Research Articles
Hepatic deletion of X-box binding protein 1 impairs bile acid metabolism in mice

https://doi.org/10.1194/jlr.M071266Get rights and content
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The unfolded protein response (UPR) is an adaptive response to endoplasmic reticulum stress and the inositol-requiring enzyme 1α/X-box binding protein 1 (IRE1α/XBP1) pathway of the UPR is important in lipid metabolism. However, its role in bile acid metabolism remains unknown. We demonstrate that liver-specific Xbp1 knockout (LS-Xbp1−/−) mice had a 45% reduction in total bile acid pool. LS-Xbp1−/− mice had lower serum 7α-hydroxy-4-cholesten-3-one (C4) levels compared with Xbp1fl/fl mice, indicating reduced cholesterol 7α-hydroxylase (CYP7A1) synthetic activity. This occurred without reductions of hepatic CYP7A1 protein expression. Feeding LS-Xbp1−/− mice cholestyramine increased hepatic CYP7A1 protein expression to levels 2-fold and 8-fold greater than cholestyramine-fed and chow-fed Xbp1fl/fl mice, respectively. However, serum C4 levels remained unchanged and were lower than both groups of Xbp1fl/fl mice. In contrast, although feeding LS-Xbp1−/− mice cholesterol did not increase CYP7A1 expression, serum C4 levels increased significantly up to levels similar to chow-fed Xbp1fl/fl mice and the total bile acid pool normalized. In conclusion, loss of hepatic XBP1 decreased the bile acid pool and CYP7A1 synthetic activity. Cholesterol feeding, but not induction of CYP7A1 with cholestyramine, increased CYP7A1 synthetic activity and corrected the genotype-specific total bile acid pools. These data demonstrate a novel role of IRE1α/XBP1 regulating bile acid metabolism.

cholesterol
cholesterol 7-alpha hydroxylase
liver
gene expression
endoplasmic reticulum
unfolded protein response
serum 7α-hydroxy-4-cholesten-3-one

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This work was supported by National Institute of Diabetes and Digestive and Kidney Diseases Grant R01 DK093807, the George Lockerbie Liver Cancer Foundation, and the Max Goldenberg Foundation. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

    Abbreviations:

    C4

    7α-hydroxy-4-cholesten-3-one

    CYP7A1

    cholesterol 7α-hydroxylase

    ER

    endoplasmic reticulum

    GO

    Gene Ontology

    IRE1α

    inositol-requiring enzyme 1α KEGG, Kyoto Encyclopedia of Genes and Genomes

    LS-Xbp1−/−

    liver-specific X-box binding protein 1 knockout

    LXR

    liver X receptor

    TC

    taurocholic acid

    TMCA

    tauromuricholic acid

    UPR

    unfolded protein response

    XBP1

    X-box binding protein 1