GPR146 regulates CYP7A1 transcription in cells and in vivo of mice

G protein-coupled receptor 146 (GPR146) plays a significant role in cholesterol metabolism in both humans and mice. Previous studies have shown that Gpr146 in mouse liver regulates cholesterol metabolism during long-term starvation, short-term starvation, and feeding conditions. Specifically, Gpr146 suppresses endogenous cholesterol synthesis and very-low-density lipoprotein secretion following feeding. However, its role in cholesterol metabolism under other feeding conditions remains unclear. The conversion of cholesterol to bile acids represents the primary pathway of cholesterol metabolism, with cytochrome P450 family 7 subfamily A member 1 (CYP7A1) serving as the critical rate-limiting enzyme. Studies have indicated that overexpression of Cyp7a1 can lower blood cholesterol levels. In this study, we systematically identified CYP7A1 as a target gene of GPR146 both in vivo and in cultured hepatocytes. Our findings revealed that silencing the expression of gpr146 in the mouse liver significantly reduced total blood cholesterol levels while markedly upregulating liver cyp7a1 expression during a 2-h fasting period. Importantly, this regulation occurs independently of farnesoid X-activated receptor (FXR)-dependent and FXR-independent cytokine pathways. These results strongly suggest that CYP7A1 is a crucial endogenous mediator of GPR146 in cholesterol metabolism both in vitro and in vivo.