Loss of GPR146 decreases plasma levels of HDL cholesterol via post-translational upregulation of SR-B1 protein levels

Abstract Aims In humans, reduced G-protein coupled receptor 146 (GPR146) expression is associated with reductions in both low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol. While the effects on LDL cholesterol are mediated via the intracellular ERK/SREBP2 pathway, the mechanism explaining how GPR146 affects HDL cholesterol levels remains to be unraveled. Methods and Results Whole-body (Gpr146-/-) and liver-specific Gpr146 knockout (Gpr146 LKO) mice were used to explore changes in HDL metabolism. Wild-type mice were treated with MEK1 inhibitor to block ERK. HDL uptake and post-translational modification of scavenger receptor class B1 (SR-B1) were studied in murine primary hepatocytes. Genetic variants in GPR146 and SCARB1 served as instruments to study HDL size and composition in human cohort studies. Studies in both Gpr146-/- and Gpr146 LKO mice revealed a 20% reduction in HDL cholesterol and a concomitant 30% increase in hepatic SR-B1 protein (no changes in Scarb1 mRNA). This increase was driven by a 2.2-fold increase in cell-surface SR-B1 via a mechanism that appears independent of ERK. In vitro studies show that loss of GPR146 increases SR-B1-mediated selective uptake of HDL lipid and HDL protein. Consistently, carriers of a GPR146 variant associated with loss-of-function and carriers of SCARB1 gain-of-function variant share reductions in apoA-I, HDL particle size, HDL cholesterol, and cholesteryl ester content compared to non-carriers. Conclusions This study suggests that loss of GPR146 reduces HDL cholesterol via post-translational upregulation of hepatic SR-B1 via an intracellular pathway that remains to be resolved. These findings imply that GPR146 inhibition to treat hypercholesterolemia will not only lower plasma levels of LDL cholesterol but also HDL cholesterol.