出版社：American Society for Biochemistry and Molecular Biology
摘要：As previously reported by us, mice with targeted disruptionof the CYP8B1 gene (CYP8B1–/–) fail to produce cholicacid (CA), upregulate their bile acid synthesis, reduce theabsorption of dietary cholesterol and, after cholesterol feeding,accumulate less liver cholesterol than wild-type (CYP8B1+/+)mice. In the present study, cholesterol-enriched diet (0.5%)or administration of a synthetic liver X receptor (LXR) agoniststrongly upregulated CYP7A1 expression in CYP8B1–/–mice, compared to CYP8B1+/+ mice. Cholesterol-fed CYP8B1–/–mice also showed a significant rise in HDL cholesterol and increasedlevels of liver ABCA1 mRNA. A combined CA (0.25%)/cholesterol(0.5%) diet enhanced absorption of intestinal cholesterol inboth groups of mice, increased their liver cholesterol content,and reduced their expression of CYP7A1 mRNA. The ABCG5/G8 livermRNA was increased in both groups of mice, but cholesterol crystalswere only observed in bile from the CYP8B1+/+ mice. The resultsdemonstrate the cholesterol-sparing effects of CA: enhancedabsorption and reduced conversion into bile acids. FarnesoidX receptor (FXR)-mediated suppression of CYP7A1 in mice seemsto be a predominant mechanism for regulation of bile acid synthesisunder normal conditions and, as confirmed, able to overrideLXR-mediated mechanisms. Interaction between FXR- and LXR-mediatedstimuli might also regulate expression of liver ABCG5/G8.Supplementary key words bile acids • farnesoid X receptor • liver X receptor • cholesterol 7-hydroxylase • sterol 12-hydroxylase
Abbreviations: CA, cholic acid; CDCA, chenodeoxycholic acid; CSI, cholesterol saturation index; DCA, deoxycholic acid; FXR, farnesoid X receptor; LXR, liver X receptor; UDCA, ursodeoxycholic acid
-hydroxylase • sterol 12
