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Hepatic low-density lipoprotein receptor-related protein deficiency in mice increases atherosclerosis independent of plasma cholesterol

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Author: Espirito Santo, S.M.S. · Pires, N.M.M. · Boesten, L.S.M. · Gerritsen, G. · Bovenschen, N. · Dijk, K.W. van · Jukema, J.W. · Princen, H.M.G. · Bensadoun, A. · Li, W.P. · Herz, J. · Havekes, L.M. · Vlijmen, B.J.M. van
Type:article
Date:2004
Institution: Gaubius Instituut TNO
Source:Blood, 10, 103, 3777-3782
Identifier: 280229
doi: doi:10.1182/blood-2003-11-4051
Keywords: Blood clotting factor 8 · Cholesterol · Ligand · Lipoprotein lipase · Liver protein · Low density lipoprotein receptor · Low density lipoprotein receptor related protein · Tissue plasminogen activator · Triacylglycerol · Von Willebrand factor · Animal experiment · Animal model · Animal tissue · Atherogenesis · Cholesterol blood level · Controlled study · Hyperlipoproteinemia type 3 · Liver function · Liver metabolism · Mouse · Nonhuman · Protein deficiency · Triacylglycerol blood level · Animals · Aorta · Apolipoproteins E · Arteriosclerosis · Blood Coagulation Factors · Cholesterol · LDL-Receptor Related Protein 1 · Lipids · Liver · Male · Mice · Mice, Knockout · Mice, Transgenic · Receptors, LDL

Abstract

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<sup>+</sup>LRP<sup>flox/flox</sup>LDLR <sup>-/-</sup>APOE<sup>-/-</sup> On an LDLR<sup>-/-</sup>APOE<sup>-/-</sup> 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<sup>+</sup>LRP<sup>flox/flox</sup>-LDLR<sup>-/-</sup>APOE<sup>-/-</sup> and control LRP<sup>flox/flox</sup>-LDLR<sup>-/-</sup>APOE<sup>-/-</sup> mice, respectively). Lower plasma cholesterol in MX1Cre<sup>+</sup>LRP <sup>flox/flox</sup>-LDLR<sup>-/-</sup>APOE<sup>-/-</sup> 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 <sup>+</sup>-LRP<sup>flox/flox</sup>LDLR<sup>-/-</sup>APOE<sup>-/-</sup> mice showed a 2-fold higher atherosclerotic lesion area compared with controls (408. 5 ± 115.1 vs 219.1 ± 86.0 10<sup>3</sup>μm<sup>2</sup>, 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. © 2004 by The American Society of Hematology. Chemicals/CAS: blood clotting factor 8, 9001-27-8; cholesterol, 57-88-5; lipoprotein lipase, 83137-80-8, 9004-02-8; tissue plasminogen activator, 105913-11-9; von Willebrand factor, 109319-16-6; Apolipoproteins E; Blood Coagulation Factors; Cholesterol, 57-88-5; LDL-Receptor Related Protein 1; Lipids; Receptors, LDL