Bone marrow-derived multidrug resistance protein ABCB4 protects against atherosclerotic lesion development in LDL receptor knockout mice.
OBJECTIVE
Several members of the ATP binding cassette (ABC)-transporter super family expressed in macrophages protect against atherosclerosis by promoting macrophage cholesterol and phospholipid efflux. Systemic disruption of ABCB4 in mice results in a virtual absence of phospholipids in bile and a strongly impaired biliary cholesterol secretion, indicating that ABCB4 plays an essential role in cellular lipid efflux. The aim of the current study was to determine the role of bone marrow-derived ABCB4 in atherosclerotic lesion development.


METHODS
Chimeras were created that specifically lack ABCB4 in bone marrow-derived cells, including macrophages, by performing a bone marrow transplantation on LDL receptor knockout (LDLr-/-) mice. Atherosclerotic lesion development was induced by feeding a high-cholesterol diet (15% fat and 0.25% cholesterol).


RESULTS
Serum cholesterol levels were significantly lower in mice reconstituted with ABCB4 knockout bone marrow as a result of reduced VLDL and LDL cholesterol levels. Despite the lower serum cholesterol levels, ABCB4 deficiency in bone marrow-derived cells resulted in a 1.8-fold (p=0.005) increase in lesion size. In vitro foam cell formation, induced with acetylated LDL (AcLDL) in peritoneal macrophages, was increased in the absence of ABCB4, possibly due to a 2-fold (p<0.05) increased association of AcLDL, while the efflux of cholesterol was unaffected.


CONCLUSIONS
Bone marrow-derived ABCB4 has an important anti-atherosclerotic function, probably by limiting macrophage foam cell formation.
Pennings
Marieke
M
Division of Biopharmaceutics, Leiden/Amsterdam Center for Drug Research, Leiden University, Einsteinweg 55, 2333 CC Leiden, The Netherlands. pennings@lacdr.leidenuniv.nl
Hildebrand
Reeni B
RB
Ye
Dan
D
Kunne
Cindy
C
Van Berkel
Theo J C
TJ
Groen
Albert K
AK
Van Eck
Miranda
M
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics / Q000502:physiology*; D000818:Animals; D001011:Aorta; D050197:Atherosclerosis / Q000378:metabolism* / Q000473:pathology; D001483:Base Sequence; D001853:Bone Marrow / Q000378:metabolism*; D016026:Bone Marrow Transplantation; D002784:Cholesterol / Q000008:administration & dosage / Q000097:blood; D017931:DNA Primers / Q000235:genetics; D005260:Female; D005487:Foam Cells / Q000378:metabolism / Q000473:pathology; D008074:Lipoproteins / Q000097:blood; D017737:Macrophages, Peritoneal / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D010743:Phospholipids / Q000378:metabolism; D011973:Receptors, LDL / Q000235:genetics*; D000097202:ATP-Binding Cassette Sub-Family B Member 4
D018435:ATP Binding Cassette Transporter, Subfamily B; D002784:Cholesterol; D017931:DNA Primers; D008074:Lipoproteins; D010743:Phospholipids; D011973:Receptors, LDL; D000097202:ATP-Binding Cassette Sub-Family B Member 4