Abstract 15260: Function of G Protein-Coupled Receptor 146 in Regulation of Blood Lipid Levels
Background and Hypothesis: Cardiovascular diseases (CVDs) remain the leading cause of death globally. Abundant data indicate that cholesterol-carrying low-density lipoproteins (LDLs) are essential causative agent for CVDs. Human genetics have recently established triglyceride (TG)-rich lipoproteins, such as very-low density lipoproteins (VLDLs), as likely to be pro-atherogenic and causal in the development of CVDs. Thus, novel strategies to lower circulating LDL/TG levels and reduce CVDs risks are needed. GPR146, encoding an orphan G-protein-coupled receptor, was discovered in a genome-wide association study (GWAS) for blood lipid levels that variants near this gene are associated with levels of total cholesterol. Considering the broad consensus that GPCRs are among the most heavily investigated drug targets in the pharmaceutical industry, it is tempting to speculate that modulators of GPR146 may be developed to lower blood cholesterol levels and reduce the risk of CVDs.
Methods and Results: To elucidate the molecular function of Gpr146 in regulation of blood lipid levels, we generated whole-body knockout (KO) and floxed mouse models by using CRISPR/Cas9 system. Functional assays showed that there are 20-25% reduction of TC, 20-40% reduction of TG and 15-30% reduction of free-fatty acid in KO mice compared to wild-type (WT) littermates. FPLC analysis revealed that lack of Gpr146 led to ~45% reduction of circulating LDL in female and ~36% reduction in male mice. Furthermore, VLDL production rate was significantly reduced in Gpr146-deficient mice, suggesting a potential role of Gpr146 in regulation of hepatic VLDL secretion. Consistently, knockout of GPR146 in human embryonic stem cell-derived hepatocyte-like cells and hepatoma Huh7 cells also resulted in substantially decreased VLDL secretion.
Conclusion: Our data demonstrated that Gpr146 plays an important role in regulating blood lipid levels, and lack of Gpr146 in mice resulted in substantially reduced circulating LDL and TG levels. Thus targeting GPR146 might be a novel therapeutic strategy to lower blood LDL/TG levels and reduce the risk of CVDs.
Author Disclosures: H. Yu: None. L.M. Ferreira: None. F. Xia: None. T. Chen: None. S. Kathiresan: None. C.A. Cowan: None.
- © 2016 by American Heart Association, Inc.