on May 3, 2007
Published online before print May 3, 2007, doi: 10.1161/ATVBAHA.107.144121
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Submitted on January 22, 2007
Accepted on April 16, 2007
Expression of Human OSBP-Related Protein 1L in Macrophages Enhances Atherosclerotic Lesion Development in LDL Receptor-Deficient Mice
Daoguang Yan ;
From the Department of Molecular Medicine (D.Y., M.J., CE., V.M.O.), National Public Health Institute, Biomedicum, Helsinki, Finland; the Division of Biopharmaceutics (R.B.H., T.J.C.V.B., M.V.E.), Leiden/Amsterdam Center for Drug Research, Gorlaeus Laboratories, Leiden, The Netherlands; and the The Departments of General Internal Medicine and Human Genetics (R.B.H., K.W.v.D.), Leiden University Medical Center, Leiden, The Netherlands.
* To whom correspondence should be addressed. E-mail: vesa.olkkonen{at}ktl.fi.
Objective--The purpose of this study was to assess the role of macrophage OSBP-related protein 1L (ORP1L) in the development of atherosclerosis.
Methods and 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 22R-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.
Key words: ABCG1 • apolipoprotein E • atherosclerosis • cholesterol efflux • macrophage • ORP1L • oxysterol binding protein • PLTP
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