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

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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
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
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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
TNO Identifier
280229
Repository link
https://resolver.tno.nl/uuid:df0823aa-37de-430b-9fcd-72d5471c9091
ISSN
00064971
Source
Blood, 103(10), pp. 3777-3782.
Pages
3777-3782
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