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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;27:1618.)
© 2007 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Expression of Human OSBP-Related Protein 1L in Macrophages Enhances Atherosclerotic Lesion Development in LDL Receptor–Deficient Mice

Daoguang Yan; Matti Jauhiainen; Reeni B. Hildebrand; Ko Willems van Dijk; Theo J.C. Van Berkel; Christian Ehnholm; Miranda Van Eck; Vesa M. Olkkonen

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 (K.W.v.D.), Leiden University Medical Center, Leiden, The Netherlands.

Correspondence Vesa M. Olkkonen, Department of Molecular Medicine, National Public Health Institute, Biomedicum, P.O. Box 104, FI-00251 Helsinki, Finland. 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 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.

LDLr^–/– animals that received bone marrow of mice expressing human ORP1L in macrophages displayed a 2.1-fold increase in aortic root lesion size relative to controls. Decreased macrophage ABCG1 and apoE expression and cholesterol efflux to HDL₂, as well as increased PLTP expression, provide plausible explanations for the increased lesion size.

Key Words: ABCG1 • apolipoprotein E • atherosclerosis • cholesterol efflux • macrophage • ORP1L • oxysterol binding protein • PLTP

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