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Updated: Jul 1, 2025

Genetically-encoded Molecular Probes to Study G Protein-coupled Receptors
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G protein-coupled receptor 146: new insights from genetics and model systems

Umesh Tharehalli1, Antoine Rimbert2

  • 1Department of Pediatrics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.

Current Opinion in Lipidology
|March 11, 2024
PubMed
Abstract

Insights

G protein-coupled receptor 146 (GPR146) shows promise for treating high cholesterol and atherosclerosis. Research is exploring its genetic links, functions, and potential as a novel therapeutic target for cardiovascular diseases.

Area of Science:

  • Cardiovascular Science
  • Metabolic Research
  • Pharmacology

Background:

  • Atherosclerotic cardiovascular diseases remain a leading global cause of mortality.
  • Novel strategies are needed to manage dyslipidemias, particularly refractory cases or those with adverse effects.
  • G protein-coupled receptor 146 (GPR146) is identified as a potential therapeutic target for hypercholesterolemia and atherosclerosis.

Purpose of the Study:

  • To review current knowledge on GPR146, including genetic evidence and functional insights.
  • To summarize GPR146's implications for cardiometabolic health.
  • To highlight recent advancements in understanding GPR146's role in lipid regulation and beyond.

Main Methods:

  • Analysis of human genetic studies linking GPR146 variants to lipid levels and metabolic parameters.
  • Investigation of GPR146's role in adipocyte differentiation, lipolysis, and inflammation.
  • Review of ongoing efforts to deorphanize GPR146 and identify its natural ligand.

Main Results:

  • Human genetic data suggest a correlation between GPR146 variants and altered plasma lipid profiles.
  • GPR146 influences metabolic processes beyond lipid regulation, including adipogenesis and inflammatory pathways.
  • The identification of a potential ligand and downstream Gαi coupling pathways are under investigation.

Conclusions:

  • Understanding GPR146's genetic basis and extra-hepatic functions is critical for therapeutic development.
  • Further research into GPR146's natural ligand(s) and inhibitory effects is essential.
  • GPR146 represents a promising target for innovative treatments of hypercholesterolemia and atherosclerosis.

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