GPR146 and HDL metabolism
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International audience. Background and Aims: Epidemiological studies revealed that G-coupled protein receptor 146 (GPR146) regulates LDL-c together with HDL-c levels. While studies in mice have shown that GPR146 affects LDL-c through modulating VLDL secretion, it remains unknown how GPR146 affects HDL metabolisms, for which we hypothesize a role for scavenger receptor class B type 1 (SR-B1).Methods: For our in vivo studies, we used Gpr146-/- and transgenic mice expressing Cas9 specifically in the liver. The latter were injected with adeno-associated virus harbouring sgRNAs targeting Gpr146. Mice were fed a chow diet. Plasma lipids and lipoproteins were assessed using FPLC and after PEG6000 precipitation. SR-B1 protein levels were measured by Western blotting. Primary mouse hepatocytes were used for HDL uptake and SR-B1 localization (biotinylation) studies.Results: Compared to controls, Gpr146-/- mice have 20% reduced plasma HDL-c and increased hepatic SR-B1 protein levels without changes at the mRNA level. In AlbCas9 mice, loss of hepatic Gpr146 was associated with dose-dependent increased levels of hepatic SR-B1. Primary hepatocytes of Gpr146-/- mice were enriched with cell-membrane SR-B1 protein and show increased uptake of HDL compared to wild-type mice.Conclusions: This study suggests that genetic ablation of Gpr146 affects HDL metabolism through changing post-translational modification of SR-B1. Whether these effects are mediated through changes in SR-B1 stability, or changes in proteasomal or lysosomal degradation of SR-B1 is under investigation.
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