(Pro)renin receptor inhibition reprograms hepatic lipid metabolism and protects mice from diet-induced obesity and hepatosteatosis

Liwei Ren, Yuan Sun, Hong Lu, Dien Ye, Lijuan Han, Na Wang, Alan Daugherty, Furong Li, Miaomiao Wang, Fengting Su, Wenjun Tao, Jie Sun, Noam Zelcer, Adam E. Mullick, A. H. Jan Danser, Yizhou Jiang, Yongcheng He, Xiongzhong Ruan, Xifeng Lu

Research output: Contribution to journalArticlepeer-review

41 Scopus citations

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.

Original languageEnglish
Pages (from-to)730-741
Number of pages12
JournalCirculation Research
Volume122
Issue number5
DOIs
StatePublished - Mar 2018

Bibliographical note

Publisher Copyright:
© 2018 American Heart Association, Inc.

Keywords

  • Dyslipidemia
  • Hypercholesterolemia
  • Hypertriglyceridemia
  • Liver
  • Renin-angiotensin system
  • Vacuolar H+-ATPase

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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