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