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Journal of Lipid Research, Vol. 47, 421-430, February 2006
Copyright © 2006 by American Society for Biochemistry and Molecular Biology

Studies on LXR- and FXR-mediated effects on cholesterol homeostasis in normal and cholic acid-depleted mice

J. Wang^*, C. Einarsson, C. Murphy^*, P. Parini, I. Björkhem^*, M. Gåfvels^* and G. Eggertsen^1,*

^* Division of Clinical Chemistry, Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital, Huddinge, Sweden
Division of Gastroenterology and Hepatology, Karolinska Institutet, Karolinska University Hospital, Huddinge, Sweden
Metabolism Unit, Center for Metabolism and Endocrinology, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Huddinge, Sweden

Published, JLR Papers in Press, November 1, 2005.

¹ To whom correspondence should be addressed. e-mail: gosta.eggertsen{at}karolinska.se

As previously reported by us, mice with targeted disruption of the CYP8B1 gene (CYP8B1^–/–) fail to produce cholic acid (CA), upregulate their bile acid synthesis, reduce the absorption 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) agonist strongly upregulated CYP7A1 expression in CYP8B1^–/– mice, compared to CYP8B1^+/+ mice. Cholesterol-fed CYP8B1^–/– mice also showed a significant rise in HDL cholesterol and increased levels of liver ABCA1 mRNA. A combined CA (0.25%)/cholesterol (0.5%) diet enhanced absorption of intestinal cholesterol in both groups of mice, increased their liver cholesterol content, and reduced their expression of CYP7A1 mRNA. The ABCG5/G8 liver mRNA was increased in both groups of mice, but cholesterol crystals were only observed in bile from the CYP8B1^+/+ mice. The results demonstrate the cholesterol-sparing effects of CA: enhanced absorption and reduced conversion into bile acids. Farnesoid X receptor (FXR)-mediated suppression of CYP7A1 in mice seems to be a predominant mechanism for regulation of bile acid synthesis under normal conditions and, as confirmed, able to override LXR-mediated mechanisms. Interaction between FXR- and LXR-mediated stimuli 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

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