{"gene":"GPR146","run_date":"2026-06-10T01:55:21","timeline":{"discoveries":[{"year":2019,"finding":"GPR146 promotes activity of hepatic SREBP2 through activation of the ERK signaling pathway, thereby regulating hepatic VLDL secretion and circulating LDL-C and triglyceride levels. GPR146 deficiency reduces plasma cholesterol and reduces aortic atherosclerotic lesions in LDLR-deficient mice.","method":"Genetic knockout mice (global and hepatic), in vivo lipid measurements, ERK/SREBP2 pathway analysis","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KO with defined cellular phenotype, ERK/SREBP2 pathway placement, replicated in multiple mouse models including LDLR-deficient background","pmids":["31778654"],"is_preprint":false},{"year":2013,"finding":"Knockdown of GPR146 blocked C-peptide-induced cFos expression in KATOIII cells; stimulation with C-peptide caused internalization of GPR146 and punctate colocalization on KATOIII cell membranes, indicating GPR146 is part of the C-peptide signaling complex.","method":"siRNA knockdown, cFos reporter assay, fluorescence colocalization/internalization microscopy","journal":"The Journal of endocrinology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — two orthogonal methods (knockdown + colocalization/internalization), single lab, but no direct binding assay","pmids":["23759446","23980258"],"is_preprint":false},{"year":2020,"finding":"Neither dynamic mass redistribution nor GPCR β-arrestin assays revealed any significant intracellular response to C-peptide in CHO-K1 cells expressing human GPR146 at concentrations up to 33 µM, and no internalization of C-peptide was observed by fluorescence microscopy. These results do NOT support GPR146 as the receptor for C-peptide.","method":"Dynamic mass redistribution assay, GPCR β-arrestin assay, fluorescence confocal microscopy in CHO-K1 cells expressing human GPR146","journal":"Bioorganic & medicinal chemistry letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal functional assays (DMR, β-arrestin, microscopy) in a heterologous expression system; NEGATIVE result contradicting prior claims","pmids":["32354568"],"is_preprint":false},{"year":2017,"finding":"GPR146 expression is induced by IFN-β and IFN-γ via a STAT1-dependent signaling pathway. Overexpression of GPR146 protects host cells from vesicular stomatitis virus and Newcastle disease virus infection. Virus-activated IRF3 signaling represses GPR146 expression through HES1-mediated transcriptional activity, establishing a dynamic equilibrium between pro-viral and antiviral states.","method":"IFN stimulation assays, overexpression and Gpr146-knockout cells/mice, VSV and NDV infection models, IRF3/HES1 transcriptional activity assays","journal":"Immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO and overexpression with defined phenotypic readouts, pathway placement via IRF3/HES1, single lab","pmids":["28464285"],"is_preprint":false},{"year":2023,"finding":"GPR146 promotes pyroptosis of pulmonary artery endothelial cells through the NLRP3/caspase-1 signaling axis, increasing IL-1β, IL-6, and IL-18; silencing GPR146 inhibited hypoxia-induced pyroptosis-related protein expression and inflammatory cytokine production.","method":"siRNA knockdown, GPR146 overexpression, western blotting, real-time PCR, ROS detection, LDH release assays, immunofluorescence in PAECs; in vivo SuHx rat PH model","journal":"European journal of pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function and gain-of-function with defined molecular pathway (NLRP3/caspase-1), multiple methods, single lab","pmids":["36638952"],"is_preprint":false},{"year":2023,"finding":"GPR146 promotes pulmonary artery smooth muscle cell proliferation through upregulation of 5-lipoxygenase (5-LO); GPR146 knockdown or siRNA intervention reversed hypoxia-induced 5-LO expression and attenuated pulmonary vascular remodeling in a mouse PH model.","method":"siRNA knockdown, GPR146 overexpression, immunohistochemistry, in vivo mouse PH model (SuHx), western blotting, PASMC proliferation assays","journal":"European journal of pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function and gain-of-function with defined cellular phenotype and pathway component (5-LO), single lab","pmids":["37926274"],"is_preprint":false},{"year":2025,"finding":"GPR146 is a Gαs-coupled GPCR that activates the cAMP-CREB1 signaling cascade in vascular smooth muscle cells; GPR146 upregulates PIEZO1 expression by enhancing CREB1 binding to the PIEZO1 promoter. Deletion of Piezo1 in SMCs blocked GPR146-induced blood pressure elevation and vascular dysfunction. GPR146 neutralization antibody injection alleviates angiotensin II-induced hypertension.","method":"Proximity ligation assay, bioluminescence resonance energy transfer (BRET), SMC-specific knockin/knockout mice, Piezo1 SMC-specific KO mice, ChIP-like CREB1 promoter binding analysis, ex vivo HP loading system, neutralization antibody injection","journal":"Circulation research","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — BRET for Gαs coupling, proximity ligation assay, multiple genetic models (global KO, SMC-specific KI/KO, Piezo1 SMC-KO), in vitro and in vivo, multiple orthogonal methods","pmids":["40636956"],"is_preprint":false},{"year":2026,"finding":"GPR146 in adipose tissue promotes adipogenesis in preadipocytes via Gαq-PKC-AKT signaling, increasing lipid storage capacity, and enhances lipolysis in mature adipocytes through ERK activation, elevating circulating free fatty acids (FFA) that drive hepatic triglyceride accumulation. Adipose-specific (but not liver-specific) GPR146 deletion reduces hepatic lipid accumulation.","method":"Constitutive and adipose-specific / liver-specific conditional knockout mice, diet-induced obesity model, FFA flux measurements, signaling pathway assays (PKC, AKT, ERK)","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — tissue-specific conditional KO dissecting adipose vs liver contributions, multiple signaling pathways validated, multiple orthogonal approaches in single study","pmids":["41775759"],"is_preprint":false},{"year":2026,"finding":"Loss of GPR146 reduces HDL cholesterol via post-translational upregulation of hepatic SR-B1 protein (without changes in Scarb1 mRNA), increasing cell-surface SR-B1 and SR-B1-mediated selective uptake of HDL lipid and protein. This mechanism appears independent of ERK signaling.","method":"Whole-body and liver-specific Gpr146 KO mice, MEK1 inhibitor treatment, SR-B1 protein/mRNA measurement in primary hepatocytes, HDL uptake assays, human cohort genetic variant analysis","journal":"Cardiovascular research","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple KO models (whole-body and liver-specific), in vitro primary hepatocyte assays, MEK inhibitor to probe ERK independence, mechanistic pathway placement (SR-B1 post-translational regulation)","pmids":["41271608"],"is_preprint":false},{"year":2025,"finding":"Silencing Gpr146 in mouse liver significantly reduced total blood cholesterol while markedly upregulating liver Cyp7a1 expression during 2-h fasting, independently of FXR-dependent and FXR-independent cytokine pathways, establishing CYP7A1 as a target gene of GPR146 in cholesterol metabolism.","method":"In vivo Gpr146 silencing (liver), Cyp7a1 expression measurement, cholesterol measurement, FXR pathway analysis in cultured hepatocytes and in vivo","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo loss-of-function with pathway placement (CYP7A1 regulation independent of FXR), single lab, limited mechanistic detail in abstract","pmids":["40414012"],"is_preprint":false},{"year":2025,"finding":"The GPR146 P61L knock-in mouse model (ortholog of human P62L variant) showed reduced plasma cholesterol due to reduced HDL cholesterol, without changes in VLDL secretion, ERK1/2 signaling, Srebp2 mRNA, or hepatocyte apoB secretion, indicating this variant confers loss of GPR146 function affecting HDL but not the ERK/SREBP2/VLDL axis.","method":"Knock-in mouse model (P61L), plasma cholesterol measurement, VLDL secretion assay, ERK1/2 phosphorylation, Srebp2 mRNA, primary hepatocyte apoB secretion","journal":"Atherosclerosis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — knock-in mouse model with multiple pathway readouts, single lab, partially negative mechanistic findings informative for pathway dissection","pmids":["40120432"],"is_preprint":false}],"current_model":"GPR146 is an orphan GPCR that signals through at least two G-protein-coupled pathways — Gαs/cAMP-CREB1 in vascular smooth muscle cells (upregulating PIEZO1 to drive hypertension) and Gαq-PKC-AKT/ERK in adipocytes (promoting adipogenesis and lipolysis) — while in hepatocytes it activates ERK-SREBP2 signaling to suppress CYP7A1 and stimulate VLDL secretion, and independently regulates HDL cholesterol via post-translational upregulation of SR-B1; additionally, GPR146 expression is induced by interferons via STAT1 and exerts antiviral activity that is in turn suppressed by IRF3/HES1 signaling."},"narrative":{"mechanistic_narrative":"GPR146 is an orphan G-protein-coupled receptor that functions as a central regulator of systemic lipid metabolism and vascular physiology through tissue-specific, multi-pathway signaling [PMID:31778654, PMID:40636956, PMID:41775759]. In hepatocytes it drives ERK-dependent activation of SREBP2 to promote VLDL secretion and elevate circulating LDL-C and triglycerides, and its loss reduces plasma cholesterol and atherosclerotic burden in LDLR-deficient mice [PMID:31778654]; in parallel and independently of ERK, GPR146 loss lowers HDL cholesterol via post-translational upregulation of hepatic SR-B1 protein, increasing cell-surface SR-B1 and selective HDL uptake [PMID:41271608], and represses CYP7A1 to constrain bile acid synthesis [PMID:40414012]. The receptor signals through distinct G-protein arms in different tissues: a Gαs–cAMP–CREB1 cascade in vascular smooth muscle cells that transcriptionally upregulates PIEZO1 to drive angiotensin II–induced hypertension and vascular dysfunction [PMID:40636956], and a Gαq–PKC–AKT arm in preadipocytes promoting adipogenesis alongside an ERK arm in mature adipocytes enhancing lipolysis and free fatty acid efflux that fuels hepatic triglyceride accumulation [PMID:41775759]. Beyond metabolism, GPR146 expression is induced by type I and II interferons through STAT1 and confers antiviral protection that is in turn repressed by virus-activated IRF3/HES1 signaling [PMID:28464285], and it promotes NLRP3/caspase-1–dependent pyroptosis and 5-lipoxygenase–driven smooth muscle proliferation in pulmonary vascular remodeling [PMID:36638952, PMID:37926274]. A human-orthologous P61L loss-of-function variant selectively impairs the HDL axis without affecting VLDL secretion or ERK/SREBP2 signaling, confirming that GPR146's HDL and VLDL functions are mechanistically separable [PMID:40120432]. Whether GPR146 has an endogenous peptide ligand remains unresolved; an early report implicated it in C-peptide signaling [PMID:23759446, PMID:23980258], but heterologous reconstitution assays failed to detect any C-peptide response [PMID:32354568].","teleology":[{"year":2013,"claim":"Addressed whether GPR146 transduces a defined extracellular signal by testing its requirement for C-peptide-induced gene expression, the first functional assignment for this orphan receptor.","evidence":"siRNA knockdown with cFos reporter and internalization/colocalization microscopy in KATOIII cells","pmids":["23759446","23980258"],"confidence":"Medium","gaps":["No direct ligand-receptor binding assay","Single cell line and single lab","Does not identify the coupled G-protein or downstream cascade"]},{"year":2017,"claim":"Established GPR146 as an interferon-inducible, STAT1-dependent gene with cell-autonomous antiviral activity, placing it in an innate immune regulatory circuit balanced by IRF3/HES1 repression.","evidence":"IFN stimulation, overexpression and knockout cells/mice, VSV and NDV infection models, IRF3/HES1 transcriptional assays","pmids":["28464285"],"confidence":"Medium","gaps":["Molecular mechanism of antiviral protection downstream of GPR146 unknown","No G-protein coupling defined for this role","Single lab"]},{"year":2019,"claim":"Defined GPR146's first major metabolic role by linking it to hepatic ERK-SREBP2 signaling controlling VLDL secretion, establishing it as a determinant of circulating LDL-C and atherosclerosis risk.","evidence":"Global and hepatic knockout mice, in vivo lipid profiling, ERK/SREBP2 pathway analysis in LDLR-deficient background","pmids":["31778654"],"confidence":"High","gaps":["Endogenous ligand driving hepatic GPR146 activity unidentified","G-protein coupling not directly resolved here","Mechanism connecting receptor to ERK not defined"]},{"year":2020,"claim":"Directly challenged the C-peptide receptor hypothesis by testing for signaling responses in a defined heterologous system, leaving the receptor functionally orphan.","evidence":"Dynamic mass redistribution, β-arrestin recruitment assays, and fluorescence microscopy in CHO-K1 cells expressing human GPR146","pmids":["32354568"],"confidence":"Medium","gaps":["Negative result; cannot exclude ligand activity requiring accessory factors absent in CHO-K1","Does not identify the true endogenous ligand"]},{"year":2023,"claim":"Extended GPR146 into pulmonary vascular pathology by linking it to NLRP3/caspase-1 pyroptosis and 5-LO-driven smooth muscle proliferation, identifying it as a driver of hypoxia-induced vascular remodeling.","evidence":"siRNA knockdown and overexpression with pyroptosis and proliferation readouts in PAECs/PASMCs plus in vivo SuHx rat/mouse PH models","pmids":["36638952","37926274"],"confidence":"Medium","gaps":["G-protein coupling and proximal signaling for these effects undefined","Connection to GPR146's metabolic signaling roles unclear","Single lab"]},{"year":2025,"claim":"Resolved a specific G-protein coupling and downstream transcriptional target by showing GPR146 is Gαs-coupled, drives cAMP-CREB1 signaling, and transcriptionally upregulates PIEZO1 to cause hypertension, providing a mechanistic and therapeutic handle.","evidence":"BRET for Gαs coupling, proximity ligation assay, SMC-specific and Piezo1 SMC-specific knockout/knockin mice, CREB1 promoter binding, neutralization antibody in vivo","pmids":["40636956"],"confidence":"High","gaps":["Activating ligand for vascular GPR146 unknown","Whether Gαs coupling operates in other tissues not addressed","Relationship to the hepatic ERK arm unresolved"]},{"year":2025,"claim":"Distinguished GPR146's HDL-regulatory function from its VLDL/ERK axis by showing it represses CYP7A1 and, via a human-orthologous P61L variant, selectively impairs HDL without affecting VLDL or ERK/SREBP2 signaling.","evidence":"In vivo liver Gpr146 silencing with Cyp7a1/cholesterol measurement and FXR pathway analysis; P61L knock-in mouse with VLDL, ERK, Srebp2, and apoB readouts","pmids":["40414012","40120432"],"confidence":"Medium","gaps":["Mechanism linking GPR146 to CYP7A1 repression undefined","How a single missense variant selectively disrupts one arm unexplained","FXR-independent pathway to CYP7A1 not fully mapped"]},{"year":2026,"claim":"Completed the dual-arm hepatic lipid model by showing GPR146 controls HDL via ERK-independent post-translational upregulation of SR-B1, and dissected an adipose program of Gαq-PKC-AKT adipogenesis and ERK-driven lipolysis that feeds hepatic steatosis.","evidence":"Whole-body, liver-specific, and adipose-specific conditional knockout mice; primary hepatocyte SR-B1 protein/mRNA and HDL uptake assays; MEK inhibitor; diet-induced obesity and FFA flux measurements","pmids":["41271608","41775759"],"confidence":"High","gaps":["Post-translational mechanism stabilizing SR-B1 not identified","How one receptor selects Gαq vs Gαs vs ERK outputs across tissues unknown","Upstream ligand for adipose and hepatic signaling unidentified"]},{"year":null,"claim":"The endogenous activating ligand of GPR146 and the molecular basis for its tissue-specific selection among Gαs, Gαq, and ERK signaling outputs remain unidentified.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No validated endogenous ligand established in the corpus","No structural model of receptor-effector coupling","Mechanism of bias toward different G-proteins across tissues unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[6,7]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1,6]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[6,7]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[0,8]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[3]}],"complexes":[],"partners":[],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q96CH1","full_name":"G-protein coupled receptor 146","aliases":["G-protein coupled receptor PGR8"],"length_aa":333,"mass_kda":36.6,"function":"G-protein coupled receptor required for the regulation of plasma cholesterol levels (PubMed:31778654, PubMed:38503280). Receptor for CHLSN, a gut derived hormone which mediates an inhibitory effect of intestinal cholesterol absorption on hepatic cholesterol synthesis. Cholesin-binding exerts an antagonistic effect by inhibiting PKA signaling and suppressing SREBF2-controlled cholesterol in the liver (PubMed:38503280)","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q96CH1/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/GPR146","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/GPR146","total_profiled":1310},"omim":[{"mim_id":"621174","title":"CHOLESIN; CHLSN","url":"https://www.omim.org/entry/621174"},{"mim_id":"621173","title":"G PROTEIN-COUPLED RECEPTOR 146; GPR146","url":"https://www.omim.org/entry/621173"},{"mim_id":"613022","title":"OXOGLUTARATE DEHYDROGENASE; OGDH","url":"https://www.omim.org/entry/613022"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"adipose 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against Hypercholesterolemia and Atherosclerosis.","date":"2019","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/31778654","citation_count":81,"is_preprint":false},{"pmid":"23759446","id":"PMC_23759446","title":"Evidence for an interaction between proinsulin C-peptide and GPR146.","date":"2013","source":"The Journal of endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/23759446","citation_count":70,"is_preprint":false},{"pmid":"27306986","id":"PMC_27306986","title":"Targeting orphan G protein-coupled receptors for the treatment of diabetes and its complications: C-peptide and GPR146.","date":"2016","source":"Journal of internal medicine","url":"https://pubmed.ncbi.nlm.nih.gov/27306986","citation_count":24,"is_preprint":false},{"pmid":"36638952","id":"PMC_36638952","title":"Hypoxia activates GPR146 which participates in pulmonary vascular remodeling by promoting pyroptosis of pulmonary artery endothelial cells.","date":"2023","source":"European journal of 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between proinsulin C-peptide and GPR146.","date":"2013","source":"The Journal of endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/23980258","citation_count":12,"is_preprint":false},{"pmid":"36047410","id":"PMC_36047410","title":"Variants in the GPR146 Gene Are Associated With a Favorable Cardiometabolic Risk Profile.","date":"2022","source":"Arteriosclerosis, thrombosis, and vascular biology","url":"https://pubmed.ncbi.nlm.nih.gov/36047410","citation_count":10,"is_preprint":false},{"pmid":"40636956","id":"PMC_40636956","title":"GPR146 Facilitates Blood Pressure Elevation and Vascular Remodeling via PIEZO1.","date":"2025","source":"Circulation research","url":"https://pubmed.ncbi.nlm.nih.gov/40636956","citation_count":6,"is_preprint":false},{"pmid":"37926274","id":"PMC_37926274","title":"GPR146 regulates pulmonary vascular remodeling by promoting pulmonary artery smooth muscle cell proliferation through 5-lipoxygenase.","date":"2023","source":"European journal of 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decreases plasma levels of HDL cholesterol via post-translational up-regulation of SR-B1 protein levels.","date":"2026","source":"Cardiovascular research","url":"https://pubmed.ncbi.nlm.nih.gov/41271608","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.04.07.25325355","title":"Hierarchical representation learning of preeclampsia interactome connecting endometrial maturation, placentation, chorioamnionitis, and HELLP syndrome","date":"2025-04-07","source":"bioRxiv","url":"https://doi.org/10.1101/2025.04.07.25325355","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":11534,"output_tokens":3028,"usd":0.040011,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10495,"output_tokens":3500,"usd":0.069987,"stage2_stop_reason":"end_turn"},"total_usd":0.109998,"stage1_batch_id":"msgbatch_01DUPACZi7AAWwuZiUjseQF4","stage2_batch_id":"msgbatch_018yt7chE3f48PEFtDwtj6AE","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2019,\n      \"finding\": \"GPR146 promotes activity of hepatic SREBP2 through activation of the ERK signaling pathway, thereby regulating hepatic VLDL secretion and circulating LDL-C and triglyceride levels. GPR146 deficiency reduces plasma cholesterol and reduces aortic atherosclerotic lesions in LDLR-deficient mice.\",\n      \"method\": \"Genetic knockout mice (global and hepatic), in vivo lipid measurements, ERK/SREBP2 pathway analysis\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean KO with defined cellular phenotype, ERK/SREBP2 pathway placement, replicated in multiple mouse models including LDLR-deficient background\",\n      \"pmids\": [\"31778654\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Knockdown of GPR146 blocked C-peptide-induced cFos expression in KATOIII cells; stimulation with C-peptide caused internalization of GPR146 and punctate colocalization on KATOIII cell membranes, indicating GPR146 is part of the C-peptide signaling complex.\",\n      \"method\": \"siRNA knockdown, cFos reporter assay, fluorescence colocalization/internalization microscopy\",\n      \"journal\": \"The Journal of endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — two orthogonal methods (knockdown + colocalization/internalization), single lab, but no direct binding assay\",\n      \"pmids\": [\"23759446\", \"23980258\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Neither dynamic mass redistribution nor GPCR β-arrestin assays revealed any significant intracellular response to C-peptide in CHO-K1 cells expressing human GPR146 at concentrations up to 33 µM, and no internalization of C-peptide was observed by fluorescence microscopy. These results do NOT support GPR146 as the receptor for C-peptide.\",\n      \"method\": \"Dynamic mass redistribution assay, GPCR β-arrestin assay, fluorescence confocal microscopy in CHO-K1 cells expressing human GPR146\",\n      \"journal\": \"Bioorganic & medicinal chemistry letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal functional assays (DMR, β-arrestin, microscopy) in a heterologous expression system; NEGATIVE result contradicting prior claims\",\n      \"pmids\": [\"32354568\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"GPR146 expression is induced by IFN-β and IFN-γ via a STAT1-dependent signaling pathway. Overexpression of GPR146 protects host cells from vesicular stomatitis virus and Newcastle disease virus infection. Virus-activated IRF3 signaling represses GPR146 expression through HES1-mediated transcriptional activity, establishing a dynamic equilibrium between pro-viral and antiviral states.\",\n      \"method\": \"IFN stimulation assays, overexpression and Gpr146-knockout cells/mice, VSV and NDV infection models, IRF3/HES1 transcriptional activity assays\",\n      \"journal\": \"Immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO and overexpression with defined phenotypic readouts, pathway placement via IRF3/HES1, single lab\",\n      \"pmids\": [\"28464285\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"GPR146 promotes pyroptosis of pulmonary artery endothelial cells through the NLRP3/caspase-1 signaling axis, increasing IL-1β, IL-6, and IL-18; silencing GPR146 inhibited hypoxia-induced pyroptosis-related protein expression and inflammatory cytokine production.\",\n      \"method\": \"siRNA knockdown, GPR146 overexpression, western blotting, real-time PCR, ROS detection, LDH release assays, immunofluorescence in PAECs; in vivo SuHx rat PH model\",\n      \"journal\": \"European journal of pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function and gain-of-function with defined molecular pathway (NLRP3/caspase-1), multiple methods, single lab\",\n      \"pmids\": [\"36638952\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"GPR146 promotes pulmonary artery smooth muscle cell proliferation through upregulation of 5-lipoxygenase (5-LO); GPR146 knockdown or siRNA intervention reversed hypoxia-induced 5-LO expression and attenuated pulmonary vascular remodeling in a mouse PH model.\",\n      \"method\": \"siRNA knockdown, GPR146 overexpression, immunohistochemistry, in vivo mouse PH model (SuHx), western blotting, PASMC proliferation assays\",\n      \"journal\": \"European journal of pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function and gain-of-function with defined cellular phenotype and pathway component (5-LO), single lab\",\n      \"pmids\": [\"37926274\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"GPR146 is a Gαs-coupled GPCR that activates the cAMP-CREB1 signaling cascade in vascular smooth muscle cells; GPR146 upregulates PIEZO1 expression by enhancing CREB1 binding to the PIEZO1 promoter. Deletion of Piezo1 in SMCs blocked GPR146-induced blood pressure elevation and vascular dysfunction. GPR146 neutralization antibody injection alleviates angiotensin II-induced hypertension.\",\n      \"method\": \"Proximity ligation assay, bioluminescence resonance energy transfer (BRET), SMC-specific knockin/knockout mice, Piezo1 SMC-specific KO mice, ChIP-like CREB1 promoter binding analysis, ex vivo HP loading system, neutralization antibody injection\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — BRET for Gαs coupling, proximity ligation assay, multiple genetic models (global KO, SMC-specific KI/KO, Piezo1 SMC-KO), in vitro and in vivo, multiple orthogonal methods\",\n      \"pmids\": [\"40636956\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"GPR146 in adipose tissue promotes adipogenesis in preadipocytes via Gαq-PKC-AKT signaling, increasing lipid storage capacity, and enhances lipolysis in mature adipocytes through ERK activation, elevating circulating free fatty acids (FFA) that drive hepatic triglyceride accumulation. Adipose-specific (but not liver-specific) GPR146 deletion reduces hepatic lipid accumulation.\",\n      \"method\": \"Constitutive and adipose-specific / liver-specific conditional knockout mice, diet-induced obesity model, FFA flux measurements, signaling pathway assays (PKC, AKT, ERK)\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — tissue-specific conditional KO dissecting adipose vs liver contributions, multiple signaling pathways validated, multiple orthogonal approaches in single study\",\n      \"pmids\": [\"41775759\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Loss of GPR146 reduces HDL cholesterol via post-translational upregulation of hepatic SR-B1 protein (without changes in Scarb1 mRNA), increasing cell-surface SR-B1 and SR-B1-mediated selective uptake of HDL lipid and protein. This mechanism appears independent of ERK signaling.\",\n      \"method\": \"Whole-body and liver-specific Gpr146 KO mice, MEK1 inhibitor treatment, SR-B1 protein/mRNA measurement in primary hepatocytes, HDL uptake assays, human cohort genetic variant analysis\",\n      \"journal\": \"Cardiovascular research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple KO models (whole-body and liver-specific), in vitro primary hepatocyte assays, MEK inhibitor to probe ERK independence, mechanistic pathway placement (SR-B1 post-translational regulation)\",\n      \"pmids\": [\"41271608\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Silencing Gpr146 in mouse liver significantly reduced total blood cholesterol while markedly upregulating liver Cyp7a1 expression during 2-h fasting, independently of FXR-dependent and FXR-independent cytokine pathways, establishing CYP7A1 as a target gene of GPR146 in cholesterol metabolism.\",\n      \"method\": \"In vivo Gpr146 silencing (liver), Cyp7a1 expression measurement, cholesterol measurement, FXR pathway analysis in cultured hepatocytes and in vivo\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo loss-of-function with pathway placement (CYP7A1 regulation independent of FXR), single lab, limited mechanistic detail in abstract\",\n      \"pmids\": [\"40414012\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"The GPR146 P61L knock-in mouse model (ortholog of human P62L variant) showed reduced plasma cholesterol due to reduced HDL cholesterol, without changes in VLDL secretion, ERK1/2 signaling, Srebp2 mRNA, or hepatocyte apoB secretion, indicating this variant confers loss of GPR146 function affecting HDL but not the ERK/SREBP2/VLDL axis.\",\n      \"method\": \"Knock-in mouse model (P61L), plasma cholesterol measurement, VLDL secretion assay, ERK1/2 phosphorylation, Srebp2 mRNA, primary hepatocyte apoB secretion\",\n      \"journal\": \"Atherosclerosis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knock-in mouse model with multiple pathway readouts, single lab, partially negative mechanistic findings informative for pathway dissection\",\n      \"pmids\": [\"40120432\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"GPR146 is an orphan GPCR that signals through at least two G-protein-coupled pathways — Gαs/cAMP-CREB1 in vascular smooth muscle cells (upregulating PIEZO1 to drive hypertension) and Gαq-PKC-AKT/ERK in adipocytes (promoting adipogenesis and lipolysis) — while in hepatocytes it activates ERK-SREBP2 signaling to suppress CYP7A1 and stimulate VLDL secretion, and independently regulates HDL cholesterol via post-translational upregulation of SR-B1; additionally, GPR146 expression is induced by interferons via STAT1 and exerts antiviral activity that is in turn suppressed by IRF3/HES1 signaling.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"GPR146 is an orphan G-protein-coupled receptor that functions as a central regulator of systemic lipid metabolism and vascular physiology through tissue-specific, multi-pathway signaling [#0, #6, #7]. In hepatocytes it drives ERK-dependent activation of SREBP2 to promote VLDL secretion and elevate circulating LDL-C and triglycerides, and its loss reduces plasma cholesterol and atherosclerotic burden in LDLR-deficient mice [#0]; in parallel and independently of ERK, GPR146 loss lowers HDL cholesterol via post-translational upregulation of hepatic SR-B1 protein, increasing cell-surface SR-B1 and selective HDL uptake [#8], and represses CYP7A1 to constrain bile acid synthesis [#9]. The receptor signals through distinct G-protein arms in different tissues: a G\\u03b1s\\u2013cAMP\\u2013CREB1 cascade in vascular smooth muscle cells that transcriptionally upregulates PIEZO1 to drive angiotensin II\\u2013induced hypertension and vascular dysfunction [#6], and a G\\u03b1q\\u2013PKC\\u2013AKT arm in preadipocytes promoting adipogenesis alongside an ERK arm in mature adipocytes enhancing lipolysis and free fatty acid efflux that fuels hepatic triglyceride accumulation [#7]. Beyond metabolism, GPR146 expression is induced by type I and II interferons through STAT1 and confers antiviral protection that is in turn repressed by virus-activated IRF3/HES1 signaling [#3], and it promotes NLRP3/caspase-1\\u2013dependent pyroptosis and 5-lipoxygenase\\u2013driven smooth muscle proliferation in pulmonary vascular remodeling [#4, #5]. A human-orthologous P61L loss-of-function variant selectively impairs the HDL axis without affecting VLDL secretion or ERK/SREBP2 signaling, confirming that GPR146's HDL and VLDL functions are mechanistically separable [#10]. Whether GPR146 has an endogenous peptide ligand remains unresolved; an early report implicated it in C-peptide signaling [#1], but heterologous reconstitution assays failed to detect any C-peptide response [#2].\",\n  \"teleology\": [\n    {\n      \"year\": 2013,\n      \"claim\": \"Addressed whether GPR146 transduces a defined extracellular signal by testing its requirement for C-peptide-induced gene expression, the first functional assignment for this orphan receptor.\",\n      \"evidence\": \"siRNA knockdown with cFos reporter and internalization/colocalization microscopy in KATOIII cells\",\n      \"pmids\": [\"23759446\", \"23980258\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No direct ligand-receptor binding assay\", \"Single cell line and single lab\", \"Does not identify the coupled G-protein or downstream cascade\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Established GPR146 as an interferon-inducible, STAT1-dependent gene with cell-autonomous antiviral activity, placing it in an innate immune regulatory circuit balanced by IRF3/HES1 repression.\",\n      \"evidence\": \"IFN stimulation, overexpression and knockout cells/mice, VSV and NDV infection models, IRF3/HES1 transcriptional assays\",\n      \"pmids\": [\"28464285\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mechanism of antiviral protection downstream of GPR146 unknown\", \"No G-protein coupling defined for this role\", \"Single lab\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined GPR146's first major metabolic role by linking it to hepatic ERK-SREBP2 signaling controlling VLDL secretion, establishing it as a determinant of circulating LDL-C and atherosclerosis risk.\",\n      \"evidence\": \"Global and hepatic knockout mice, in vivo lipid profiling, ERK/SREBP2 pathway analysis in LDLR-deficient background\",\n      \"pmids\": [\"31778654\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Endogenous ligand driving hepatic GPR146 activity unidentified\", \"G-protein coupling not directly resolved here\", \"Mechanism connecting receptor to ERK not defined\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Directly challenged the C-peptide receptor hypothesis by testing for signaling responses in a defined heterologous system, leaving the receptor functionally orphan.\",\n      \"evidence\": \"Dynamic mass redistribution, \\u03b2-arrestin recruitment assays, and fluorescence microscopy in CHO-K1 cells expressing human GPR146\",\n      \"pmids\": [\"32354568\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Negative result; cannot exclude ligand activity requiring accessory factors absent in CHO-K1\", \"Does not identify the true endogenous ligand\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Extended GPR146 into pulmonary vascular pathology by linking it to NLRP3/caspase-1 pyroptosis and 5-LO-driven smooth muscle proliferation, identifying it as a driver of hypoxia-induced vascular remodeling.\",\n      \"evidence\": \"siRNA knockdown and overexpression with pyroptosis and proliferation readouts in PAECs/PASMCs plus in vivo SuHx rat/mouse PH models\",\n      \"pmids\": [\"36638952\", \"37926274\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"G-protein coupling and proximal signaling for these effects undefined\", \"Connection to GPR146's metabolic signaling roles unclear\", \"Single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Resolved a specific G-protein coupling and downstream transcriptional target by showing GPR146 is G\\u03b1s-coupled, drives cAMP-CREB1 signaling, and transcriptionally upregulates PIEZO1 to cause hypertension, providing a mechanistic and therapeutic handle.\",\n      \"evidence\": \"BRET for G\\u03b1s coupling, proximity ligation assay, SMC-specific and Piezo1 SMC-specific knockout/knockin mice, CREB1 promoter binding, neutralization antibody in vivo\",\n      \"pmids\": [\"40636956\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Activating ligand for vascular GPR146 unknown\", \"Whether G\\u03b1s coupling operates in other tissues not addressed\", \"Relationship to the hepatic ERK arm unresolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Distinguished GPR146's HDL-regulatory function from its VLDL/ERK axis by showing it represses CYP7A1 and, via a human-orthologous P61L variant, selectively impairs HDL without affecting VLDL or ERK/SREBP2 signaling.\",\n      \"evidence\": \"In vivo liver Gpr146 silencing with Cyp7a1/cholesterol measurement and FXR pathway analysis; P61L knock-in mouse with VLDL, ERK, Srebp2, and apoB readouts\",\n      \"pmids\": [\"40414012\", \"40120432\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking GPR146 to CYP7A1 repression undefined\", \"How a single missense variant selectively disrupts one arm unexplained\", \"FXR-independent pathway to CYP7A1 not fully mapped\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Completed the dual-arm hepatic lipid model by showing GPR146 controls HDL via ERK-independent post-translational upregulation of SR-B1, and dissected an adipose program of G\\u03b1q-PKC-AKT adipogenesis and ERK-driven lipolysis that feeds hepatic steatosis.\",\n      \"evidence\": \"Whole-body, liver-specific, and adipose-specific conditional knockout mice; primary hepatocyte SR-B1 protein/mRNA and HDL uptake assays; MEK inhibitor; diet-induced obesity and FFA flux measurements\",\n      \"pmids\": [\"41271608\", \"41775759\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Post-translational mechanism stabilizing SR-B1 not identified\", \"How one receptor selects G\\u03b1q vs G\\u03b1s vs ERK outputs across tissues unknown\", \"Upstream ligand for adipose and hepatic signaling unidentified\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The endogenous activating ligand of GPR146 and the molecular basis for its tissue-specific selection among G\\u03b1s, G\\u03b1q, and ERK signaling outputs remain unidentified.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No validated endogenous ligand established in the corpus\", \"No structural model of receptor-effector coupling\", \"Mechanism of bias toward different G-proteins across tissues unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [6, 7]},\n      {\"term_id\": \"GO:0004930\", \"supporting_discovery_ids\": [6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [6, 7]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [0, 8]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"complexes\": [],\n    \"partners\": [],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":6,"faith_pct":83.33333333333333}}