Year: 2019
Type: article
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.
Source: Cell
Institutions: Beth Israel Deaconess Medical Center, Harvard University, Harvard Stem Cell Institute, Centre National de la Recherche Scientifique, University Medical Center Groningen, Inserm, University of Groningen, Institut du Thorax, Massachusetts General Hospital, Broad Institute, Massachusetts Institute of Technology
Language: English
Subfield: Biochemistry
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $5,200
Awards: Developing the differentiation methods from pluripotent stem cells to glomerular endothelial cells for diabetic research, Systematic cell-based functional screening for LDL and triglyceride genes, Genetic mechanisms of metformin's pro-longevity and anti-cancer effects, Isogenic Human Pluripotent Stem Cell-Based Models of Human Disease Mutations, G3796613390, TSE Systems Phenomaster Indirect Calorimetry Apparatus, G9000029259, Boston Area Nutrition Obesity Research Center (NORC)
OpenAlex ID: W2990248610