Abstract
Bile salt-dependent lipase (BSDL) is an enzyme involved in the duodenal hydrolysis and absorption of cholesteryl esters. Although some BSDL is transported to blood, the role of circulating BSDL is unknown. Here, we demonstrate that BSDL is stored in platelets and released upon platelet activation. Because BSDL contains a region that is structurally homologous to the V3 loop of HIV-1, which binds to CXC chemokine receptor 4 (CXCR4), we hypothesized that BSDL might bind to CXCR4 present on platelets. In human platelets in vitro, both BSDL and a peptide corresponding to its V3-like loop induced calcium mobilization and enhanced thrombin-mediated platelet aggregation, spreading, and activated alpha(IIb)beta(3) levels. These effects were abolished by CXCR4 inhibition. BSDL also increased the production of prostacyclin by human endothelial cells. In a mouse thrombosis model, BSDL accumulated at sites of vessel wall injury. When CXCR4 was antagonized, the accumulation of BSDL was inhibited and thrombus size was reduced. In BSDL(-/-) mice, calcium mobilization in platelets and thrombus formation were attenuated and tail bleeding times were increased in comparison with those of wild-type mice. We conclude that BSDL plays a role in optimal platelet activation and thrombus formation by interacting with CXCR4 on platelets.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Absorption
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Animals
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Bleeding Time
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Blood Platelets / metabolism*
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Calcium / metabolism
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Calcium Signaling / drug effects
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Calcium Signaling / genetics
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Cell Line
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Cholesterol Esters / metabolism
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Disease Models, Animal
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Duodenum / enzymology
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Endothelial Cells / metabolism
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Epoprostenol / biosynthesis
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Epoprostenol / genetics
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HIV Envelope Protein gp120 / genetics
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HIV Envelope Protein gp120 / metabolism
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HIV-1 / genetics
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HIV-1 / metabolism
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Mice
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Mice, Knockout
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Platelet Aggregation* / drug effects
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Platelet Aggregation* / genetics
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Platelet Glycoprotein GPIIb-IIIa Complex / genetics
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Platelet Glycoprotein GPIIb-IIIa Complex / metabolism
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Protein Structure, Secondary
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Receptors, CXCR4 / agonists
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Receptors, CXCR4 / antagonists & inhibitors
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Receptors, CXCR4 / genetics
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Receptors, CXCR4 / metabolism*
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Sequence Homology, Amino Acid
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Sterol Esterase / genetics
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Sterol Esterase / metabolism*
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Sterol Esterase / pharmacology
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Thrombosis / chemically induced
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Thrombosis / enzymology*
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Thrombosis / genetics
Substances
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CXCR4 protein, mouse
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Cholesterol Esters
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HIV Envelope Protein gp120
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Platelet Glycoprotein GPIIb-IIIa Complex
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Receptors, CXCR4
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gp120 protein, Human immunodeficiency virus 1
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Epoprostenol
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bile salt-stimulated lipase
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Sterol Esterase
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Calcium