Expression of human OSBP-related protein 1L in macrophages enhances atherosclerotic lesion development in LDL receptor-deficient mice.
OBJECTIVE
The purpose of this study was to assess the role of macrophage OSBP-related protein 1L (ORP1L) in the development of atherosclerosis.


RESULTS
C57BL/6 mice overexpressing human ORP1L in macrophages driven by scavenger receptor A promoter were generated. Bone marrow (BM) of the mice was transplanted into LDLr-/- animals, and aortic root lesion area in the recipients was determined after Western-type diet feeding. The recipients of ORP1L BM displayed 2.1-fold increase (P<0.001) in lesion size as compared with recipients of wild-type littermate BM. Macrophages of the ORP1L BM recipients showed a decrease in ABCG1 and APOE mRNAs and proteins, and an increase in PLTP message; also the plasma PLTP activity was elevated. The effect of ORP1L on cholesterol efflux was assessed using macrophages loaded with [3H]cholesterol oleate-acLDL or labeled with [3H]cholesterol. The ORP1L transgenic macrophages displayed 30% reduction (P<0.01) in cholesterol efflux to HDL2, but not to apoA-I. ORP1L was shown to bind 25- and 22(R)-hydroxycholesterol, identifying it as an oxysterol binding protein. Furthermore, ORP1L attenuated the response of ABCG1 mRNA to 22(R)-hydroxycholesterol, the effect on ABCA1 being less pronounced.


CONCLUSIONS
The results demonstrate that macrophage ORP1L can act as a modulator of atherosclerotic lesion development and provide clues to the underlying mechanism.
Yan
Daoguang
D
Department of Molecular Medicine, National Public Health Institute, Biomedicum, P.O. Box 104, FI-00251 Helsinki, Finland.
Jauhiainen
Matti
M
Hildebrand
Reeni B
RB
Willems van Dijk
Ko
K
Van Berkel
Theo J C
TJ
Ehnholm
Christian
C
Van Eck
Miranda
M
Olkkonen
Vesa M
VM
D000818:Animals; D001057:Apolipoproteins E / Q000378:metabolism*; D050197:Atherosclerosis / Q000503:physiopathology*; D001693:Biological Transport, Active; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D006801:Humans; D008264:Macrophages / Q000166:cytology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011336:Probability; D011485:Protein Binding; D012333:RNA, Messenger / Q000032:analysis; D011973:Receptors, LDL / Q000172:deficiency; D051122:Scavenger Receptors, Class B / Q000235:genetics / Q000378:metabolism*; D012680:Sensitivity and Specificity
D001057:Apolipoproteins E; D012333:RNA, Messenger; D011973:Receptors, LDL; D051122:Scavenger Receptors, Class B