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

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetyl-CoA Carboxylase / metabolism
  • Adaptor Proteins, Vesicular Transport / metabolism
  • Animals
  • Cells, Cultured
  • Diet, High-Fat / adverse effects
  • Fatty Liver / etiology
  • Fatty Liver / metabolism*
  • Gene Silencing
  • Hep G2 Cells
  • Hepatocytes / metabolism*
  • Humans
  • Lipid Metabolism*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Obesity / etiology
  • Obesity / metabolism*
  • Pyruvate Dehydrogenase Complex / metabolism
  • Receptors, Cell Surface / genetics
  • Receptors, Cell Surface / metabolism*

Substances

  • Adaptor Proteins, Vesicular Transport
  • Pyruvate Dehydrogenase Complex
  • Receptors, Cell Surface
  • prorenin receptor
  • Acetyl-CoA Carboxylase
  • sortilin