2. Academic Validation
  3. Loss of GPR146 decreases plasma levels of HDL cholesterol via post-translational upregulation of SR-B1 protein levels

Loss of GPR146 decreases plasma levels of HDL cholesterol via post-translational upregulation of SR-B1 protein levels

  • Cardiovasc Res. 2025 Nov 21:cvaf254. doi: 10.1093/cvr/cvaf254.
Boyan Zhang 1,  Natalia Loaiza 1,  Antoine Rimbert 2,  Federico Oldoni 1,  Lisanne L Blauw 3,  Patrick C N Rensen 3,  Laurent O Martinez 4,  Jerome Robert 5,  Arnold von Eckardstein 5,  Justina Clarinda Wolters 1,  Nicolette Huijkman 1,  Niels Kloosterhuis 1,  Marieke Smit 1,  Bart van de Sluis 1,  Jan Albert Kuivenhoven 1,  Umesh Tharehalli 1
Affiliations

Affiliations

  • 1 Department of Pediatrics, University Medical Center Groningen, University of Groningen, the Netherlands.
  • 2 Nantes Université, CNRS, INSERM, l'institut du thorax, F-44000 Nantes, France.
  • 3 Department of Medicine, Division of Endocrinology, and Einthoven Laboratory for Experimental Medicine, Leiden University Medical Center, Leiden, the Netherlands.
  • 4 LiMitAging, Institute of Metabolic and Cardiovascular Diseases, I2MC UMR1297, IHU HealthAge, INSERM, University of Toulouse, Université Toulouse III - Paul Sabatier (UPS), Toulouse University Hospital (CHU Toulouse), Toulouse, France.
  • 5 University Hospital of Zurich, University of Zurich, Zurich, Switzerland.
PMID: 41271608 DOI: 10.1093/cvr/cvaf254
Abstract

Aims: In humans, reduced G-protein coupled receptor 146 (GPR146) expression is associated with reductions in both low-density lipoprotein (LDL) and high-density lipoprotein (HDL) Cholesterol. While the effects on LDL Cholesterol are mediated via the intracellular ERK/SREBP2 pathway, the mechanism explaining how GPR146 affects HDL Cholesterol levels remains to be unraveled.

Methods and results: Whole-body (Gpr146-/-) and liver-specific Gpr146 knockout (Gpr146 LKO) mice were used to explore changes in HDL metabolism. Wild-type mice were treated with MEK1 Inhibitor to block ERK. HDL uptake and post-translational modification of scavenger receptor class B1 (SR-B1) were studied in murine primary hepatocytes. Genetic variants in GPR146 and SCARB1 served as instruments to study HDL size and composition in human cohort studies. Studies in both Gpr146-/- and Gpr146 LKO mice revealed a 20% reduction in HDL Cholesterol and a concomitant 30% increase in hepatic SR-B1 protein (no changes in Scarb1 mRNA). This increase was driven by a 2.2-fold increase in cell-surface SR-B1 via a mechanism that appears independent of ERK. In vitro studies show that loss of GPR146 increases SR-B1-mediated selective uptake of HDL lipid and HDL protein. Consistently, carriers of a GPR146 variant associated with loss-of-function and carriers of SCARB1 gain-of-function variant share reductions in apoA-I, HDL particle size, HDL Cholesterol, and cholesteryl ester content compared to non-carriers.

Conclusions: This study suggests that loss of GPR146 reduces HDL Cholesterol via post-translational upregulation of hepatic SR-B1 via an intracellular pathway that remains to be resolved. These findings imply that GPR146 inhibition to treat hypercholesterolemia will not only lower plasma levels of LDL Cholesterol but also HDL Cholesterol.

Keywords

G protein-coupled receptor; GPR146; High-density lipoprotein; SR-B1.

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