Orphan GPR146: an alternative therapeutic pathway to achieve cholesterol homeostasis?

Brendan P Wilkins; Angela M Finch; Yan Wang; Nicola J Smith

doi:10.1016/j.tem.2022.04.008

Orphan GPR146: an alternative therapeutic pathway to achieve cholesterol homeostasis?

Trends Endocrinol Metab. 2022 Jul;33(7):481-492. doi: 10.1016/j.tem.2022.04.008. Epub 2022 May 10.

Authors

Brendan P Wilkins¹, Angela M Finch², Yan Wang³, Nicola J Smith⁴

Affiliations

¹ Orphan 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.
² Molecular Pharmacology Drug Design, School of Medical Sciences, University of New South Wales, Sydney, NSW, Australia.
³ Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan, China.
⁴ Orphan 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. Electronic address: nicola.smith@unsw.edu.au.

PMID: 35550855
DOI: 10.1016/j.tem.2022.04.008

Abstract

Atherosclerosis predisposes to myriad cardiovascular complications, including myocardial infarction and stroke. Statins have revolutionised cholesterol management but they do not work for all patients, particularly those with familial hypercholesterolaemia (FH). Genome-wide association studies have linked SNPs at orphan G protein-coupled receptor 146 (GPR146) to human atherosclerosis but how GPR146 influences serum cholesterol homeostasis was only recently described. Gpr146 deletion in mice reduces serum cholesterol and atherosclerotic plaque burden, confirming GPR146 as a potential therapeutic target for managing circulating cholesterol. Critically, this effect was independent of the low-density lipoprotein receptor. While still an orphan, the activation of GPR146 by serum suggests identification of its endogenous ligand is tantalisingly close. Herein, we discuss the evidence for GPR146 inhibition as a treatment for atherosclerosis.

Keywords: G protein-coupled receptor; GPR146; atherosclerosis; cholesterol; familial hypercholesterolaemia; orphan.

Publication types

Review
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Atherosclerosis* / drug therapy
Atherosclerosis* / genetics
Cholesterol
Genome-Wide Association Study*
Homeostasis / genetics
Humans
Mice
Receptors, G-Protein-Coupled / genetics
Receptors, G-Protein-Coupled / metabolism

Substances

Receptors, G-Protein-Coupled
Cholesterol