Lithocholic acid disrupts phospholipid and sphingolipid homeostasis leading to cholestasis in mice

Authors

  • Tsutomu Matsubara,

    1. Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD
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  • Naoki Tanaka,

    1. Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD
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  • Andrew D. Patterson,

    1. Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD
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  • Joo-Youn Cho,

    1. Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD
    Current affiliation:
    1. Department of Pharmacology and Clinical Pharmacology, Seoul National University College of Medicine and Hospital, Seoul 110-744, Republic of Korea
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  • Kristopher W. Krausz,

    1. Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD
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  • Frank J. Gonzalez

    Corresponding author
    1. Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD
    • Laboratory of Metabolism, National Cancer Institute, Building 37, Room 3106, Bethesda, MD 20892
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    • fax: 301-496-8419.


  • Supported by the National Cancer Institute Intramural Research Program, Center for Cancer Research. T.M. was supported by a fellowship from the Japanese Society for the Promotion of Science.

  • Potential conflict of interest: Nothing to report.

Abstract

Lithocholic acid (LCA) is an endogenous compound associated with hepatic toxicity during cholestasis. LCA exposure in mice resulted in decreased serum lysophosphatidylcholine (LPC) and sphingomyelin levels due to elevated lysophosphatidylcholine acyltransferase (LPCAT) and sphingomyelin phosphodiesterase (SMPD) expression. Global metabolome analysis indicated significant decreases in serum palmitoyl-, stearoyl-, oleoyl-, and linoleoyl-LPC levels after LCA exposure. LCA treatment also resulted in decreased serum sphingomyelin levels and increased hepatic ceramide levels, and induction of LPCAT and SMPD messenger RNAs (mRNAs). Transforming growth factor-β (TGF-β) induced Lpcat2/4 and Smpd3 gene expression in primary hepatocytes and the induction was diminished by pretreatment with the SMAD3 inhibitor SIS3. Furthermore, alteration of the LPCs and Lpcat1/2/4 and Smpd3 expression was attenuated in LCA-treated farnesoid X receptor-null mice that are resistant to LCA-induced intrahepatic cholestasis. Conclusion: This study revealed that LCA induced disruption of phospholipid/sphingolipid homeostasis through TGF-β signaling and that serum LPC is a biomarker for biliary injury. (HEPATOLOGY 2011;)

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