Increased plasma levels of cholesterol are a major risk factor for atherosclerotic cardiovascular disease. In the PhD research of Boyan Zhang, the role of GPR146, identified through genome-wide assocation, in regulating blood cholesterol levels was investigated. By analyzing large-scale human genetic data and using genetically modified mouse models, I found that individuals carrying rare, naturally occurring variants in GPR146 have lower blood cholesterol levels. To study whether this was due to a functional effect of one variant, we developed a knock-in mouse model which conclusively demonstrated reduced blood cholesterol levels.
In experimental mouse models, loss of GPR146 function results in a decrease in HDL cholesterol. This was shown to be driven by increased protein levels of hepatic SR-B1, a receptor responsible for HDL catabolism. This study reveals a new mechanism by which HDL cholesterol levels are regulated.
Additionally, we explored the therapeutic potential of combining the inhibiton of GPR146 with ANGPTL3, which is already targeted in the clinic to lower cholesterol. Dual inhibition resulted in greater reductions in blood cholesterol than inhibiting either gene alone which revealed potential of this strategy to treat familial hypercholesterolemia, a severe inherited disorder of cholesterol metabolism.
This work has revealed new insight into the role of GPR146 in lipid and lipoprotein metabolism that will help to explore its potential as a drug target to reduce plasma lipids and possibly cardiometabolic disease.
Boyan Zhang is part of MoHAD.
