Adult sea lamprey tolerates biliary atresia by altering bile salt composition and renal excretion

Authors

  • Shi-Ying Cai,

    Corresponding author
    1. Department of Internal Medicine and Liver Center, Yale University School of Medicine, New Haven, CT
    2. Mount Desert Island Biological Laboratory, Salisbury Cove, ME
    • Liver Center, Yale University School of Medicine, 333 Cedar St., 1080 LMP, New Haven, CT 06520
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    • fax: 203-785-7273

  • Daniël A. Lionarons,

    1. Department of Internal Medicine and Liver Center, Yale University School of Medicine, New Haven, CT
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  • Lee Hagey,

    1. Department of Medicine, University of California, San Diego, La Jolla, CA
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  • Carol J. Soroka,

    1. Department of Internal Medicine and Liver Center, Yale University School of Medicine, New Haven, CT
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  • Albert Mennone,

    1. Department of Internal Medicine and Liver Center, Yale University School of Medicine, New Haven, CT
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  • James L. Boyer

    Corresponding author
    1. Department of Internal Medicine and Liver Center, Yale University School of Medicine, New Haven, CT
    2. Mount Desert Island Biological Laboratory, Salisbury Cove, ME
    • Ensign Professor of Medicine, Emeritus Director, Liver Center, Yale University School of Medicine, 333 Cedar St., 1080 LMP, New Haven, CT 06520
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  • Potential conflict of interest: Nothing to report.

  • Supported by National Institutes of Health USPHS grants R37 DK25636 (to J.L.B.) and P30 DK34989 (Yale Liver Center).

  • fax: 203-785-7273

Abstract

The sea lamprey (Petromyzon marinus) is a genetically programmed animal model for biliary atresia, as it loses its bile ducts and gallbladder during metamorphosis. However, in contrast to patients with biliary atresia or other forms of cholestasis who develop progressive disease, the postmetamorphosis lampreys grow normally to adult size. To understand how the adult lamprey thrives without the ability to secrete bile, we examined bile salt homeostasis in larval and adult lampreys. Adult livers were severely cholestatic, with levels of bile salts >1 mM, but no evidence of necrosis, fibrosis, or inflammation. Interestingly, both larvae and adults had normal plasma levels (∼10 μM) of bile salts. In larvae, petromyzonol sulfate (PZS) was the predominant bile salt, whereas the major bile salts in adult liver were sulfated C27 bile alcohols. Cytotoxicity assays revealed that PZS was highly toxic. Pharmacokinetic studies in free-swimming adults revealed that ∼35% of intravenously injected bromosulfophthalein (BSP) was eliminated over a 72-hour period. Collection of urine and feces demonstrated that both endogenous and exogenous organic anions, including biliverdin, bile salts, and BSP, were predominantly excreted by way of the kidney, with minor amounts also detected in feces. Gene expression analysis detected marked up-regulation of orthologs of known organic anion and bile salt transporters in the kidney, with lesser effects in the intestine and gills in adults compared to larvae. These findings indicate that adult lampreys tolerate cholestasis by altering hepatic bile salt composition, while maintaining normal plasma bile salt levels predominantly through renal excretion of bile products. Therefore, we conclude that strategies to accelerate renal excretion of bile salt and other toxins should be beneficial for patients with cholestasis. (HEPATOLOGY 2013;57:2418–2426)

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