Recently, Yu et al. [1] revealed that G protein-coupled receptor 146 (GPR146) exerts a detrimental effect on the regulation of systemic cholesterol metabolism. Mechanically, GPR146 induces hepatic sterol regulatory element binding protein 2 (SREBP2) via the activation of extracellular signal-regulated kinase 1/2 (ERK1/2) signaling, consequently resulting in hepatic low-density lipoprotein (VLDL) secretion. Notably, GPR146 depletion reduces VLDL secretion and decreases aortic atherosclerotic lesions in low-density lipoprotein receptor (LDLR)-deficient mice via the suppression of ERK1/2/SREBP2 pathway, suggesting that GPR146 may contribute to the incidence of atherosclerosis (AS) and familial hypercholesterolemia (HoFH). Taken together, inhibition of GPR146 is likely to be an effective strategy for AS and HoFH treatment for modulating cholesterol levels.

中文翻译：

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GPR146：高胆固醇血症和动脉粥样硬化的新兴治疗靶点。

最近，Yu等人。[1] 揭示 G 蛋白偶联受体 146 (GPR146) 对全身胆固醇代谢的调节产生不利影响。在机械上，GPR146 通过激活细胞外信号调节激酶 1/2 (ERK1/2) 信号诱导肝甾醇调节元件结合蛋白 2 (SREBP2)，从而导致肝脏低密度脂蛋白 (VLDL) 分泌。值得注意的是，GPR146 耗竭通过抑制 ERK1/2/SREBP2 通路减少了低密度脂蛋白受体 (LDLR) 缺陷小鼠的 VLDL 分泌并减少了主动脉粥样硬化病变，这表明 GPR146 可能有助于动脉粥样硬化 (AS) 和家族性动脉粥样硬化的发生。高胆固醇血症 (HoFH)。总之，抑制 GPR146 可能是 AS 和 HoFH 治疗调节胆固醇水平的有效策略。