To further investigate the role of hepatic FXR in mediating bile acid regulation of biliary and fecal cholesterol content, we fed wild-type, liver-specific Fxr knockout (L-FXR-KO) and intestine-specific selleck compound Fxr knockout (I-FXR-KO) mice either a chow diet or a chow diet supplemented with 0.5% CA for 1 week. Deletion of the Fxr gene in the liver or the intestine

did not significantly alter hepatic cholesterol content (Fig. 6A). CA feeding significantly increased biliary cholesterol content by three-fold in wild-type, two-fold in I-FXR-KO mice, and approximately 0.3-fold in L-FXR-KO mice (Fig. 6B) suggesting that FXR-independent bile acid signaling may be also involved in biliary cholesterol secretion. CA feeding also resulted in a small but significant increase in biliary phospholipid levels in all three genotypes. This suggests that a bile acid effect on biliary phospholipid content may be independent of FXR (Fig. 6C). Gene expression analysis showed that CA feeding significantly induced ABCG5 and ABCG8 mRNA expression in the livers of wild-type mice and I-FXR-KO mice, but not in GSI-IX ic50 the livers of L-FXR-KO mice (Fig. 7A). In contrast, CA feeding had no effect on the mRNA expression of intestine ABCG5 and ABCG8 in mice of all three genotypes (Fig. 7B). These results further

confirmed the role of liver FXR in mediating the bile acid induction of ABCG5/G8 expression in the liver. 上海皓元医药股份有限公司 CA strongly repressed CYP7A1 mRNA expression in wild-type mice as expected, but surprisingly had a much weaker effect in L-FXR-KO mice (Fig. 7C), even though loss of liver Fxr abolished CA induction of hepatic SHP, whereas loss of intestine Fxr completely abolished intestine FGF15 induction (Fig. 7D,E). The attenuated

repression of CYP7A1 by CA in L-FXR-KO mice may be due to abolished SHP induction in the liver. Taken together, these results suggest that redundant pathways mediate bile acid repression of the Cyp7a1 gene. This study demonstrated that induction of CYP7A1 had profound effects on hepatic cholesterol synthesis, uptake, catabolism, and secretion, but hepatic cholesterol homeostasis is maintained to prevent hypercholesterolemia. Increased CYP7A1 expression promotes biliary and fecal cholesterol secretion without affecting intestine cholesterol absorption in Cyp7a1-tg mice. Induction of CYP7A1 increases CDCA in the bile acid pool, which is the most efficacious ligand of FXR that induces expression of hepatic, but not the intestinal cholesterol transporters ABCG5/ABCG8 and SR-B1, and the hepatic bile acid efflux transporter BSEP. Thus, bile acid synthesis is directly linked to biliary bile acid and cholesterol secretion, but not intestinal cholesterol absorption. In a previous study, lowering circulating cholesterol levels in Cyp7a1-tg mice was attributed to compensatory up-regulation of LDL-mediated uptake of cholesterol, which is converted to bile acids in the liver.