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

Sonia M S Espirito Santo; Nuno M M Pires; Lianne S M Boesten; Gery Gerritsen; Niels Bovenschen; Ko Willems van Dijk; J Wouter Jukema; Hans M G Princen; André Bensadoun; Wei-Ping Li; Joachim Herz; Louis M Havekes; Bart J M van Vlijmen

doi:10.1182/blood-2003-11-4051

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

Sonia M S Espirito Santo, Nuno M M Pires, Lianne S M Boesten, Gery Gerritsen, Niels Bovenschen, Ko Willems van Dijk, J Wouter Jukema, Hans M G Princen, André Bensadoun, Wei-Ping Li, Joachim Herz, Louis M Havekes, Bart J M van Vlijmen

Research output: Contribution to journal › Article › Academic › peer-review

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(+)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.

Original language	English
Pages (from-to)	3777-82
Number of pages	6
Journal	Blood
Volume	103
Issue number	10
DOIs	https://doi.org/10.1182/blood-2003-11-4051
Publication status	Published - 2004
Externally published	Yes

Keywords

Animals
Aorta
Apolipoproteins E
Arteriosclerosis
Blood Coagulation Factors
Cholesterol
Lipids
Liver
Low Density Lipoprotein Receptor-Related Protein-1
Male
Mice
Mice, Knockout
Mice, Transgenic
Receptors, LDL

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10.1182/blood-2003-11-4051

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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. (2004). Hepatic low-density lipoprotein receptor-related protein deficiency in mice increases atherosclerosis independent of plasma cholesterol. Blood, 103(10), 3777-82. https://doi.org/10.1182/blood-2003-11-4051

@article{1151523ffe44404b89ea7e0298ba7672,

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

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(+)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.",

keywords = "Animals, Aorta, Apolipoproteins E, Arteriosclerosis, Blood Coagulation Factors, Cholesterol, Lipids, Liver, Low Density Lipoprotein Receptor-Related Protein-1, Male, Mice, Mice, Knockout, Mice, Transgenic, Receptors, LDL",

author = "{Espirito Santo}, {Sonia M S} and Pires, {Nuno M M} and Boesten, {Lianne S M} and Gery Gerritsen and Niels Bovenschen and {van Dijk}, {Ko Willems} and Jukema, {J Wouter} and Princen, {Hans M G} and Andr{\'e} Bensadoun and Wei-Ping Li and Joachim Herz and Havekes, {Louis M} and {van Vlijmen}, {Bart J M}",

year = "2004",

doi = "10.1182/blood-2003-11-4051",

language = "English",

volume = "103",

pages = "3777--82",

journal = "Blood",

issn = "0006-4971",

publisher = "Elsevier",

number = "10",

}

Espirito Santo, SMS, Pires, NMM, Boesten, LSM, Gerritsen, G, Bovenschen, N, van Dijk, KW, Jukema, JW, Princen, HMG, Bensadoun, A, Li, W-P, Herz, J, Havekes, LM & van Vlijmen, BJM 2004, 'Hepatic low-density lipoprotein receptor-related protein deficiency in mice increases atherosclerosis independent of plasma cholesterol', Blood, vol. 103, no. 10, pp. 3777-82. https://doi.org/10.1182/blood-2003-11-4051

TY - JOUR

T1 - Hepatic low-density lipoprotein receptor-related protein deficiency in mice increases atherosclerosis independent of plasma cholesterol

AU - Espirito Santo, Sonia M S

AU - Pires, Nuno M M

AU - Boesten, Lianne S M

AU - Gerritsen, Gery

AU - Bovenschen, Niels

AU - van Dijk, Ko Willems

AU - Jukema, J Wouter

AU - Princen, Hans M G

AU - Bensadoun, André

AU - Li, Wei-Ping

AU - Herz, Joachim

AU - Havekes, Louis M

AU - van Vlijmen, Bart J M

PY - 2004

Y1 - 2004

N2 - 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.

AB - 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.

KW - Animals

KW - Aorta

KW - Apolipoproteins E

KW - Arteriosclerosis

KW - Blood Coagulation Factors

KW - Cholesterol

KW - Lipids

KW - Liver

KW - Low Density Lipoprotein Receptor-Related Protein-1

KW - Male

KW - Mice

KW - Mice, Knockout

KW - Mice, Transgenic

KW - Receptors, LDL

U2 - 10.1182/blood-2003-11-4051

DO - 10.1182/blood-2003-11-4051

M3 - Article

C2 - 14739216

SN - 0006-4971

VL - 103

SP - 3777

EP - 3782

JO - Blood

JF - Blood

IS - 10

ER -

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

Abstract

Keywords

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