Lipoprotein-X reduces LDL atherogenicity in primary biliary cirrhosis by preventing LDL oxidation.
Hypercholesterolemic human LDL contains oxidized subfractions that have atherogenic properties. Paradoxically, atherosclerosis incidence is low in patients with primary biliary cirrhosis (PBC), a disease characterized by marked increases in plasma LDL, including the LDL subfraction lipoprotein-X (Lp-X). To investigate the mechanisms underlying this paradox, we first examined the propensity to oxidation of unfractionated LDL isolated from PBC patients. After prolonged incubation with copper, PBC-LDL failed to increase the oxidation index or electrophoretic mobility noted in control LDL. An admixture of PBC-LDL or Lp-X with control LDL prevented oxidation of the latter in a dose-dependent manner. PBC-LDL was also noncompetitive against copper-oxidized LDL (oxLDL) for binding with a murine monoclonal anti-oxLDL antibody in a competitive ELISA. OxLDL exerts its proapoptotic and antiangiogenic effects in part by inhibiting fibroblast growth factor 2 (FGF2) expression. Preincubation of oxLDL with PBC-LDL, but not control LDL, attenuated the inhibitory effects of oxLDL on FGF2 expression in cultured bovine aortic endothelial cells (ECs). The antioxidant and prosurvival properties of PBC-LDL diminished after the patients underwent orthotopic liver transplantation. These results suggest that Lp-X reduces LDL atherogenicity by preventing LDL oxidation to protect EC integrity in the presence of hypercholesterolemia. They also suggest that altering LDL composition may be as important as reducing LDL concentration in preventing or treating atherosclerosis.
Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan.
Po-Yuan
PY
Chang
Shao-Chun
SC
Lu
Ta-Chen
TC
Su
San-Fang
SF
Chou
Wen-Huei
WH
Huang
Joel D
JD
Morrisett
Chu-Huang
CH
Chen
Chiau-Suong
CS
Liau
Yuan-Teh
YT
Lee
D000818:Animals; D001011:Aorta / Q000166:cytology; D017209:Apoptosis; D002417:Cattle; D002478:Cells, Cultured; D002850:Chromatography, Gel; D015536:Down-Regulation; D004587:Electrophoresis, Agar Gel; D004730:Endothelium, Vascular / Q000166:cytology; D004797:Enzyme-Linked Immunosorbent Assay; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D049673:History, 20th Century; D008024:Ligands; D008073:Lipoprotein-X / Q000378:metabolism*; D008077:Lipoproteins, LDL / Q000378:metabolism; D008105:Liver Cirrhosis, Biliary / Q000378:metabolism*; D010100:Oxygen / Q000378:metabolism*; D010455:Peptides / Q000737:chemistry; D012333:RNA, Messenger / Q000378:metabolism; D013997:Time Factors
D008024:Ligands; D008073:Lipoprotein-X; D008077:Lipoproteins, LDL; D010455:Peptides; D012333:RNA, Messenger; D016222:Fibroblast Growth Factor 2; D010100:Oxygen