Circulation research · 2018
(Pro)renin Receptor Inhibition Reprograms Hepatic Lipid Metabolism and Protects Mice From Diet-Induced Obesity and Hepatosteatosis.
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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
Аннотация
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.
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.