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

M Gåfvels,C Murphy,C Einarsson,I Björkhem,J Wang,P Parini,G Eggertsen

doi:10.1194/jlr.m500441-jlr200

Abstract

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.

Highlights

As previously reported by us, mice with targeted disruption of the CYP8B1 gene (CYP8B12/2) 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 (CYP8B11/1) mice
The present results show that the CYP8B12/2 mice, despite a preexisting elevated expression of CYP7A1, were able to further upregulate their transcription rate of cholesterol 7a-hydroxylase when fed a cholesterol-enriched diet
The difference in CYP7A1 mRNA levels between cholesterol-fed CYP8B11/1 and CYP8B12/2 mice illustrates the repressive power of the Farnesoid X receptor (FXR)-mediated mechanism, with 4-fold higher levels of CYP7A1 mRNA occurring in the CYP8B12/2 mice, analysis of fecal bile acids indicated a doubling of the production rate

Summary

Introduction

As previously reported by us, mice with targeted disruption of the CYP8B1 gene (CYP8B12/2) 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 (CYP8B11/1) mice. 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. 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. Studies on LXR- and FXR-mediated effects on cholesterol homeostasis in normal and cholic acid-depleted mice. CA is a key factor, together with phospholipids, in the formation of micelles to achieve an efficient absorption of cholesterol In the mouse, it functions as a specific ligand for the nuclear receptor farnesoid X receptor (FXR), which mediates the downregulation of CYP7A1 and CYP8B1 [2].

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Conclusion