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

Jin Wang, Curt Einarsson, Charlotte Murphy, Paolo Parini, Ingemar Björkhem, Mats Gåfvels, and Gösta Eggertsen

Dep. of Laboratory Medicine, Div. of Clinical Chemistry, Karolinska Institutet, Karolinska University Hosp., Stockholm 141 86S

Corresponding Author: gosta.eggertsen{at}karolinska.se

We have previously shown that mice unable to produce cholic acid (CA) due to targeted disruption of the Cyp8b1 gene (Cyp8b1-/-) have an upregulated bile acid synthesis, reduced 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 an synthetic LXR agonist further upregulated the Cyp7a1 expression and bile acid production in Cyp8b1-/- mice compared to Cyp8b1+/+ mice. Only minor elevations of serum cholesterol were observed in Cyp8b1+/+ and Cyp8b1-/- mice, but the latter showed a significant rise in HDL cholesterol and increased levels of liver Abca1 mRNA. A combined CA (0.25%)/cholesterol (0.5%) diet enhanced the intestinal absorption of cholesterol in both groups of mice, increased their liver cholesterol content, and markedly reduced expression of Cyp7a1 mRNA. CA also increased the Abcg5/g8 liver mRNA in both groups of mice, and cholesterol crystals were observed in the bile of the Cyp8b1+/+ but not in the Cyp8b1-/- mice. The results demonstrate the cholesterol-sparing effects of CA in mice: enhanced absorption and reduced conversion into bile acids. 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. A similar interplay between FXR- and LXR-mediated stimuli might also regulate expression of liver Abcg5/g8.

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