LR11/SorLA links triglyceride-rich lipoproteins to risk of developing cardiovascular disease in FH patients

Ranitha Vongpromek; Hideaki Bujo; Menno Hoekstra; Wolfgang J. Schneider; Leonie van der Zee; Arend F.L. Schinkel; Suzanne J Korporaal; Willem A.  Dik; Hiroyuki  Ebinuma; Meizi Jiang; Adrie J.M.  Verhoeven; Eric J. G. Sijbrands; Monique T. Mulder

doi:10.1016/j.atherosclerosis.2015.10.009

LR11/SorLA links triglyceride-rich lipoproteins to risk of developing cardiovascular disease in FH patients

Ranitha Vongpromek
, Hideaki Bujo
, Menno Hoekstra
, Wolfgang J. Schneider
, Leonie van der Zee
, Arend F.L. Schinkel
, Suzanne J Korporaal
, Willem A. Dik
, Hiroyuki Ebinuma
, Meizi Jiang
, Adrie J.M. Verhoeven
, Eric J. G. Sijbrands
, Monique T. Mulder^*

^*Corresponding author for this work

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

1 Citation (Scopus)

Abstract

Objective: Familial Hypercholesterolemia (FH) is associated with an increased risk of cardiovascular disease (CVD). However, whether an individual heterozygous FH patient will develop CVD depends on other genetic- and environmental risk factors as well. LDL receptor-related protein with 11 ligand binding repeat (LR11) and its soluble form (sLR11) play a role in the progression of atherosclerosis. We investigated the involvement of LR11 and sLR11 in CVD development in FH patients and in LDLR deficient (Ldlr-/-) mice.

Approach and results: In statin-treated asymptomatic male heterozygous FH subjects, plasma sLR11 levels correlated with carotid intima-media thickness. Increased plasma sLR11 levels were found in Ldlr-/- and also in wild-type mice exclusively after high-fat feeding. Hepatic LR11 mRNA levels, however, were higher in chow-fed Ldlr-/- in comparison with wild-type mice and were further increased after a high fat diet. Similar results were obtained with Apoe-/- mice, but not with wild-type mice. LR11 mRNA and protein levels and release of sLR11 from cultured HepG2 and aortic smooth muscle cells were upregulated by postprandial triglyceride-rich lipoproteins (TGRL). Overexpression of human LR11 in CHO cells resulted in increased binding and association of 12I-labeled TGRL, but not of 12I-labeled LDL.

Conclusion: Our data strongly suggest an involvement of LR11 in mediating the harmful effects of a high-fat diet on CVD progression. Elevated sLR11 levels may increase the CVD risk especially in subjects with delayed clearance of triglyceride-rich remnants, such as in FH patients.

Original language	English
Pages (from-to)	429-437
Number of pages	9
Journal	Atherosclerosis
Volume	243
Issue number	2
DOIs	https://doi.org/10.1016/j.atherosclerosis.2015.10.009
Publication status	Published - 1 Dec 2015

Keywords

LR11
TGRL
FAMILIAL HYPERCHOLESTEROLEMIA
HFD

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10.1016/j.atherosclerosis.2015.10.009

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Vongpromek, R., Bujo, H., Hoekstra, M., Schneider, W. J., van der Zee, L., Schinkel, A. F. L., Korporaal, S. J., Dik, W. A., Ebinuma, H., Jiang, M., Verhoeven, A. J. M., Sijbrands, E. J. G., & Mulder, M. T. (2015). LR11/SorLA links triglyceride-rich lipoproteins to risk of developing cardiovascular disease in FH patients. Atherosclerosis, 243(2), 429-437. https://doi.org/10.1016/j.atherosclerosis.2015.10.009

@article{e383cde564c848d993ce6c5bfe046160,

title = "LR11/SorLA links triglyceride-rich lipoproteins to risk of developing cardiovascular disease in FH patients",

abstract = "Objective: Familial Hypercholesterolemia (FH) is associated with an increased risk of cardiovascular disease (CVD). However, whether an individual heterozygous FH patient will develop CVD depends on other genetic- and environmental risk factors as well. LDL receptor-related protein with 11 ligand binding repeat (LR11) and its soluble form (sLR11) play a role in the progression of atherosclerosis. We investigated the involvement of LR11 and sLR11 in CVD development in FH patients and in LDLR deficient (Ldlr-/-) mice. Approach and results: In statin-treated asymptomatic male heterozygous FH subjects, plasma sLR11 levels correlated with carotid intima-media thickness. Increased plasma sLR11 levels were found in Ldlr-/- and also in wild-type mice exclusively after high-fat feeding. Hepatic LR11 mRNA levels, however, were higher in chow-fed Ldlr-/- in comparison with wild-type mice and were further increased after a high fat diet. Similar results were obtained with Apoe-/- mice, but not with wild-type mice. LR11 mRNA and protein levels and release of sLR11 from cultured HepG2 and aortic smooth muscle cells were upregulated by postprandial triglyceride-rich lipoproteins (TGRL). Overexpression of human LR11 in CHO cells resulted in increased binding and association of 12I-labeled TGRL, but not of 12I-labeled LDL. Conclusion: Our data strongly suggest an involvement of LR11 in mediating the harmful effects of a high-fat diet on CVD progression. Elevated sLR11 levels may increase the CVD risk especially in subjects with delayed clearance of triglyceride-rich remnants, such as in FH patients. ",

keywords = "LR11, TGRL, FAMILIAL HYPERCHOLESTEROLEMIA, HFD",

author = "Ranitha Vongpromek and Hideaki Bujo and Menno Hoekstra and Schneider, \{Wolfgang J.\} and \{van der Zee\}, Leonie and Schinkel, \{Arend F.L.\} and Korporaal, \{Suzanne J\} and Dik, \{Willem A.\} and Hiroyuki Ebinuma and Meizi Jiang and Verhoeven, \{Adrie J.M.\} and Sijbrands, \{Eric J. G.\} and Mulder, \{Monique T.\}",

year = "2015",

month = dec,

day = "1",

doi = "10.1016/j.atherosclerosis.2015.10.009",

language = "English",

volume = "243",

pages = "429--437",

journal = "Atherosclerosis",

issn = "0021-9150",

publisher = "Elsevier Ireland Ltd",

number = "2",

}

Vongpromek, R, Bujo, H, Hoekstra, M, Schneider, WJ, van der Zee, L, Schinkel, AFL, Korporaal, SJ, Dik, WA, Ebinuma, H, Jiang, M, Verhoeven, AJM, Sijbrands, EJG & Mulder, MT 2015, 'LR11/SorLA links triglyceride-rich lipoproteins to risk of developing cardiovascular disease in FH patients', Atherosclerosis, vol. 243, no. 2, pp. 429-437. https://doi.org/10.1016/j.atherosclerosis.2015.10.009

TY - JOUR

T1 - LR11/SorLA links triglyceride-rich lipoproteins to risk of developing cardiovascular disease in FH patients

AU - Vongpromek, Ranitha

AU - Bujo, Hideaki

AU - Hoekstra, Menno

AU - Schneider, Wolfgang J.

AU - van der Zee, Leonie

AU - Schinkel, Arend F.L.

AU - Korporaal, Suzanne J

AU - Dik, Willem A.

AU - Ebinuma, Hiroyuki

AU - Jiang, Meizi

AU - Verhoeven, Adrie J.M.

AU - Sijbrands, Eric J. G.

AU - Mulder, Monique T.

PY - 2015/12/1

Y1 - 2015/12/1

N2 - Objective: Familial Hypercholesterolemia (FH) is associated with an increased risk of cardiovascular disease (CVD). However, whether an individual heterozygous FH patient will develop CVD depends on other genetic- and environmental risk factors as well. LDL receptor-related protein with 11 ligand binding repeat (LR11) and its soluble form (sLR11) play a role in the progression of atherosclerosis. We investigated the involvement of LR11 and sLR11 in CVD development in FH patients and in LDLR deficient (Ldlr-/-) mice. Approach and results: In statin-treated asymptomatic male heterozygous FH subjects, plasma sLR11 levels correlated with carotid intima-media thickness. Increased plasma sLR11 levels were found in Ldlr-/- and also in wild-type mice exclusively after high-fat feeding. Hepatic LR11 mRNA levels, however, were higher in chow-fed Ldlr-/- in comparison with wild-type mice and were further increased after a high fat diet. Similar results were obtained with Apoe-/- mice, but not with wild-type mice. LR11 mRNA and protein levels and release of sLR11 from cultured HepG2 and aortic smooth muscle cells were upregulated by postprandial triglyceride-rich lipoproteins (TGRL). Overexpression of human LR11 in CHO cells resulted in increased binding and association of 12I-labeled TGRL, but not of 12I-labeled LDL. Conclusion: Our data strongly suggest an involvement of LR11 in mediating the harmful effects of a high-fat diet on CVD progression. Elevated sLR11 levels may increase the CVD risk especially in subjects with delayed clearance of triglyceride-rich remnants, such as in FH patients.

AB - Objective: Familial Hypercholesterolemia (FH) is associated with an increased risk of cardiovascular disease (CVD). However, whether an individual heterozygous FH patient will develop CVD depends on other genetic- and environmental risk factors as well. LDL receptor-related protein with 11 ligand binding repeat (LR11) and its soluble form (sLR11) play a role in the progression of atherosclerosis. We investigated the involvement of LR11 and sLR11 in CVD development in FH patients and in LDLR deficient (Ldlr-/-) mice. Approach and results: In statin-treated asymptomatic male heterozygous FH subjects, plasma sLR11 levels correlated with carotid intima-media thickness. Increased plasma sLR11 levels were found in Ldlr-/- and also in wild-type mice exclusively after high-fat feeding. Hepatic LR11 mRNA levels, however, were higher in chow-fed Ldlr-/- in comparison with wild-type mice and were further increased after a high fat diet. Similar results were obtained with Apoe-/- mice, but not with wild-type mice. LR11 mRNA and protein levels and release of sLR11 from cultured HepG2 and aortic smooth muscle cells were upregulated by postprandial triglyceride-rich lipoproteins (TGRL). Overexpression of human LR11 in CHO cells resulted in increased binding and association of 12I-labeled TGRL, but not of 12I-labeled LDL. Conclusion: Our data strongly suggest an involvement of LR11 in mediating the harmful effects of a high-fat diet on CVD progression. Elevated sLR11 levels may increase the CVD risk especially in subjects with delayed clearance of triglyceride-rich remnants, such as in FH patients.

KW - LR11

KW - TGRL

KW - FAMILIAL HYPERCHOLESTEROLEMIA

KW - HFD

UR - https://www.scopus.com/pages/publications/84946434114

U2 - 10.1016/j.atherosclerosis.2015.10.009

DO - 10.1016/j.atherosclerosis.2015.10.009

M3 - Article

C2 - 26520897

AN - SCOPUS:84946434114

SN - 0021-9150

VL - 243

SP - 429

EP - 437

JO - Atherosclerosis

JF - Atherosclerosis

IS - 2

ER -

LR11/SorLA links triglyceride-rich lipoproteins to risk of developing cardiovascular disease in FH patients

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