近日，美国哈佛大学Chad A. Cowan、Haojie Yu等研究人员合作发现，GPR146缺陷可预防高胆固醇血症和动脉粥样硬化。相关论文于2019年11月27日发表于国际学术期刊《细胞》。

研究人员证明孤儿G蛋白偶联受体146（GPR146）通过激活细胞外信号调节激酶（ERK）信号传导途径来促进肝固醇调节元件结合蛋白2（SREBP2）的活性，从而调节肝极低密度脂蛋白（VLDL）分泌，随后循环的低密度脂蛋白胆固醇（LDL-C）和甘油三酸酯（TG）水平。

值得注意的是，GPR146缺乏症可在野生型和LDL受体（LDLR）缺乏症小鼠中大幅降低血浆胆固醇水平。

最后，在雄性和雌性LDLR缺陷的小鼠中，GPR146去除后，主动脉粥样硬化病变分别减少了90％和70％。

综上所述，这些发现概述了GPR146/ERK信号轴在全身胆固醇代谢中的调节作用，并表明抑制GPR146可能是降低血浆胆固醇水平和动脉粥样硬化的有效策略。

据悉，尽管人类遗传研究牵涉到许多与血浆脂质水平相关的易感基因，但它们的生理和分子功能尚未得到充分表征。

附：英文原文

Title: GPR146 Deficiency Protects against Hypercholesterolemia and Atherosclerosis

Author: Haojie Yu, Antoine Rimbert, Alice E. Palmer, Takafumi Toyohara, Yulei Xia, Fang Xia, Leonardo M.R. Ferreira, Zhifen Chen, Tao Chen, Natalia Loaiza, Nathaniel Brooks Horwitz, Michael C. Kacergis, Liping Zhao, Alexander A. Soukas, Jan Albert Kuivenhoven, Sekar Kathiresan, Chad A. Cowan

Issue&Volume: 2019/11/27

Abstract: Although human genetic studies have implicated many susceptible genes associated withplasma lipid levels, their physiological and molecular functions are not fully characterized.Here we demonstrate that orphan G protein-coupled receptor 146 (GPR146) promotes activity of hepatic sterol regulatory element binding protein 2 (SREBP2)through activation of the extracellular signal-regulated kinase (ERK) signaling pathway,thereby regulating hepatic very low-density lipoprotein (VLDL) secretion, and subsequentlycirculating low-density lipoprotein cholesterol (LDL-C) and triglycerides (TG) levels.Remarkably, GPR146 deficiency reduces plasma cholesterol levels substantially in bothwild-type and LDL receptor (LDLR)-deficient mice. Finally, aortic atheroscleroticlesions are reduced by 90% and 70%, respectively, in male and female LDLR-deficientmice upon GPR146 depletion. Taken together, these findings outline a regulatory rolefor the GPR146/ERK axis in systemic cholesterol metabolism and suggest that GPR146inhibition could be an effective strategy to reduce plasma cholesterol levels andatherosclerosis.

DOI: 10.1016/j.cell.2019.10.034

Source: https://www.cell.com/cell/fulltext/S0092-8674(19)31211-5