Hepatic G-protein coupled receptor 146 (GPR146) promotes hepatic cholesterol synthesis via a signaling pathway. Genome-wide association studies (GWAS) have identified variants in the GPR146 gene that modulate plasma total cholesterol (TC) concentrations. Preclinical studies have further demonstrated that GPR146 regulates hepatic secretion of very low-density lipoprotein (VLDL), a mechanism mediated through extracellular signals. Consequently, circulating low-density lipoprotein cholesterol (LDL-C) also increases. GPR146-deficient mice exhibited reduced VLDL secretion and lowered plasma TC and other lipoproteins. These findings can partially be translated to humans: variants that increased GPR146 expression were not only associated with elevated plasma TC and lipoproteins, but also liver enzymes, while decreased GPR146 expression showed the opposite phenotype. Recent Mendelian Randomization (MR) studies support a causal role for GPR146 in regulating plasma lipids and liver function. Lipoprotein subclasses reflect dynamic lipid metabolism and are partly genetically determined. Liver function also influences lipoprotein profiles, as hepatic impairment can increase the secretion of large VLDL particles, precursors to atherogenic small dense LDL. While GPR146 regulates hepatic VLDL secretion, its broader role in liver function and lipoprotein metabolism remains unclear. Cholesin, a gut-derived protein encoded by C7orf50, antagonizes hepatic GPR146’s role in cholesterol synthesis. Since GPR146 is nested within the C7orf50 locus in the human genome, genetic variants in C7orf50 may regulate GPR146, though this has not been explored. This project will use UK Biobank phenotypic and genetic data to study associations between variants in GPR146 and C7orf50 and major lipids, lipoprotein subclasses, and liver enzymes. The aim is to elucidate novel functions of these genes in lipoprotein metabolism and map GWAS signals to underlying cholesterol-regulating mechanisms.
