Functional Insights Into Novel Regulators of Plasma Lipids: STAP1 and GPR146

Elucidating the mechanisms how novel genes regulate plasma lipids promises to expand the current understanding of the origins of dyslipidemias and atherosclerotic cardiovascular diseases (ASCVD). New insights can also offer possibilities to develop additional treatment strategies to alleviate ASCVD, currently the largest cause of death worldwide. This thesis offers insights into how STAP1 (Signal Transducing Adaptor Family Member 1) and GPR146 (G-protein coupled receptor 146) regulate plasma lipids. Our functional studies into STAP1, a previously proposed Familial Hypercholesterolemia (FH) gene, show that STAP1 does not regulate LDL-cholesterol in mice or humans. Consequently, we have proposed to delist STAP1 as an FH gene. For GPR146, we studied common and rare variants and their associated plasma lipid profiles in large population cohorts. Our findings support a novel role for GPR146 in human hypolipidemia, with carriers of GPR146 loss-of-function variants exhibiting an overall beneficial cardiometabolic risk profile. It remains to be demonstrated whether genetic or pharmaceutical inhibition of GPR146 confers atheroprotection in humans. We also found that GPR146 expression is negatively associated with SR-B1 protein levels. However, our experimental findings indicated that SR-B1 probably is not the causal driver of this phenotype. In conclusion, our studies suggest that hepatic GPR146 inactivation might constitute a potential therapeutic strategy to reduce plasma cholesterol and atherosclerosis independently of the LDLR and SR-B1. However, the current biological understanding of GPR146 functions and interactions, hepatic and extrahepatic, remains incomplete; therefore, additional efforts to clarify its true potential as a drug target are required.