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Blood, 15 May 2004, Vol. 103, No. 10, pp. 3777-3782. Prepublished online as a Blood First Edition Paper on February 5, 2004; DOI 10.1182/blood-2003-11-4051. This Article Full Text Full Text (PDF) All Versions of this Article: 2003-11-4051v1 2003-11-4051v2 103/10/3777    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Espirito Santo, S. M. S. Articles by van Vlijmen, B. J. M. Search for Related Content PubMed PubMed Citation Articles by Espirito Santo, S. M. S. Articles by van Vlijmen, B. J. M. Related Collections Hemostasis, Thrombosis, and Vascular Biology Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY Hepatic low-density lipoprotein receptor–related protein deficiency in mice increases atherosclerosis independent of plasma cholesterol Sonia M. S. Espirito Santo, Nuno M. M. Pires, Lianne S. M. Boesten, Gery Gerritsen, Niels Bovenschen, Ko Willems van Dijk, J. Wouter Jukema, Hans M. G. Princen, André Bensadoun, Wei-Ping Li, Joachim Herz, Louis M. Havekes, and Bart J. M. van Vlijmen From the TNO-Prevention and Health, Gaubius Laboratory, Leiden, the Netherlands; the Departments of Cardiology, Human Genetics, and General Internal Medicine, Leiden University Medical Center, Leiden, the Netherlands; the Department of Plasma Proteins, Sanquin Research at CLB, Amsterdam, the Netherlands; the Division of Nutritional Sciences, Cornell University, Ithaca, NY; and the Departments of Cell Biology and Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX. The low-density lipoprotein (LDL) receptor–related protein (LRP) has a well-established role in the hepatic removal of atherogenic apolipoprotein E (APOE)–rich remnant lipoproteins from plasma. In addition, LRP recognizes multiple distinct pro- and antiatherogenic ligands in vitro. Here, we investigated the role of hepatic LRP in atherogenesis independent of its role in removal of APOE-rich remnant lipoproteins. Mice that allow inducible inactivation of hepatic LRP were combined with LDL receptor and APOE double-deficient mice (MX1Cre+LRPflox/floxLDLR–/–APOE–/–). On an LDLR–/–APOE–/– background, hepatic LRP deficiency resulted in decreased plasma cholesterol and triglycerides (cholesterol: 17.1 ± 5.2 vs 23.4 ± 6.3 mM, P = .025; triglycerides: 1.1 ± 0.5 vs 2.2 ± 0.8 mM, P = .002, for MX1Cre+LRPflox/flox-LDLR–/–APOE–/– and control LRPflox/flox-LDLR–/–APOE–/– mice, respectively). Lower plasma cholesterol in MX1Cre+LRPflox/flox-LDLR–/–APOE–/– mice coincided with increased plasma lipoprotein lipase (71.2 ± 7.5 vs 19.1 ± 2.4 ng/ml, P = .002), coagulation factor VIII (4.4 ± 1.1 vs 1.9 ± 0.5 U/mL, P = .001), von Willebrand factor (2.8 ± 0.6 vs 1.4 ± 0.3 U/mL, P = .001), and tissue-type plasminogen activator (1.7 ± 0.7 vs 0.9 ± 0.5 ng/ml, P = .008) compared with controls. Strikingly, MX1Cre+LRPflox/floxLDLR–/–APOE–/– mice showed a 2-fold higher atherosclerotic lesion area compared with controls (408.5 ± 115.1 vs 219.1 ± 86.0 103µm2, P = .003). Our data indicate that hepatic LRP plays a clear protective role in atherogenesis independent of plasma cholesterol, possibly due to maintaining low levels of its proatherogenic ligands. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: A. P. Lillis, L. B. Van Duyn, J. E. Murphy-Ullrich, and D. K. Strickland LDL Receptor-Related Protein 1: Unique Tissue-Specific Functions Revealed by Selective Gene Knockout Studies Physiol Rev, July 1, 2008; 88(3): 887 - 918. [Abstract] [Full Text] [PDF] C. D. Overton, P. G. Yancey, A. S. Major, M. F. Linton, and S. Fazio Deletion of Macrophage LDL Receptor-Related Protein Increases Atherogenesis in the Mouse Circ. Res., March 16, 2007; 100(5): 670 - 677. [Abstract] [Full Text] [PDF] L. Hu, L.S.M. Boesten, P. May, J. Herz, N. Bovenschen, M.V. Huisman, J.F.P. Berbee, L.M. Havekes, B.J.M. van Vlijmen, and J.T. Tamsma Macrophage Low-Density Lipoprotein Receptor-Related Protein Deficiency Enhances Atherosclerosis in ApoE/LDLR Double Knockout Mice Arterioscler. Thromb. Vasc. Biol., December 1, 2006; 26(12): 2710 - 2715. [Abstract] [Full Text] [PDF] K. E. Kypreos and V. I. Zannis LDL receptor deficiency or apoE mutations prevent remnant clearance and induce hypertriglyceridemia in mice J. Lipid Res., March 1, 2006; 47(3): 521 - 529. [Abstract] [Full Text] [PDF] N. Bovenschen, K. Mertens, L. Hu, L. M. Havekes, and B. J. M. van Vlijmen LDL receptor cooperates with LDL receptor-related protein in regulating plasma levels of coagulation factor VIII in vivo Blood, August 1, 2005; 106(3): 906 - 912. [Abstract] [Full Text] [PDF] S. M. S. E. Santo, P. C. N. Rensen, J. R. Goudriaan, A. Bensadoun, N. Bovenschen, P. J. Voshol, L. M. Havekes, and B. J. M. van Vlijmen Triglyceride-rich lipoprotein metabolism in unique VLDL receptor, LDL receptor, and LRP triple-deficient mice J. Lipid Res., June 1, 2005; 46(6): 1097 - 1102. [Abstract] [Full Text] [PDF]

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