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.
  
  
  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.
  
  
  CONCLUSIONS
  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.affiliation: Department of Internal Medicine, Section of Pharmacology Vascular and Metabolic Diseases, Cardiovascular Research School COEUR, Erasmus Medical Center, Wytemaweg 80, 301CN, Rotterdam, The Netherlands.
authors.forename: Ranitha
authors.initials: R
authors.lastname: Vongpromek
authors.affiliation: Department of Clinical-Laboratory and Experimental-Research Medicine, Toho University, Sakura Medical Center, 564-1 Shimoshizu, Sakura-shi, Chiba, 285-8741, Japan.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Bujo
authors.affiliation: Department of Biopharmaceutics, Leiden Academic Centre for Drug Research, Leiden University, Einsteinweg 55, 2322 CC, Leiden, The Netherlands.
authors.forename: Menno
authors.initials: M
authors.lastname: Hoekstra
authors.affiliation: Department of Medical Biochemistry, Medical University of Vienna, Max. F. Perutz Laboratories, Dr. Bohr-Gasse 9, 1030, Vienna, Austria.
authors.forename: Wolfgang J
authors.initials: WJ
authors.lastname: Schneider
authors.affiliation: Department of Internal Medicine, Section of Pharmacology Vascular and Metabolic Diseases, Cardiovascular Research School COEUR, Erasmus Medical Center, Wytemaweg 80, 301CN, Rotterdam, The Netherlands.
authors.forename: Leonie
authors.initials: L
authors.lastname: van der Zee
authors.affiliation: Department of Cardiology, Faculty of Medicine, Erasmus Medical Center, s'Gravendijkwal 230, 3015CE, Rotterdam, The Netherlands.
authors.forename: Arend F L
authors.initials: AF
authors.lastname: Schinkel
authors.affiliation: Department of Biopharmaceutics, Leiden Academic Centre for Drug Research, Leiden University, Einsteinweg 55, 2322 CC, Leiden, The Netherlands.
authors.forename: Suzanne J A
authors.initials: SJ
authors.lastname: Korporaal
authors.affiliation: Department of Immunology, Section Medical Immunology, Faculty of Medicine, Erasmus Medical Center, s'Gravendijkwal 230, 3015CE, Rotterdam, The Netherlands.
authors.forename: Willem A
authors.initials: WA
authors.lastname: Dik
authors.affiliation: Tsukuba Research Institute, Sekisui Medical, 3-3-1 Koyodai, Ryugasaki, 301-0852, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Ebinuma
authors.affiliation: Department of Clinical-Laboratory and Experimental-Research Medicine, Toho University, Sakura Medical Center, 564-1 Shimoshizu, Sakura-shi, Chiba, 285-8741, Japan.
authors.forename: Meizi
authors.initials: M
authors.lastname: Jiang
authors.affiliation: Department of Internal Medicine, Section of Pharmacology Vascular and Metabolic Diseases, Cardiovascular Research School COEUR, Erasmus Medical Center, Wytemaweg 80, 301CN, Rotterdam, The Netherlands.
authors.forename: Adrie J M
authors.initials: AJ
authors.lastname: Verhoeven
authors.affiliation: Department of Internal Medicine, Section of Pharmacology Vascular and Metabolic Diseases, Cardiovascular Research School COEUR, Erasmus Medical Center, Wytemaweg 80, 301CN, Rotterdam, The Netherlands.
authors.forename: Eric J G
authors.initials: EJ
authors.lastname: Sijbrands
authors.affiliation: Department of Internal Medicine, Section of Pharmacology Vascular and Metabolic Diseases, Cardiovascular Research School COEUR, Erasmus Medical Center, Wytemaweg 80, 301CN, Rotterdam, The Netherlands. Electronic address: m.t.mulder@erasmusmc.nl.
authors.forename: Monique T
authors.initials: MT
authors.lastname: Mulder
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D015415:Biomarkers / Q000097:blood; D016466:CHO Cells; D002340:Carotid Artery Diseases / Q000097:blood / Q000175:diagnosis / Q000209:etiology* / Q000517:prevention & control; D059168:Carotid Intima-Media Thickness; D053298:Chylomicron Remnants / Q000097:blood; D003412:Cricetulus; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D056945:Hep G2 Cells; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use; D006938:Hyperlipoproteinemia Type II / Q000097:blood / Q000150:complications* / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics; D026502:LDL-Receptor Related Proteins / Q000097:blood* / Q000235:genetics; D008074:Lipoproteins / Q000097:blood*; D008297:Male; D026901:Membrane Transport Proteins / Q000097:blood* / Q000235:genetics; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D034622:RNA Interference; D011973:Receptors, LDL / Q000097:blood* / Q000235:genetics / Q000378:metabolism; D012307:Risk Factors; D013997:Time Factors; D014162:Transfection; D014280:Triglycerides / Q000097:blood*
chemical_list: D001057:Apolipoproteins E; D015415:Biomarkers; D053298:Chylomicron Remnants; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D026502:LDL-Receptor Related Proteins; C573412:LDLR protein, human; D008074:Lipoproteins; D026901:Membrane Transport Proteins; D011973:Receptors, LDL; C102582:SORL1 protein, human; C491168:Sorl1 protein, mouse; D014280:Triglycerides
keywords: Familial hypercholesterolemia; HFD; LR11; TGRL