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Blood, 15 May 2004, Vol. 103, No. 10, pp. 3777-3782. Prepublished online as a Blood First Edition Paper on January 22, 2004February 5, 2004; DOI 10.1182/blood-2003-11-4051. This Article 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 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 Articles by van Vlijmen, B. J Search for Related Content PubMed PubMed Citation Articles by Espirito Santo, S. M Articles by van Vlijmen, B. J Social Bookmarking                   What's this? Submitted December 1, 2003 Accepted January 12, 2004 Hepatic Low-Density Lipoprotein Receptor-Related Protein Deficiency in Mice Increases Atherosclerosis Independent of Plasma Cholesterol Sonia M Espirito Santo, Nuno M Pires, Lianne S Boesten, Gery Gerritsen, Niels Bovenschen, Ko Willems van Dijk, J W Jukema, Hans M Princen, Andre Bensadoun, Wei-Ping Li, Joachim Herz, Louis M Havekes, and Bart J van Vlijmen* Biomedical Research, TNO-Prevention and Health, Leiden, The Netherlands; Cardiology, Leiden University Medical Center, Leiden, The Netherlands Human Genetics, Leiden University Medical Center, Leiden, The Netherlands Biomedical Research, TNO-Prevention and Health, Leiden, The Netherlands; Plasma proteins, Sanquin Research at CLB, Amsterdam, The Netherlands Human Genetics, Leiden University Medical Center, Leiden, The Netherlands; General Internal Medicine, Leiden University Medical Center, Leiden, The Netherlands Cardiology, Leiden University Medical Center, Leiden, The Netherlands Biomedical Research, TNO-Prevention and Health, Leiden, The Netherlands Division of Nutritional Sciences, Cornell University, Ithaca, NY, USA Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX, USA Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX, USA Biomedical Research, TNO-Prevention and Health, Leiden, The Netherlands; Cardiology, Leiden University Medical Center, Leiden, The Netherlands; Plasma proteins, Sanquin Research at CLB, Amsterdam, The Netherlands * Corresponding author; email: bjm.vanvlijmen{at}pg.tno.nl. The low-density lipoprotein (LDL) receptor-related protein (LRP) has a well-established role in the hepatic removal of atherogenic apolipoprotein (APO) E-rich remnant lipoproteins from plasma. In addition, LRP recognizes multiple distinct pro- and anti-atherogenic 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 a 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=0.025; triglycerides: 1.1±0.5 vs. 2.2±0.8 mM, P=0.002; for MX1Cre+LRPflox/floxLDLR-/-APOE-/- and control LRPflox/floxLDLR-/-APOE-/- mice, respectively). Lower plasma cholesterol in MX1Cre+LRPflox/floxLDLR-/-APOE-/- mice coincided with increased plasma lipoprotein lipase (71.2±7.5 vs. 19.1±2.4 ng/ml, P=0.002), coagulation factor VIII (4.4±1.1 vs. 1.9±0.5 U/mL, P=0.001), von Willebrand factor (2.8±0.6 vs. 1.4±0.3 U/mL, P=0.001), and tissue-type plasminogen activator (1.7±0.7 vs. 0.9±0.5 ng/ml, P=0.008) as compared to controls. Strikingly, MX1Cre+LRPflox/floxLDLR-/-APOE-/- mice showed a 2-fold higher atherosclerotic lesion area as compared to controls (408.5±115.1 vs. 219.1±86.0 103µm2, P=0.003). 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 pro-atherogenic ligands. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: P. L.S.M. Gordts, S. Reekmans, A. Lauwers, A. Van Dongen, L. Verbeek, and A. J.M. Roebroek Inactivation of the LRP1 Intracellular NPxYxxL Motif in LDLR-Deficient Mice Enhances Postprandial Dyslipidemia and Atherosclerosis Arterioscler Thromb Vasc Biol, September 1, 2009; 29(9): 1258 - 1264. [Abstract] [Full Text] [PDF] 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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