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

Po-Yuan Chang, Shao-Chun Lu, Ta-Chen Su, San-Fang Chou, Wen-Huei Huang, Joel D. Morrisett, Chu-Huang Chen, Chiau-Suong Liau, and Yuan-Teh Lee

Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan 100

Corresponding Author: 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 as noted in control LDL. 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. The antioxidant and prosurvival properties of PBC-LDL diminished after the patients received orthotopic liver transplantation. These results suggest that Lp-X reduces LDL atherogenicity by preventing LDL oxidation to protect endothelial cell integrity in the presence of hypercholesterolemia. These results also suggest that altering LDL composition may be as important as reducing LDL concentration in preventing or treating atherosclerosis.

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