Disrupted coordinate regulation of farnesoid X receptor target genes in a patient with cerebrotendinous xanthomatosis

Takeshi Hirayama,Yasushi Matsuzaki,Mikio Doy,Ashok K. Batta,Gerald Salen,Guorong Xu,Akira Honda,Sarah Shefer,G. Stephen Tint

doi:10.1194/jlr.m400256-jlr200

Abstract

Cerebrotendinous xanthomatosis (CTX), sterol 27-hydroxylase (CYP27A1) deficiency, is associated with markedly reduced chenodeoxycholic acid (CDCA), the most powerful activating ligand for farnesoid X receptor (FXR). We investigated the effects of reduced CDCA on FXR target genes in humans. Liver specimens from an untreated CTX patient and 10 control subjects were studied. In the patient, hepatic CDCA concentration was markedly reduced but the bile alcohol level exceeded CDCA levels in control subjects (73.5 vs. 37.8 +/- 6.2 nmol/g liver). Cholesterol 7alpha-hydroxylase (CYP7A1) and Na+/taurocholate-cotransporting polypeptide (NTCP) were upregulated 84- and 8-fold, respectively. However, small heterodimer partner (SHP) and bile salt export pump were normally expressed. Marked CYP7A1 induction with normal SHP expression was not explained by the regulation of liver X receptor alpha (LXRalpha) or pregnane X receptor. However, another nuclear receptor, hepatocyte nuclear factor 4alpha (HNF4alpha), was induced 2.9-fold in CTX, which was associated with enhanced mRNA levels of HNF4alpha target genes, CYP7A1, 7alpha-hydroxy-4-cholesten-3-one 12alpha-hydroxylase, CYP27A1, and NTCP. In conclusion, the coordinate regulation of FXR target genes was lost in CTX. The mechanism of the disruption may be explained by a normally stimulated FXR pathway attributable to markedly increased bile alcohols with activation of HNF4alpha caused by reduced bile acids in CTX liver.

Highlights

Cerebrotendinous xanthomatosis (CTX), sterol 27hydroxylase (CYP27A1) deficiency, is associated with markedly reduced chenodeoxycholic acid (CDCA), the most powerful activating ligand for farnesoid X receptor (FXR)
Recent studies have shown that bile acids are physiological ligands for the farnesoid X receptor (FXR; NR1H4), an orphan nuclear receptor, and chenodeoxycholic acid (CDCA) activates the receptor function most powerfully [2,3,4]
The liver from CDCA-treated patient CTX2 contained a significant amount of CDCA (5.9-fold of CTX1) with normal CA level, so that hepatic total bile acid concentration was within the normal range

Summary

Introduction

Cerebrotendinous xanthomatosis (CTX), sterol 27hydroxylase (CYP27A1) deficiency, is associated with markedly reduced chenodeoxycholic acid (CDCA), the most powerful activating ligand for farnesoid X receptor (FXR). Marked CYP7A1 induction with normal SHP expression was not explained by the regulation of liver X receptor ␣ (LXR␣) or pregnane X receptor Another nuclear receptor, hepatocyte nuclear factor 4␣ (HNF4␣), was induced 2.9-fold in CTX, which was associated with enhanced mRNA levels of HNF4␣ target genes, CYP7A1, 7␣-hydroxy-4-cholesten-3-one 12␣hydroxylase, CYP27A1, and NTCP. Activated FXR induces the expression of small heterodimer partner (SHP; NR0B2), and the increased SHP protein forms an inactivating heterodimeric complex with ␣-fetoprotein transcription factor (FTF; NR5A2), turning off the transcription of cholesterol 7␣-hydroxylase (CYP7A1) [5,6,7,8], the rate-limiting enzyme in the classic bile acid bio-

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Conclusion