Enhanced bridging function and augmented monocyte adhesion by lipoprotein lipase N9: insights into increased risk of coronary artery disease in N9 carriers.
Lipoprotein lipase (LPL) is central to triacylglycerol (TG) metabolism, having both hydrolytic and bridging functions. The common LPL gene variant D9N is associated with raised TG, reduced HDL-cholesterol concentrations and increased risk of coronary artery disease (CAD). To investigate the functional basis for the phenotype in N9 carriers, CHO K1 cells were stably transfected with wild type (D9) or mutant (N9) LPL cDNA. LPL RNA expression levels, monomer-to-dimer ratios, and dimer specific activities were similar in D9 and N9 cells. Significantly enhanced binding (4.6-fold) and internalisation (2.6-fold) of 125I-LDL by N9 compared with D9 cells was eradicated by pre-treatment with either heparin or heparinase, confirming involvement of LPL and cell surface proteoglycans. N9 cells bound and internalised 3.8- and 4.4-fold more oxidised 125I-LDL, respectively, than D9 cells (both P<0.0001). Binding of monocytes was 7-fold greater to plates coated with purified LPL-N9 dimer compared with LPL-D9 (P<=0.005). Thus once on the cell surface, LPL-N9 enhances bridging, as assessed both by LDL binding and internalisation, and monocyte adhesion. This augmented LPL-N9 bridging provides a mechanism for the reported increased CAD risk in N9 carriers.
Fisher
Rachel M
RM
Department of Medicine, Royal Free and University College Medical School, Rayne Institute, 5 University Street, London WC1E 6JJ, UK. rachel.fisher@medks.ki.se
Benhizia
Ferdaous
F
Schreiber
Renate
R
Makoveichuk
Elena
E
Putt
Wendy
W
Al-Haideri
Maysoon
M
Deckelbaum
Richard J
RJ
Olivecrona
Gunilla
G
Humphries
Steve E
SE
Talmud
Philippa J
PJ
D001483:Base Sequence; D002448:Cell Adhesion; D002478:Cells, Cultured; D003324:Coronary Artery Disease / Q000235:genetics* / Q000503:physiopathology; D020022:Genetic Predisposition to Disease; D006579:Heterozygote; D006801:Humans; D008071:Lipoprotein Lipase / Q000235:genetics* / Q000378:metabolism; D008969:Molecular Sequence Data; D009000:Monocytes / Q000502:physiology; D011336:Probability; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012307:Risk Factors; D012680:Sensitivity and Specificity; D014280:Triglycerides / Q000235:genetics* / Q000378:metabolism
D012333:RNA, Messenger; D014280:Triglycerides; D008071:Lipoprotein Lipase