{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nG protein‐coupled receptor 146 (GPR146) has been shown to play a pivotal role in lipid metabolism. In the liver, GPR146 activation enhances the activity of sterol regulatory element binding protein 2 (SREBP2) via the extracellular signal‐regulated kinase (ERK) pathway, which in turn promotes very low-density lipoprotein (VLDL) secretion. This cascade leads to an increase in circulating low-density lipoprotein cholesterol (LDL-C) and triglyceride levels, impacting the development of atherosclerosis. Notably, deficiency of GPR146 results in a marked reduction of plasma cholesterol and a significant decrease in atherosclerotic lesions."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its metabolic function, GPR146 is implicated in the host antiviral response. Its expression is robustly induced by interferon (IFN)-β and IFN-γ in a STAT1-dependent manner, conferring protection against RNA viral infections such as vesicular stomatitis virus and Newcastle disease virus. However, this protective role is finely tuned by virus-triggered IFN regulatory factor 3 (IRF3) signalling, which, by engaging HES1-mediated transcriptional repression, eventually downregulates GPR146 expression to balance pro-viral and antiviral phases."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nFurthermore, GPR146 contributes to the pathogenesis of hypoxic pulmonary hypertension (PH) through its effects on pulmonary vascular remodeling. Elevated expression of GPR146 in the pulmonary vasculature, particularly in smooth muscle cells, enhances cell proliferation by upregulating 5-lipoxygenase (5-LO) and promoting lipid peroxidation. Genetic ablation of GPR146 in mouse models of PH attenuates pulmonary artery smooth muscle cell proliferation, reduces right ventricular hypertrophy, and mitigates pulmonary vascular remodeling, highlighting its potential as a therapeutic target in PH."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Haojie Yu, Antoine Rimbert, Alice E Palmer, et al. "}, {"type": "b", "children": [{"type": "t", "text": "GPR146 Deficiency Protects against Hypercholesterolemia and Atherosclerosis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.cell.2019.10.034"}], "href": "https://doi.org/10.1016/j.cell.2019.10.034"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31778654"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31778654"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Hongjun Huang, Na Zhang, Qingqing Xiong, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Elimination of GPR146-mediated antiviral function through IRF3/HES1-signalling pathway."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Immunology (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/imm.12752"}], "href": "https://doi.org/10.1111/imm.12752"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28464285"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28464285"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Jie Huang, Yongpeng Xie, Bing Chen, et al. "}, {"type": "b", "children": [{"type": "t", "text": "GPR146 regulates pulmonary vascular remodeling by promoting pulmonary artery smooth muscle cell proliferation through 5-lipoxygenase."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Eur J Pharmacol (2023)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.ejphar.2023.176123"}], "href": "https://doi.org/10.1016/j.ejphar.2023.176123"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "37926274"}], "href": "https://pubmed.ncbi.nlm.nih.gov/37926274"}]}]}]}