GPR146

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).

1. 2013 Medium

   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

   PMID:23759446 PMID:23980258

   Open questions at the time

   • No direct ligand-receptor binding assay
   • Single cell line and single lab
   • Does not identify the coupled G-protein or downstream cascade
2. 2017 Medium

   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

   PMID:28464285

   Open questions at the time

   • Molecular mechanism of antiviral protection downstream of GPR146 unknown
   • No G-protein coupling defined for this role
   • Single lab
3. 2019 High

   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

   PMID:31778654

   Open questions at the time

   • Endogenous ligand driving hepatic GPR146 activity unidentified
   • G-protein coupling not directly resolved here
   • Mechanism connecting receptor to ERK not defined
4. 2020 Medium

   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

   PMID:32354568

   Open questions at the time

   • Negative result; cannot exclude ligand activity requiring accessory factors absent in CHO-K1
   • Does not identify the true endogenous ligand
5. 2023 Medium

   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

   PMID:36638952 PMID:37926274

   Open questions at the time

   • G-protein coupling and proximal signaling for these effects undefined
   • Connection to GPR146's metabolic signaling roles unclear
   • Single lab
6. 2025 High

   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

   PMID:40636956

   Open questions at the time

   • Activating ligand for vascular GPR146 unknown
   • Whether Gαs coupling operates in other tissues not addressed
   • Relationship to the hepatic ERK arm unresolved
7. 2025 Medium

   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

   PMID:40120432 PMID:40414012

   Open questions at the time

   • 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
8. 2026 High

   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

   PMID:41271608 PMID:41775759

   Open questions at the time

   • 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

• The endogenous activating ligand of GPR146 and the molecular basis for its tissue-specific selection among Gαs, Gαq, and ERK signaling outputs remain unidentified.
• 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