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

Abstract

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. -Chang, P-Y., S-C. Lu, T-C. Su, S-F. Chou, W-H. Huang, J. D. Morrisett, C-H. Chen, C-S. Liau, and Y-T. Lee. Lipoprotein-X reduces LDL atherogenicity in primary biliary cirrhosis by preventing LDL oxidation.

Cholesterol metabolism in cholestatic liver disease and liver transplantation: From molecular mechanisms to clinical implications

“…Nuclear magnetic resonance spectroscopy measurements of lipoproteins reveal that Lp-X exist in PBC patients more commonly than currently recognized [48] . This phenomenon explains why high LDL cholesterol concentrations within the context of PBC, when actually caused by Lp-X, show no association with atherosclerotic events [38][39][40][41] . Lp-X formation is typically associated with a low apo B-100 concentration together with a high total cholesterol concentration [44] .…”

“…Despite reduced cholesterol synthesis, high serum total and LDL cholesterol concentrations and even xanthomata are common features in PBC and other forms of cholestatic liver disease [35,[38][39][40][41][42][43][44][45][46][47] . In PBC, serum total cholesterol varies widely, ranging from 2.9 to 46.1 mmol/L (112-1779 mg/dL), and even up to 83 mmol/L (3204 mg/dL) [43] .…”

Lecithin:cholesterol acyltransferase: old friend or foe in atherosclerosis?

“…LCAT knockout mice of Sakai et al that were fed an atherogenic diet containing 15% fat, 1.25% cholesterol, and 0.5% cholic acid displayed not only nearly absent HDL levels but also remarkably lower plasma levels of proatherogenic apoB-containing lipoproteins, probably through upregulation of the LDL receptor and an increase in plasma apoE ( 9,129 ). In addition, some mice accumulated lipoprotein X (Lp-X), an abnormal lipoprotein particle within the LDL density region that is rich in free cholesterol and phospholipids ( 130 ). This particle also accumulates in cholic liver disease and has been shown to have anti-oxidant properties ( 130 ).…”

“…In addition, some mice accumulated lipoprotein X (Lp-X), an abnormal lipoprotein particle within the LDL density region that is rich in free cholesterol and phospholipids ( 130 ). This particle also accumulates in cholic liver disease and has been shown to have anti-oxidant properties ( 130 ). The subset of LCAT knockout mice that accumulated lipoprotein X also developed proteinuria and glomerulosclerosis characterized by mesangial cell proliferation, sclerosis, lipid accumulation, and deposition of electron dense material throughout the glomeruli on the atherogenic diet ( 129 ).…”

Lipoprotein X in a patient with cholestasis and hypertriglyceridaemia

“…It has been documented that lipoprotein X prevents the origination of oxidized LDL products and thus reducing LDL atherogenicity. 16,17 Moreover, the presence of lipoprotein X is a transient phenomenon and resolves with improvement in liver function tests. Thus, the effect of the lipoprotein X on atherosclerosis is negligible.…”