Presenter of 1 Presentation
O078 - PREVENTION OF ATHEROSCLEROSIS AND HEPATIC STEATOSIS BY COMBINED, LIVER-SPECIFIC DELETION OF GPR146 AND ANGPTL3 (ID 205)
Abstract
Background and Aims
GWAS identified GPR146 as a novel lipid gene. Subsequent studies in mice validated Gpr146 deletion reduces circulating lipids and is atheroprotective, independent of LDL-R. Whereas, Mendelian randomisation studies highlight that GPR146 is causally linked with plasma levels of ALT, AST, and CRP. Several lines of evidence point to a role for ANGPTL3 mediating the effects of GPR146.
Methods
We used somatic gene editing to generate liver-specific deletions of Gpr146, Angptl3, and Gpr146/Angptl3. The experimental groups were fed with a regular chow and 60% kcal HFD, independently. Plasma levels of total cholesterol (TC), triglycerides (TG), ALT and AST and hepatic lipids were measured. Hepatic and aortic histology, RNAseq, qRT-PCR, western blotting and targeted proteomics were used to characterise the mouse model.
Results
Somatic gene editing showed 85% reductions in the targeted genes at the mRNA and protein levels. Compared to chow-fed controls, plasma TG was reduced by 28%, 58% and 75%, whereas plasma TC was reduced by 21%, 37% and 58% and hepatic lipid levels were reduced by 21%, 26%, and 46% in Gpr146, Angptl3 and Gpr146/Angptl3 deleted mice, respectively. Body and liver weights of the experimental groups remained unchanged.
Conclusions
This study shows that function of Gpr146 is independent of Angptl3, and combined deletion of both genes has a favourable outcome by reducing circulating and hepatic lipids in an additive manner. These findings indicate the therapeutic potential of targeting Gpr146 and Angptl3 to protect against atherosclerosis and fatty liver disease.