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(Circulation Research. 2007;100:678.)
© 2007 American Heart Association, Inc.

Molecular Medicine

Important Role for Bone Marrow–Derived Cholesteryl Ester Transfer Protein in Lipoprotein Cholesterol Redistribution and Atherosclerotic Lesion Development in LDL Receptor Knockout Mice

Miranda Van Eck^*, Dan Ye^*, Reeni B. Hildebrand, J. Kar Kruijt, Willeke de Haan, Menno Hoekstra, Patrick C.N. Rensen, Christian Ehnholm, Matti Jauhiainen, Theo J.C. Van Berkel

From the Division of Biopharmaceutics, Leiden/Amsterdam Center for Drug Research, Gorlaeus Laboratories (M.V.E., D.Y., R.B.H., J.K.K., M.H., T.J.C.V.B.), Leiden University, Leiden, The Netherlands; Department of Molecular Medicine (C.E., M.J.), National Public Health Institute, Biomedicum, Helsinki, Finland; Department of General Internal Medicine, Endocrinology and Metabolic Diseases (W.d.H., P.C.N.R.), Leiden University Medical Center, Leiden, The Netherlands.

Correspondence to M. Van Eck, Division of Biopharmaceutics, Gorlaeus Laboratories, Einsteinweg 55, 2333 CC Leiden, The Netherlands. E-mail M.Eck{at}LACDR.LeidenUniv.nl

Abundant amounts of cholesteryl ester transfer protein (CETP) are found in macrophage-derived foam cells in the arterial wall, but its function in atherogenesis is unknown. To investigate the role of macrophage CETP in atherosclerosis, LDL receptor knockout mice were transplanted with bone marrow from CETP transgenic mice, which express the human CETP transgene under control of its natural promoter and major regulatory elements. CETP production by bone marrow-derived cells induced a 1.8-fold (P<0.01) increase in atherosclerotic lesion development. The increase in lesion size coincided with an increase in VLDL/LDL cholesterol and a decrease in HDL cholesterol. The cholesterol redistribution in serum was a direct effect of the substantial serum CETP activity and mass (38±3 nmol/mL/h and 4.8±0.5 µg/mL, respectively) induced by CETP production by bone marrow-derived cells. Conversely, specific disruption of CETP production by bone marrow-derived cells in CETP transgenic mice resulted in a 2-fold (P<0.0001) reduction in serum CETP activity and mass, demonstrating the quantitative relevance of bone marrow-derived CETP. Finally, we show that in liver Kupffer cells, hepatic macrophages, contribute 50% to the total hepatic CETP expression. In conclusion, bone marrow-derived CETP induces a proatherogenic lipoprotein profile and promotes the development of atherosclerotic lesions in LDL receptor knockout mice. Most importantly, we show for the first time that bone marrow-derived CETP is an important contributor to total serum CETP activity and mass.

Key Words: atherosclerosis • macrophages • lipoproteins • bone marrow transplantation • mouse models

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