Differential regulation of bile acid homeostasis by the farnesoid X receptor in liver and intestine

Aug 28, 2007Journal of lipid research

How the Farnesoid X Receptor Controls Bile Acid Balance Differently in the Liver and Intestine

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Abstract

FXR deficiency in either liver or intestine increased bile acid pool size.

Activation of the farnesoid X receptor (FXR) represses transcription of the CYP7A1 gene, which is crucial for bile acid synthesis.
Intestinal FXR activation is necessary for short-term repression of CYP7A1 in the liver.
The hormone FGF15 may play a role in mediating the intestinal-specific effects of FXR on CYP7A1 suppression.
FXR's repression of CYP8B1 is more reliant on liver FXR than intestinal FXR.
Recombinant FGF15 repressed CYP7A1 mRNA levels without impacting CYP8B1 expression.

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Bile acid concentrations are controlled by a feedback regulatory pathway whereby activation of the farnesoid X receptor (FXR) represses transcription of both the CYP7A1 gene, encoding the rate-limiting enzyme in the classic bile acid synthesis pathway, and the CYP8B1 gene, required for synthesis of cholic acid. The tissue-specific roles of FXR were examined using liver- and intestine-specific FXR-null models. FXR deficiency in either liver (Fxr DeltaL) or intestine (Fxr DeltaIE) increased bile acid pool size. Treatment with the FXR-selective agonist GW4064 significantly repressed CYP7A1 in Fxr DeltaL mice but not Fxr DeltaIE mice, demonstrating that activation of FXR in intestine but not liver is required for short-term repression of CYP7A1 in liver. This intestinal-specific effect of FXR is likely mediated through induction of the hormone FGF15, which suppresses CYP7A1. In comparison to CYP7A1, FXR-mediated repression of CYP8B1 was more dependent on the presence of FXR in liver and less dependent on its presence in intestine. Consistent with these findings, recombinant FGF15 repressed CYP7A1 mRNA levels without affecting CYP8B1 expression. These data provide evidence that FXR-mediated repression of bile acid synthesis requires the complementary actions of FXR in both liver and intestine and reveal mechanistic differences in feedback repression of CYP7A1 and CYP8B1.

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Differential regulation of bile acid homeostasis by the farnesoid X receptor in liver and intestine

Abstract

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