(Pro)renin Receptor Inhibition Reprograms Hepatic Lipid Metabolism and Protects Mice From Diet-Induced Obesity and Hepatosteatosis.
(Pro)renin Receptor Inhibition Reprograms Hepatic Lipid Metabolism and Protects Mice From Diet-Induced Obesity and Hepatosteatosis.
复制标题
肾素原受体抑制可重新编程肝脏脂质代谢并保护小鼠免受饮食引起的肥胖和肝脂肪变性
DOI：
10.1161/circresaha.117.312422
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发表时间：
2018-03-02
影响因子：
20.1
通讯作者：
Lu X
中科院分区：
文献类型：
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作者：
Ren L;Sun Y;Lu H;Ye D;Han L;Wang N;Daugherty A;Li F;Wang M;Su F;Tao W;Sun J;Zelcer N;Mullick AE;Danser AHJ;Jiang Y;He Y;Ruan X;Lu X
血浆LDL（低密度脂蛋白）水平升高是心血管疾病的既定危险因素。最近，我们报道了（原）肾素受体（[P]RR）在体外通过LDLR（LDL受体）和SORT 1（分拣蛋白-1）调节LDL代谢，独立于肾素-血管紧张素系统。探讨（P）RR在体内脂质代谢中的生理作用。我们使用N-乙酰半乳糖胺修饰的反义寡核苷酸特异性抑制C57 BL/6小鼠肝脏（P）RR表达，并研究了这对脂质代谢的影响。与我们早期的报告一致，肝脏（P）RR沉默增加了血浆LDL-C（LDL胆固醇）。出乎意料的是，这也导致在喂食正常或高脂肪饮食的C57 BL/6小鼠中以SORT 1非依赖性方式显著降低血浆甘油三酯。在LDL R缺陷小鼠中，肝脏（P）RR抑制以非饮食依赖性方式降低血浆胆固醇和甘油三酯。从机制上讲，我们发现（P）RR抑制降低了ACC（乙酰辅酶A羧化酶）和PDH（丙酮酸脱氢酶）的蛋白质丰度。这种改变重新编程肝脏代谢，导致脂质合成减少和脂肪酸氧化增加。因此，肝（P）RR抑制减弱饮食诱导的肥胖和肝脂肪变性。总之，我们的研究表明，（P）RR通过整合肝脏葡萄糖和脂质代谢，在能量稳态和血脂调节中起关键作用。
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.