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

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...

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Published in:Circulation research Vol. 122; no. 5; p. 730
Main 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
Format: Journal Article
Language:English
Published: United States 02.03.2018
Subjects:
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
Prorenin Receptor
Pyruvate Dehydrogenase Complex - metabolism
Receptors, Cell Surface - genetics
Receptors, Cell Surface - metabolism
hypertriglyceridemia
dyslipidemia
liver
vacuolar H+-ATPase
hypercholesterolemia
renin–angiotensin system
ISSN:1524-4571, 1524-4571
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Summary: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. To investigate the physiological role of (P)RR in lipid metabolism in vivo. 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. 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.
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ISSN:1524-4571
1524-4571
DOI:10.1161/CIRCRESAHA.117.312422