Print Email Facebook Twitter Hepatic low-density lipoprotein receptor-related protein deficiency in mice increases atherosclerosis independent of plasma cholesterol Title Hepatic low-density lipoprotein receptor-related protein deficiency in mice increases atherosclerosis independent of plasma cholesterol Author Espirito Santo, S.M.S. Pires, N.M.M. Boesten, L.S.M. Gerritsen, G. Bovenschen, N. van Dijk, K.W. Jukema, J.W. Princen, H.M.G. Bensadoun, A. Li, W.P. Herz, J. Havekes, L.M. van Vlijmen, B.J.M. Gaubius Instituut TNO Publication year 2004 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+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+LRP flox/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. © 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 Subject Blood clotting factor 8CholesterolLigandLipoprotein lipaseLiver proteinLow density lipoprotein receptorLow density lipoprotein receptor related proteinTissue plasminogen activatorTriacylglycerolVon Willebrand factorAnimal experimentAnimal modelAnimal tissueAtherogenesisCholesterol blood levelControlled studyHyperlipoproteinemia type 3Liver functionLiver metabolismMouseNonhumanProtein deficiencyTriacylglycerol blood levelAnimalsAortaApolipoproteins EArteriosclerosisBlood Coagulation FactorsCholesterolLDL-Receptor Related Protein 1LipidsLiverMaleMiceMice, KnockoutMice, TransgenicReceptors, LDL To reference this document use: http://resolver.tudelft.nl/uuid:df0823aa-37de-430b-9fcd-72d5471c9091 DOI https://doi.org/10.1182/blood-2003-11-4051 TNO identifier 280229 ISSN 0006-4971 Source Blood, 103 (10), 3777-3782 Document type article Files To receive the publication files, please send an e-mail request to TNO Library.