Increased Levels of Low-Density Lipoprotein Oxidation in Patients with Familial Hypercholesterolemia and in End-Stage Renal Disease Patients on Hemodialysis

Abstract

SUMMARY:Patients with familial hypercholesterolemia (FH) and patients with end-stage renal disease (ESRD) undergoing dialysis suffer from accelerated atherosclerosis. Oxidation of low-density lipoprotein (LDL) cholesterol is crucial in atherogenesis. In the present study, we determined the LDL oxidation level and oxidizability of isolated LDL of 11 male patients with FH, 15 male ESRD patients on hemodialysis, and 15 age-matched male normolipidemic healthy controls. FH patients were without lipid-lowering medication for at least 4 weeks and were reassessed after 2 years of cholesterol-lowering therapy (statins). LDL oxidation level was measured by ELISA using monoclonal antibody 4E6 to oxidized LDL (oxLDL) as the capture antibody and anti-human apoB antibody for detection; results were expressed as percentage oxLDL. In FH patients and in ESRD patients on hemodialysis, both groups having a higher percentage of cardiovascular disease, mean plasma LDL oxidation levels were significantly elevated compared with controls (4.9 Ϯ 1.3; 3.7 Ϯ 2.0; 1.7 Ϯ 0.6%, respectively). Within each group of subjects, LDL oxidation level was not associated with history of cardiovascular disease. Furthermore, in neither group was a significant correlation found between plasma concentration of LDL cholesterol and LDL oxidation level. After cholesterol-lowering therapy, LDL oxidation level in FH patients had not changed significantly and remained elevated compared with controls, despite a reduction of LDL cholesterol by 55% on average. Also, absolute plasma oxLDL concentrations, obtained by multiplying LDL oxidation level with plasma LDL cholesterol concentration, were significantly higher in FH patients before and after cholesterollowering therapy and in ESRD patients on hemodialysis than in controls (489 Ϯ 145; 189 Ϯ 122; 100 Ϯ 65; and 59 Ϯ 27 moles/L, respectively). No correlation was found between plasma oxLDL concentration and parameters of LDL oxidizability, LDL fatty acids, and LDL alpha-tocopherol content. We conclude that cholesterol-lowering therapy does not normalize elevated LDL oxidation levels in FH patients and elevated LDL oxidation level in FH and in ESRD might mirror atherosclerosis. (Lab Invest 2003, 83:13-21).

Serum Apolipoprotein J in Health, Coronary Heart Disease and Type 2 Diabetes Mellitus

“…The same paper reported that the expression of apo J mRNA in HepG2 cells was induced by oxidized LDLs 16) . As the concentration of apo B-containing lipoproteins is raised in humans by diets rich in saturated fats and cholesterol 28) , and hypercholesterolemic subjects have raised concentrations of oxidatively modified LDLs 29) , the association of serum apo J with apo B concentration might be a consequence of a primary effect of oxidized lipids or oxidatively modified LDLs on apo J synthesis in liver.…”

Quantification of Carbamylated LDL in Human Sera by a New Sandwich ELISA

“…The classic methods are mainly based on gradient ultracentrifugation followed by LDL isolation and measurement of protein modification (32,33 ). Protein carbamylation in serum can be assayed by a colorimetric method using diacetyl monoxime as a detector and homocitrulline as a calibrator (14 ).…”

Association of apolipoprotein E gene polymorphism with end-stage renal disease and hyperlipidemia in patients on long-term hemodialysis

“…Genetic factors are not excluded. Several studies have demonstrated the existence of genetic abnormalities among dialysis patients that lead to lipid metabolism disturbances, such as familial hypercholesterolemia, 1 polymorphism of the apolipoprotein (apo) AI-CII-AIV gene cluster 2 and paraoxonase (PON) polymorphism. 3 However, it is not yet well established how these factors contribute to the development of accelerated atherosclerosis in dialysis patients.…”