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.

• Authors: Ranitha Vongpromek, Hideaki Bujo, Menno Hoekstra, Wolfgang J Schneider, Leonie van der Zee, Arend F L Schinkel, Suzanne J A Korporaal, Willem A Dik, Hiroyuki Ebinuma, Meizi Jiang, Adrie J M Verhoeven, Eric J G Sijbrands, Monique T Mulder
• Journal: Atherosclerosis (Atherosclerosis) Vol. 243 Issue 2 Pg. 429-37 (Dec 2015) ISSN: 1879-1484 [Electronic] Ireland
• PMID: 26520897 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Chemical References

• Apolipoproteins E
• Biomarkers
• Chylomicron Remnants
• Hydroxymethylglutaryl-CoA Reductase Inhibitors
• LDL-Receptor Related Proteins
• LDLR protein, human
• Lipoproteins
• Membrane Transport Proteins
• Receptors, LDL
• SORL1 protein, human
• Sorl1 protein, mouse
• Triglycerides

Topics

• Animals
• Apolipoproteins E (deficiency, genetics)
• Biomarkers (blood)
• CHO Cells
• Carotid Artery Diseases (blood, diagnosis, etiology, prevention & control)
• Carotid Intima-Media Thickness
• Chylomicron Remnants (blood)
• Cricetulus
• Diet, High-Fat
• Disease Models, Animal
• Hep G2 Cells
• Humans
• Hydroxymethylglutaryl-CoA Reductase Inhibitors (therapeutic use)
• Hyperlipoproteinemia Type II (blood, complications, diagnosis, drug therapy, genetics)
• LDL-Receptor Related Proteins (blood, genetics)
• Lipoproteins (blood)
• Male
• Membrane Transport Proteins (blood, genetics)
• Mice, Inbred C57BL
• Mice, Knockout
• RNA Interference
• Receptors, LDL (blood, genetics, metabolism)
• Risk Factors
• Time Factors
• Transfection
• Triglycerides (blood)