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A Familial Hypercholesterolemia Human Liver Chimeric Mouse Model Using Induced Pluripotent Stem Cell-derived Hepatocytes
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Orphan GPR146: an alternative therapeutic pathway to achieve cholesterol homeostasis?

Brendan P Wilkins1, Angela M Finch2, Yan Wang3

  • 1Orphan Receptor Pharmacology Laboratory, School of Medical Sciences, University of New South Wales, Sydney, NSW, Australia; Molecular Pharmacology Drug Design, School of Medical Sciences, University of New South Wales, Sydney, NSW, Australia.

Trends in Endocrinology and Metabolism: TEM
|May 13, 2022
PubMed

Insights

Targeting G protein-coupled receptor 146 (GPR146) may reduce atherosclerosis and lower cholesterol. GPR146 inhibition offers a promising therapeutic strategy for cardiovascular complications, independent of LDL receptors.

Area of Science:

  • Cardiovascular Science
  • Genetics
  • Pharmacology

Background:

  • Atherosclerosis leads to heart attack and stroke, with statins offering incomplete treatment, especially for familial hypercholesterolemia (FH).
  • Genome-wide association studies identified single nucleotide polymorphisms (SNPs) at G protein-coupled receptor 146 (GPR146) associated with human atherosclerosis.
  • The precise role of GPR146 in serum cholesterol homeostasis remained largely unelucidated until recent discoveries.

Purpose of the Study:

  • To investigate the role of GPR146 in cholesterol regulation and atherosclerosis.
  • To evaluate the therapeutic potential of targeting GPR146 for cardiovascular disease management.

Main Methods:

  • Utilized Gpr146 knockout mouse models to assess serum cholesterol levels and atherosclerotic plaque burden.
  • Examined the effect of Gpr146 deletion independently of the low-density lipoprotein receptor pathway.

Main Results:

  • Gpr146 deletion in mice significantly reduced serum cholesterol levels.
  • Atherosclerotic plaque burden was decreased in Gpr146-deficient mice.
  • The cholesterol-lowering effect of Gpr146 deletion was independent of the low-density lipoprotein receptor.

Conclusions:

  • GPR146 plays a crucial role in regulating serum cholesterol and atherosclerosis.
  • Inhibition of GPR146 presents a potential novel therapeutic strategy for managing atherosclerosis and associated cardiovascular risks.
  • Further research into GPR146's endogenous ligand may accelerate therapeutic development.

Keywords:
G protein-coupled receptorGPR146atherosclerosischolesterolfamilial hypercholesterolaemiaorphan

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