Hypercholesterolemia risk-associated GPR146 is an orphan G-protein coupled receptor that regulates blood cholesterol levels in humans and mice

摘要

a rs1997243 and three other SNPs that have strong LD with rs1997243 are located in the genome active region. b Minor allele of rs1997243 increases its promoter activity. c Minor allele of rs1997243 is significantly associated with increased GPR146 expression in humans. d Targeted activation of rs1997243 site increases GPR146 expression in HepG2 cells. e GPR146 is located on plasma membrane of 293 T cells. f GPR146 responds to heat-inactivated serum and actives CRE activity in HepG2 cells. Part of the cells was treated together with PKA inhibitor H89 (10 μM). g Li-gpr146−/− mice have decreased blood cholesterol levels with normal chow (NC) and high-fat high-cholesterol (HFHC) diets feeding. Samples were collected after overnight fasting (n = 6, female, 10–13 weeks). h Li-gpr146−/− mice are protected from high-fat diet (HFD)-induced hypercholesterolemia. Samples were collected after overnight fasting (n = 7–11, male, 10–12 weeks). i Knocking down gpr146 in adult mice decreases blood cholesterol levels (n = 6, male, 8 weeks). Samples were collected after 4 h fasting in the morning. All data are expressed as means ± SEM and P values were calculated with Student’s test (*P < 0.05, **P < 0.01, ***P < 0.001).