Hepatic low-density lipoprotein receptor-related protein deficiency in mice increases atherosclerosis independent of plasma cholesterol.
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(+)LRP(flox/flox)LDLR(-/-)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(+)LRP(flox/flox)-LDLR(-/-)APOE(-/-) and control LRP(flox/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(+)LRP(flox/flox)LDLR(-/-)APOE(-/-) mice showed a 2-fold higher atherosclerotic lesion area compared with controls (408.5 +/- 115.1 vs 219.1 +/- 86.0 10(3)microm(2), 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.
Espirito Santo
Sonia M S
SM
TNO-Prevention and Health, Leiden, the Netherlands.
Pires
Nuno M M
NM
Boesten
Lianne S M
LS
Gerritsen
Gery
G
Bovenschen
Niels
N
van Dijk
Ko Willems
KW
Jukema
J Wouter
JW
Princen
Hans M G
HM
Bensadoun
André
A
Li
Wei-Ping
WP
Herz
Joachim
J
Havekes
Louis M
LM
van Vlijmen
Bart J M
BJ
D000818:Animals; D001011:Aorta / Q000737:chemistry; D001057:Apolipoproteins E / Q000172:deficiency; D001161:Arteriosclerosis / Q000097:blood / Q000209:etiology* / Q000473:pathology; D001779:Blood Coagulation Factors / Q000032:analysis; D002784:Cholesterol / Q000097:blood*; D008055:Lipids / Q000097:blood; D008099:Liver / Q000737:chemistry*; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000172:deficiency* / Q000502:physiology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011973:Receptors, LDL / Q000172:deficiency
D001057:Apolipoproteins E; D001779:Blood Coagulation Factors; D008055:Lipids; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D011973:Receptors, LDL; D002784:Cholesterol