ESPE Yearbook of Paediatric Endocrinology

To read the full abstract: Cell. 2019;179(6):1276–88 e14. doi: 10.1016/j.cell.2019.10.034

Short summary: Deficiency in the orphan G protein coupled receptor 146 (GPR146) decreases blood lipid levels and protects against atherosclerosis in mice, independent of LDL receptor activity.

Comment: Monogenic hypercholesterolemia is a heterogeneous group of disorders, characterized by marked increases in LDL-C or triglycerides, or both, and a very high risk of premature atherosclerotic disease. Known causes include mutations in the LDL receptor (LDLR ), apolipoprotein B-100 (APOB ), PCSK9 and the LDLR adaptor protein 1 (LDLRAP1 ) genes.

In large population studies, over 300 gene loci have been shown to be associated with plasma lipid levels. The current study assessed the function of GPR146, an orphan G protein-coupled receptor, as a regulator of plasma cholesterol levels. In a series of experiments, GPR146 was shown to regulate plasma lipid levels in mice through activation of extracellular signal regulated kinase (ERK) signalling in hepatocytes, upon feeding or after a short period of fasting. The activation of ERK signalling enhances activity of hepatic sterol regulatory element binding protein 2 (SREBP2) and of very-low-density lipoprotein secretion. This in turn increases circulating LDL-C and triglyceride levels.

Hence, the depletion of GPR146 in mice substantially reduces circulating LDL-C and triglyceride levels and protects mice against atherosclerosis, reducing lesion areas by up to 90%, in an LDL receptor-independent manner.

To the best of our knowledge, human gain-of-function and loss-of-function GPR146 mutation have not been described. As deficiency protects against hypercholesterolaemia, the identification of small molecules that inhibit GPR146 is potentially an effective strategy to treat hypercholesterolaemia and atherosclerosis.