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Cell. 2019 Nov 27;179(6):1276-1288.e14. doi: 10.1016/j.cell.2019.10.034.

GPR146 Deficiency Protects against Hypercholesterolemia and Atherosclerosis.

Author information

1
Department of Medicine, Division of Cardiology, Beth Israel Deaconess Medical Center (BIDMC), Harvard Medical School, Boston, MA 02215, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA. Electronic address: hyu3@bidmc.harvard.edu.
2
Department of Pediatrics, Section Molecular Genetics, University of Groningen, University Medical Center, Antonius Deusinglaan 1, 9713 AV, Groningen, the Netherlands; Institute of Thorax, INSERM, CNRS, UNIV Nantes, Nantes, 44007, France.
3
Department of Medicine, Division of Cardiology, Beth Israel Deaconess Medical Center (BIDMC), Harvard Medical School, Boston, MA 02215, USA.
4
Department of Medicine, Division of Cardiology, Beth Israel Deaconess Medical Center (BIDMC), Harvard Medical School, Boston, MA 02215, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA.
5
Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.
6
Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA 02138, USA.
7
Department of Pediatrics, Section Molecular Genetics, University of Groningen, University Medical Center, Antonius Deusinglaan 1, 9713 AV, Groningen, the Netherlands.
8
Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA 02138, USA.
9
Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.
10
Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Cardiovascular Disease Initiative of the Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
11
Department of Medicine, Division of Cardiology, Beth Israel Deaconess Medical Center (BIDMC), Harvard Medical School, Boston, MA 02215, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA. Electronic address: ccowan@bidmc.harvard.edu.

Abstract

Although human genetic studies have implicated many susceptible genes associated with plasma lipid levels, their physiological and molecular functions are not fully characterized. Here we demonstrate that orphan G protein-coupled receptor 146 (GPR146) promotes activity of hepatic sterol regulatory element binding protein 2 (SREBP2) through activation of the extracellular signal-regulated kinase (ERK) signaling pathway, thereby regulating hepatic very low-density lipoprotein (VLDL) secretion, and subsequently circulating low-density lipoprotein cholesterol (LDL-C) and triglycerides (TG) levels. Remarkably, GPR146 deficiency reduces plasma cholesterol levels substantially in both wild-type and LDL receptor (LDLR)-deficient mice. Finally, aortic atherosclerotic lesions are reduced by 90% and 70%, respectively, in male and female LDLR-deficient mice upon GPR146 depletion. Taken together, these findings outline a regulatory role for the GPR146/ERK axis in systemic cholesterol metabolism and suggest that GPR146 inhibition could be an effective strategy to reduce plasma cholesterol levels and atherosclerosis.

KEYWORDS:

ERK1/2; SREBP2 pathway; atherosclerosis; hypercholesterolemia; orphan G protein-coupled receptor 146

PMID:
31778654
PMCID:
PMC6889877
[Available on 2020-11-27]
DOI:
10.1016/j.cell.2019.10.034

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