhen University Health Science Center, Shenzhen University, China (L.R., Y.S., D.Y., L.H., N.W., M.W., F.S., W.T., J.S., X.R., X.L.); Translational Medicine Collaborative Innovation Center, The Second Clinical Medical College (Shenzhen People's Hospital) of Jinan University, Shenzhen, China (L.R., Y.S., F.L., X.L.); Division of Pharmacology and Vascular Medicine, Department of Internal Medicine, Erasmus Medical Center, Rotterdam University, The Netherlands (L.R., Y.S., A.H.J.D.); Saha Cardiovascular Research Center and Department of Physiology, University of Kentucky, Lexington (H.L., A.D.); Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, The Netherlands (N.Z.); Ionis Pharmaceuticals, Inc, Carlsbad, CA (A.E.M.); Institute for Advanced Study, Shenzhen University, China (Y.J.); The First Affiliated Hospital of Shenzhen University, China (Y.H.); and John Moorhead Laboratory, Center for Nephrology, University College London, United Kingdom (X.R.). x.lu@szu.edu.cn xiongzruan@gmail.com.

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.

KEYWORDS:

dyslipidemia; hypercholesterolemia; hypertriglyceridemia; liver; renin–angiotensin system; vacuolar H+-ATPase

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