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Am J Physiol Gastrointest Liver Physiol 278: G57-G63, 2000;
0193-1857/00 $5.00
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Vol. 278, Issue 1, G57-G63, January 2000

Bile salt excretion in skate liver is mediated by a functional analog of Bsep/Spgp, the bile salt export pump

Nazzareno Ballatori1, James F. Rebbeor1, Gregory C. Connolly1, David J. Seward2, Benjamin E. Lenth3, John H. Henson4, Pazhani Sundaram5, and James L. Boyer5

1 Department of Environmental Medicine, University of Rochester School Medicine, Rochester, New York 14642; 2 Williams College, Williamstown, Massachusetts 01267; 3 Wesleyan University, Middletown, Connecticut 06459; 4 Department of Biology, Dickinson College, Carlisle, Pennsylvania 17013; 5 Liver Center, Department of Medicine, Yale University School of Medicine, New Haven, Connecticut 06520; and Mount Desert Island Biological Laboratory, Salsbury Cove, Maine 04672

Biliary secretion of bile salts in mammals is mediated in part by the liver-specific ATP-dependent canalicular membrane protein Bsep/Spgp, a member of the ATP-binding cassette superfamily. We examined whether a similar transport activity exists in the liver of the evolutionarily primitive marine fish Raja erinacea, the little skate, which synthesizes mainly sulfated bile alcohols rather than bile salts. Western blot analysis of skate liver plasma membranes using antiserum raised against rat liver Bsep/Spgp demonstrated a dominant protein band with an apparent molecular mass of 210 kDa, a size larger than that in rat liver canalicular membranes, ~160 kDa. Immunofluorescent localization with anti-Bsep/Spgp in isolated, polarized skate hepatocyte clusters revealed positive staining of the bile canaliculi, consistent with its selective apical localization in mammalian liver. Functional characterization of putative ATP-dependent canalicular bile salt transport activity was assessed in skate liver plasma membrane vesicles, with [3H]taurocholate as the substrate. [3H]taurocholate uptake into the vesicles was mediated by ATP-dependent and -independent mechanisms. The ATP-dependent component was saturable, with a Michaelis-Menten constant (Km) for taurocholate of 40 ± 7 µM and a Km for ATP of 0.6 ± 0.1 mM, and was competitively inhibited by scymnol sulfate (inhibition constant of 23 µM), the major bile salt in skate bile. ATP-dependent uptake of taurocholate into vesicles was inhibited by known substrates and inhibitors of Bsep/Spgp, including other bile salts and bile salt derivatives, but not by inhibitors of the multidrug resistance protein-1 or the canalicular multidrug resistance-associated protein, indicating a distinct transport mechanism. These findings provide functional and structural evidence for a Bsep/Spgp-like protein in the canalicular membrane of the skate liver. This transporter is expressed early in vertebrate evolution and transports both bile salts and bile alcohols.

bile salt transport; ATP dependent; membrane vesicles


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