| First Author | Yu H | Year | 2019 |
| Journal | Cell | Volume | 179 |
| Issue | 6 | Pages | 1276-1288.e14 |
| PubMed ID | 31778654 | Mgi Jnum | J:289767 |
| Mgi Id | MGI:6435306 | Doi | 10.1016/j.cell.2019.10.034 |
| Citation | Yu H, et al. (2019) GPR146 Deficiency Protects against Hypercholesterolemia and Atherosclerosis. Cell 179(6):1276-1288.e14 |
| abstractText | 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. |
