Although human genetic studies have implicated many susceptible genes associated with plasma 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 subsequently circulating low-density lipoprotein cholesterol (LDL-C) and triglycerides (TG) levels. Remarkably, GPR146 deficiency reduces plasma cholesterol levels substantially in both wild-type and LDL receptor (LDLR)-deficient mice. Finally, aortic atherosclerotic lesions are reduced by 90% and 70%, respectively, in male and female LDLR-deficient mice upon GPR146 depletion. Taken together, these findings outline a regulatory role for the GPR146/ERK axis in systemic cholesterol metabolism and suggest that GPR146 inhibition could be an effective strategy to reduce plasma cholesterol levels and atherosclerosis.

中文翻译：

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GPR146 缺乏可预防高胆固醇血症和动脉粥样硬化。

尽管人类遗传研究涉及许多与血脂水平相关的易感基因，但它们的生理和分子功能尚未完全表征。在这里，我们证明孤儿 G 蛋白偶联受体 146 (GPR146) 通过激活细胞外信号调节激酶 (ERK) 信号通路促进肝甾醇调节元件结合蛋白 2 (SREBP2) 的活性，从而调节肝脏极低密度脂蛋白(VLDL) 分泌，以及随后的循环低密度脂蛋白胆固醇 (LDL-C) 和甘油三酯 (TG) 水平。值得注意的是，GPR146 缺乏显着降低了野生型和 LDL 受体 (LDLR) 缺陷小鼠的血浆胆固醇水平。最后，主动脉粥样硬化病变分别减少了 90% 和 70%，在 GPR146 耗尽的雄性和雌性 LDLR 缺陷小鼠中。总之，这些发现概述了 GPR146/ERK 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。