Bile salt-dependent lipase interacts with platelet CXCR4 and modulates thrombus formation in mice and humans

Laurence Panicot-Dubois; Grace M Thomas; Barbara C Furie; Bruce Furie; Dominique Lombardo; Christophe Dubois

doi:10.1172/JCI32655

Bile salt-dependent lipase interacts with platelet CXCR4 and modulates thrombus formation in mice and humans

J Clin Invest. 2007 Dec;117(12):3708-19. doi: 10.1172/JCI32655.

Authors

Laurence Panicot-Dubois¹, Grace M Thomas, Barbara C Furie, Bruce Furie, Dominique Lombardo, Christophe Dubois

Affiliation

¹ Division of Hemostasis and Thrombosis, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA. lpdubois@medicine.univ-mrs.fr

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

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Absorption
Animals
Bleeding Time
Blood Platelets / metabolism*
Calcium / metabolism
Calcium Signaling / drug effects
Calcium Signaling / genetics
Cell Line
Cholesterol Esters / metabolism
Disease Models, Animal
Duodenum / enzymology
Endothelial Cells / metabolism
Epoprostenol / biosynthesis
Epoprostenol / genetics
HIV Envelope Protein gp120 / genetics
HIV Envelope Protein gp120 / metabolism
HIV-1 / genetics
HIV-1 / metabolism
Mice
Mice, Knockout
Platelet Aggregation* / drug effects
Platelet Aggregation* / genetics
Platelet Glycoprotein GPIIb-IIIa Complex / genetics
Platelet Glycoprotein GPIIb-IIIa Complex / metabolism
Protein Structure, Secondary
Receptors, CXCR4 / agonists
Receptors, CXCR4 / antagonists & inhibitors
Receptors, CXCR4 / genetics
Receptors, CXCR4 / metabolism*
Sequence Homology, Amino Acid
Sterol Esterase / genetics
Sterol Esterase / metabolism*
Sterol Esterase / pharmacology
Thrombosis / chemically induced
Thrombosis / enzymology*
Thrombosis / genetics

Substances

CXCR4 protein, mouse
Cholesterol Esters
HIV Envelope Protein gp120
Platelet Glycoprotein GPIIb-IIIa Complex
Receptors, CXCR4
gp120 protein, Human immunodeficiency virus 1
Epoprostenol
bile salt-stimulated lipase
Sterol Esterase
Calcium