Lack of biliary lipid excretion in the little skate, Raja erinacea, indicates the absence of functional Mdr2, Abcg5, and Abcg8 transporters.
The ABC transporters bile salt export pump (BSEP; encoded by the ABCB11 gene), MDR3 P-glycoprotein (ABCB4), and sterolin 1 and 2 (ABCG5 and ABCG8) are crucial for the excretion of bile salt, phospholipid, and cholesterol, respectively, into the bile of mammals. The current paradigm is that phospholipid excretion mainly serves to protect membranes of the biliary tree against bile salt micelles. Bile salt composition and cytotoxicity, however, differ greatly between species. We investigated whether biliary phospholipid and cholesterol excretion occurs in a primitive species, the little skate, which almost exclusively excretes the sulphated bile alcohol scymnolsulphate. We observed no phospholipid and very little cholesterol excretion into bile of these animals. Conversely, when scymnolsulphate was added to the perfusate of isolated mouse liver perfusions, it was very well capable of driving biliary phospholipid and cholesterol excretion. Furthermore, in an erythrocyte cytolysis assay, scymnolsulphate was found to be at least as cytotoxic as taurocholate. These results demonstrate that the little skate does not have a system for the excretion of phospholipid and cholesterol and that both the MDR3 and the two half-transporter genes, ABCG5 and ABCG8, have evolved relatively late in evolution to mediate biliary lipid excretion. Little skate plasma membranes may be protected against bile salt micelles mainly by their high sphingomyelin content.
Elferink
Ronald P J Oude
RP
AMC Liver Center, Academic Medical Center S1-162, Meibergdreef 69-71, 1105 BK Amsterdam. r.p.oude-elferink@amc.uva.nl
Ottenhoff
Roelof
R
Fricker
Gert
G
Seward
David J
DJ
Ballatori
Nazzareno
N
Boyer
James
J
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000378:metabolism*; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000818:Animals; D001646:Bile / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism*; D002756:Cholagogues and Choleretics / Q000008:administration & dosage; D002777:Cholestanols / Q000008:administration & dosage / Q000506:poisoning; D004396:Coloring Agents / Q000493:pharmacokinetics; D004912:Erythrocytes / Q000187:drug effects; D006801:Humans; D007208:Indocyanine Green / Q000493:pharmacokinetics; D050356:Lipid Metabolism; D008074:Lipoproteins / Q000378:metabolism*; D008099:Liver / Q000187:drug effects; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D010477:Perfusion; D012860:Skates, Fish / Q000378:metabolism*; D013448:Sulfobromophthalein / Q000493:pharmacokinetics; D013655:Taurochenodeoxycholic Acid / Q000008:administration & dosage; D013656:Taurocholic Acid / Q000008:administration & dosage
D018435:ATP Binding Cassette Transporter, Subfamily B; D018528:ATP-Binding Cassette Transporters; D002352:Carrier Proteins; D002756:Cholagogues and Choleretics; D002777:Cholestanols; D004396:Coloring Agents; D008074:Lipoproteins; D013448:Sulfobromophthalein; C059448:scymnol sulfate ester; C012479:dibromosulphthalein; D013655:Taurochenodeoxycholic Acid; D013656:Taurocholic Acid; C095122:multidrug resistance protein 3; D007208:Indocyanine Green