Elevated HDL2-paraoxonase and reduced CETP activity are associated with a dramatically lower ratio of LDL-cholesterol/total cholesterol in a hypercholesterolemic and hypertriglyceridemic patient

Abstract

Abstract.A female patient (64 years of age; body mass index, 26) had a markedly and relatively low low-density lipoprotein-cholesterol (LDL-C) level (97 mg/dl) despite high serum total cholesterol (TC) (331 mg/dl) and triacylglyceride levels (307 mg/dl). Since the expected LDL-C was 222 mg/dl, there was a significant difference between the calculation and measurement based on direct enzyme assay. Only 30% of serum cholesterol was associated with LDL-C in this patient. To determine the basis for the markedly low LDL-C/TC ratio, we isolated and analyzed lipoproteins from the patient as well as age-and gender-matched controls. The patient had lowered serum CETP activity and elevated paraoxonase activity with GOT and GPT values in the normal range. The very low-density lipoprotein particles from the patient were larger than those of the controls and enriched with lipid and protein, while the LDL from the patient (LDL-P) had a lower particle number and protein content than the controls. The LDL-P was more resistant to cupric ion-mediated oxidation. HDL 2 from the patient (HDL 2 -P) had highly enhanced paraoxonase activity and antioxidant ability. The patient had a 1.5-fold higher level of apolipoprotein (apo) A-I expression in HDL 2 . ApoA-I in HDL 2 and HDL 3 from the patient showed no fragmentation, while the control had fragmented bands (17 and 21 kDa) in the HDL. The HDL 2 -P also had a larger particle size and greater protein content with less lipid content. HDL 3 -associated cholesteryl ester transfer protein was reduced in the patient, although the particle size was similar to the controls. In conclusion, a patient who had a markedly lower LDL-C/TC ratio despite hyperlipidemia associated with higher paraoxonase activity, higher apoA-I level and lower CETP activity without fragmentation of apoA-I in the HDL fraction is presented. The enhanced antioxidant and anti-inflammatory activity of HDL might contribute to the low LDL-C/TC ratio in this patient. IntroductionDyslipidemia is an important risk factor for coronary heart disease (CHD), and low-density lipoprotein-cholesterol (LDL-C) is a strong biomarker to predict the risk of CHD (1). Patients with diabetes and metabolic syndrome have a strong association with atherogenic dyslipidemia, which includes high levels of triacylglycerides (TG) and elevated levels of small dense LDL (2). The most widely used method to calculate LDL-C is the Friedewald equation (3), although several methods of direct measurement are currently used. However, the estimated LDL-C using the Friedewald equation does not produce an accurate number when the plasma TG is >400 mg/dl or when plasma is not collected in the fasting state (4). Otherwise, a discrepancy in the number of measured LDL-C and the Friedewald LDL-C might indicate a modified lipoprotein metabolism. The National Cholesterol Education Program (NCEP) guidelines recommend development of direct assays to measure LDL-C (5) since LDL-C can be influenced by the dynamic interaction of apolipoprotein and several lipoprotein-associat...