Gpr146, an orphan G protein-coupled receptor, is involved in crucial physiological processes. It plays a role in regulating cholesterol metabolism through its influence on the extracellular signal-regulated kinase (ERK) signaling pathway, specifically by promoting the activity of hepatic sterol regulatory element binding protein 2 (SREBP2) [1]. This regulation impacts hepatic very low-density lipoprotein (VLDL) secretion, and subsequently, circulating low-density lipoprotein cholesterol (LDL-C) and triglycerides (TG) levels. Genetic models, such as knockout mice, have been instrumental in studying its function.

In Gpr146-deficient mice, plasma cholesterol levels are substantially reduced in both wild-type and LDL receptor (LDLR)-deficient mice. Additionally, aortic atherosclerotic lesions are significantly decreased in male and female LDLR-deficient mice upon Gpr146 depletion [1]. Also, in a hypoxic pulmonary hypertension (PH) mouse model, Gpr146 deficiency induction shows protective effects against hypoxia-induced elevation of right ventricular systolic blood pressure (RVSP), right ventricular hypertrophy, and pulmonary vascular remodeling, as it attenuates the hypoxia-triggered proliferation of pulmonary artery smooth muscle cells (PASMCs) [2].

In conclusion, Gpr146 is a key regulator in cholesterol metabolism and pulmonary vascular remodeling. The study of Gpr146 using gene knockout mouse models has revealed its significance in hypercholesterolemia and atherosclerosis, as well as in PH. These findings suggest that targeting Gpr146 could be a potential therapeutic strategy for treating these diseases.

References:

1. Yu, Haojie, Rimbert, Antoine, Palmer, Alice E, Kathiresan, Sekar, Cowan, Chad A. . GPR146 Deficiency Protects against Hypercholesterolemia and Atherosclerosis. In Cell, 179, 1276-1288.e14. doi:10.1016/j.cell.2019.10.034. https://pubmed.ncbi.nlm.nih.gov/31778654/

2. Huang, Jie, Xie, Yongpeng, Chen, Bing, Sun, Zengxian, Liu, Yun. 2023. GPR146 regulates pulmonary vascular remodeling by promoting pulmonary artery smooth muscle cell proliferation through 5-lipoxygenase. In European journal of pharmacology, 961, 176123. doi:10.1016/j.ejphar.2023.176123. https://pubmed.ncbi.nlm.nih.gov/37926274/