Gpr146, an orphan G protein-coupled receptor, plays a significant role in regulating cholesterol metabolism. It promotes the activity of hepatic sterol regulatory element binding protein 2 (SREBP2) via the extracellular signal-regulated kinase (ERK) signaling pathway, thus influencing hepatic very low-density lipoprotein (VLDL) secretion and circulating low-density lipoprotein cholesterol (LDL-C) and triglycerides (TG) levels [1].

Gpr146 deficiency in both wild-type and LDL receptor (LDLR)-deficient mice leads to a substantial reduction in plasma cholesterol levels. Specifically, in male and female LDLR-deficient mice, aortic atherosclerotic lesions are decreased by 90% and 70% respectively upon Gpr146 depletion [1]. Additionally, in hypoxic pulmonary hypertension (PH) mouse models, Gpr146 deficiency protects 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 crucial in cholesterol metabolism and pulmonary vascular remodeling. Gene knockout mouse models have revealed its role in hypercholesterolemia and atherosclerosis, as well as in PH. These findings suggest that targeting Gpr146 could be a potential therapeutic strategy for these diseases.