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Originally published In Press as doi:10.1194/jlr.M400229-JLR200 on August 16, 2004

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Journal of Lipid Research, Vol. 45, 2116-2122, November 2004
Copyright © 2004 by American Society for Biochemistry and Molecular Biology

Lipoprotein-X reduces LDL atherogenicity in primary biliary cirrhosis by preventing LDL oxidation

Po-Yuan Chang1,*, Shao-Chun Lu1,{dagger}, Ta-Chen Su*, San-Fang Chou{dagger}, Wen-Huei Huang{dagger}, Joel D. Morrisett§, Chu-Huang Chen§, Chiau-Suong Liau* and Yuan-Teh Lee2,*

* Departments of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan
{dagger} Biochemistry and Molecular Biology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan
§ Department of Medicine, Baylor College of Medicine, Houston, TX

2 To whom correspondence should be addressed. e-mail: ytlee{at}ha.mc.ntu.edu.tw

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.

Abbreviations: BAEC, bovine aortic endothelial cell; EC, endothelial cell; FGF2, fibroblast growth factor 2; LDL-C, low density lipoprotein cholesterol; Lp-X, lipoprotein-X; oxLDL, copper-oxidized low density lipoprotein; PBC, primary biliary cirrhosis; TBARS, thiobarbituric acid-reactive substances

Supplementary key words hypercholesterolemia • low density lipoprotein oxidation • fibroblast growth factor 2 • endothelium


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