Atherogenic impact of lecithin-cholesterol acyltransferase and its relation to cholesterol esterification rate in HDL (FER(HDL)) and AIP [log(TG/HDL-C)] biomarkers: the butterfly effect?

The atherogenic impact and functional capacity of LCAT was studied and discussed over a half century. This review aims to clarify the key points that may affect the final decision on whether LCAT is an anti-atherogenic or atherogenic factor. There are three main processes involving the efflux of free cholesterol from peripheral cells, LCAT action in intravascular pool where cholesterol esterification rate is under the control of HDL, LDL and VLDL subpopulations, and finally the destination of newly produced cholesteryl esters either to the catabolism in liver or to a futile cycle with apoB lipoproteins. The functionality of LCAT substantially depends on its mass together with the composition of the phospholipid bilayer as well as the saturation and the length of fatty acyls and other effectors about which we know yet nothing. Over the years, LCAT puzzle has been significantly supplemented but yet not so satisfactory as to enable how to manipulate LCAT in order to prevent cardiometabolic events. It reminds the butterfly effect when only a moderate change in the process of transformation free cholesterol to cholesteryl esters may cause a crucial turn in the intended target. On the other hand, two biomarkers - FER(HDL) (fractional esterification rate in HDL) and AIP [log(TG/HDL-C)] can offer a benefit to identify the risk of cardiovascular disease (CVD). They both reflect the rate of cholesterol esterification by LCAT and the composition of lipoprotein subpopulations that controls this rate. In clinical practice, AIP can be calculated from the routine lipid profile with help of AIP calculator www.biomed.cas.cz/fgu/aip/calculator.php.

Biomarkers of cardiometabolic risk in obese/overweight children: effect of lifestyle intervention.

Obesity is a strong cardiometabolic (CM) risk factor in children. We tested potential CM risk in obese/overweight children and the effect of an intensive lifestyle intervention using newer CM markers: atherogenic index of plasma AIP [Log(TG/HDL-C)], apoB/apoAI ratio and a marker of insulin resistance HOMA-IR. The participants (194 girls, 115 boys, average age 13) were enrolled in an intensive, one-month, inpatient weight reduction program. The program consisted of individualised dietary changes and the exercise program comprised aerobic and resistance training. Anthropometrical and biochemical parameters in plasma and CM risk biomarkers - (AIP, apoB/apoAI ratio and HOMA-IR) were examined before and after the intervention. AIP and HOMA-IR significantly correlated with BMI while apoB/apoAI ratio did not. Only AIP and HOMA-IR showed systematic increases according to the level of obesity by BMI quartiles. Lifestyle intervention significantly improved anthropometrical and biochemical values and the biomarkers too. The response of lipid parameters to the intervention was considerably higher in boys than in girls. The children were stratified into three risk categories according to AIP, where 13.8 % of boys and 5.3 % of girls fell into high risk category. The monitored biomarkers may complement each other in the prognosis of CM risk. AIP was strongly related to obesity and to lipid and glycid metabolism, while the relationship of the apoB/apoAI ratio to obesity and glycid metabolism was not significant. The obese children benefited from the intensive lifestyle intervention which improved the anthropometrical and biochemical parameters and CM risk biomarkers.

Association of metabolic and genetic factors with cholesterol esterification rate in HDL plasma and atherogenic index of plasma in a 40 years old Slovak population.

We assessed association between novel biomarkers of cardiovascular disease and conventional factors in 40 years old subjects (208 men and 266 women) from the general population of Slovakia. FER(HDL) (cholesterol esterification rate in HDL plasma), AIP--Atherogenic Index of Plasma [Log(TG/HDL-C)] as markers of lipoprotein particle size, and CILP2, FTO and MLXIPL polymorphisms, were examined in relation to biomarkers and conventional risk factors. Univariate analyses confirmed correlation between AIP, FER(HDL) and the most of measured parameters. Relations between AIP and CILP2, FTO and MLXIPL were not significant. However, CILP2 was significantly related to FER(HDL) in both genders. In multivariate analysis BMI was the strongest correlate of AIP levels. In multivariate model variability of FER(HDL) was best explained by AIP (R(2) = 0.55) in both genders with still significant effect of CILP2 SNP in men. In a model where AIP was omitted, TG levels explained 43 % of the FER(HDL) variability in men, while in women HDL-C was the major determinant (42 %). In conclusions, FER(HDL) and AIP related to the known markers of cardiovascular risk provide means to express their subtle interactions by one number. Our novel finding of association between CILP2 polymorphism and FER(HDL) supports its role in lipid metabolism.

[AIP--atherogenic index of plasma as a significant predictor of cardiovascular risk: from research to practice]. / AIP--aterogenní index plazmy jako významný prediktor kardiovaskulárního rizika: od výzkumu do praxe.

BACKGROUND: Various indices have been used for the diagnosis and prognosis of cardiovascular disease (CVD). Atherogenic index of plasma (AIP) is a logarithmically transformed ratio of molar concentrations of triglycerides to HDL-cholesterol. The strong correlation of AIP with lipoprotein particle size may explain its high predictive value. Here we summarize data on AIP calculated in 8394 subjects from 6 population and clinical studies. RESULTS: AIP values increase with increasing CV risk. Thus umbilical cord, young children, healthy women have values below 0.1 while men and subjects with CV risk factors such as hypertension, diabetes, dyslipidemia have increasing values up to 0.4. Based on these data we suggest that AIP values of -0.3 to 0.1 are associated with low, 0.1 to 0.24 with medium and above 0.24 with high CV risk. In the population study men had higher AIP values than women. In a cohort undergoing coronary angiography AIP, in model that included age, BMI, waist circumference, type 2. DM, blood pressure, smoking, TG, TC, LDL-C, apoB, HDL-C, and TC/HDL-C, AIP was the best predictor of positive findings. AIP was also a highly sensitive marker of differences of lipoprotein profiles in families of patients with premature myocardial infarction and control families. Treatment with ciprofibrate, and combination of statin and niacin dramatically decreased AIP. Combination with hypoglycemic therapy that included pioglitazone decreased AIP in patiens with type 2. diabetes. CONCLUSIONS: AIP can be easily calculated from standard lipid profile. As a marker of lipoprotein particle size it adds predictive value beyond that of the individual lipids, and/or TC/HDL-C ratio.

Relations between particle size of HDL and LDL lipoproteins and cholesterol esterification rate.

Particle size of low density (LDL) and high density (HDL) lipoproteins and cholesterol esterification rate in HDL plasma (FER(HDL)) are important independent predictors of coronary artery diseases (CAD). In this study we assessed the interrelations between these indicators and routinely examined plasma lipid parameters and plasma glucose concentrations. In 141 men, healthy volunteers, we examined plasma total cholesterol (TC), triglycerides (TG), HDL and LDL cholesterol (HDL-C, LDL-C) and HDL unesterified cholesterol (HDL-UC). Particle size distribution in HDL and LDL was assessed by gradient gel electrophoresis and FER(HDL) was estimated by radioassay. An effect of particle size and FER(HDL) on atherogenic indexes as the Log(TG/HDL-C) and TC/HDL-C was evaluated. Subjects in the study had plasma concentrations (mean +/- S.D.) of TC 5.2+/-0.9 mmol/l, HDL-C 1.2+/-0.3 mmol/l, TG 2.1+/-1.7 mmol/l, glucose 5+/-0.8 mmol/l. Relative concentration of HDL(2b) was 17.6+/-11.5 % and 14.6+/-11.8 % of HDL(3b,c). The mean diameter of LDL particles was 25.8+/-1.5 nm. The increase in FER(HDL) significantly correlated with the decrease in HDL(2b) and LDL particle size (r = -0.537 and -0.583, respectively, P<0.01) and the increase in HDL(3b,c) (0.473, P<0.01). Strong interrelations among TG and HDL-C or HDL-UC and FER(HDL) and particle size were found, but TC or LDL-C did not have such an effect. Atherogenic indexes Log(TG/HDL-C) and TC/HDL-C correlated with FER(HDL) (0.827 and 0.750, respectively, P<0.0001) and with HDL and LDL particle size.

Gender differences in plasma levels of lipoprotein (a) in patients with angiographically proven coronary artery disease.

The objective of the study was to assess the association between plasma levels of lipoprotein(a) [Lp(a)] and the presence of angiographically defined coronary artery disease (aCAD). Patients (346 men and 184 women) undergoing selective coronary angiography (SCA) were classified into groups with positive [aCAD(+)] and negative [aCAD(-)] findings and their age, body mass index (BMI), waist circumference, blood pressure, smoking, plasma total, LDL-, HDL-cholesterol (TC, LDL-C, HDL-C), triglycerides (TG), apolipoprotein B (apoB), Log(TG/HDL-C) and TC/HDL-C were determined. Concentration of plasma Lp(a) was estimated using the commercial solid phase two-side immunoradiometric assay of apolipoprotein apo(a). The plasma Lp(a) was significantly higher in both women and men with aCAD(+) compared to those with aCAD(-). While there was no significant difference in the Lp(a) level between men and women with aCAD(-) (median 138 vs. 145 units/l), the women with aCAD(+) had almost twice as high Lp(a) levels as men (median 442 vs. 274 units/l, p<0.001). Women with aCAD(+) had also significantly lower HDL cholesterol levels (1.09 vs. 1.20 mmol/l, p<0.05), higher triglycerides (1.82 vs. 1.46 mmol/l, p<0.05) and Log(TG/HDL-C) than women with aCAD(-). The differences in Lp(a) between positive and negative findings remained highly significant (p<0.001 in women, p<0.05 in men) after the adjustment for age, plasma HDL- and LDL-cholesterol and triglycerides in logistic regression analyses. In logistic regression model the Lp(a) and Log(TG/HDL-C) and smoking in women but smoking and age in men were the most powerful predictors of positive aCAD findings. Our findings suggest that Lp(a) is more strongly associated with aCAD+ in women than in men.

[Consumption of white wine retards development of atherosclerosis and affects anticoagulation]. / Pití bílého vína k veceri oddaluje aterosklerózu a pusobí antikoagulacne.

BACKGROUND: An inverse relationship between moderate alcohol use and coronary heart disease was found in various countries. Aims of the study were to find out whether drinking of moravian white wine will have the same effect on lipoproteins and fibrinogen as described in foreign wines. Blood pressure, body mass, blood glucose and a hepatic enzyme were also measured before and after drinking. METHODS AND RESULTS: Drinking of the Moravian white wine (vintage 1999; alcohol 11.48 vol %) was studied in 50 men aged 44.4 (SD 9.25) years. Drinking of 350 ml (40.2 g of alcohol) every evening for four weeks without any change of dietary factors followed in 45 men by statistically significant increase in HDL cholesterol from 1.17 to 1.25 mmol/l (p < 0.001) and free HDL cholesterol from 0.17 to 0.20 mmol/l (p < 0.0001) and highly significant (p < 0.00001) decrease in plasma fibrinogen level from 3.77 to 3.35 g/l. Nor triglycerides, or blood glucose and BMI were changed after increasing source of carbohydrates in wine. Mean systolic blood pressure of 123.4 mmHg did not change and diastolic blood pressure decreased insignificantly from 78.0 to 76.7 mmHg. Minimal decrease of ALT from 0.60 to 0.59 mukat/l disproved any hepatic disturbance. CONCLUSIONS: Everynight moderate drinking of Moravian white wine has similar beneficial effect as consumption of foreign alcohol drinks.

The plasma parameter log (TG/HDL-C) as an atherogenic index: correlation with lipoprotein particle size and esterification rate in apoB-lipoprotein-depleted plasma (FER(HDL)).

OBJECTIVES: To evaluate if logarithm of the ratio of plasma concentration of triglycerides to HDL-cholesterol (Log[TG/HDL-C]) correlates with cholesterol esterification rates in apoB-lipoprotein-depleted plasma (FER(HDL)) and lipoprotein particle size. DESIGN AND METHODS: We analyzed previous data dealing with the parameters related to the FER(HDL) (an indirect measure of lipoprotein particle size). In a total of 1433 subjects from 35 cohorts with various risk of atherosclerosis (cord plasma, children, healthy men and women, pre- and postmenopausal women, patients with hypertension, type 2 diabetes, dyslipidemia and patients with positive or negative angiography findings) were studied. RESULTS: The analysis revealed a strong positive correlation (r = 0.803) between FER(HDL) and Log(TG/HDL-C). This parameter, which we propose to call "atherogenic index of plasma" (AIP) directly related to the risk of atherosclerosis in the above cohorts. We also confirmed in a cohort of 35 normal subjects a significant inverse correlation of LDL size with FER(HDL) (r = -0.818) and AIP (r = -0.776). CONCLUSION: Values of AIP correspond closely to those of FER(HDL) and to lipoprotein particle size and thus could be used as a marker of plasma atherogenicity.

The role of risk factors in the development of atherosclerosis.

Our understanding of risk factors for atherogenesis has changed significantly over the last decade. In addition to better grasp of the mechanism of action of the "classic" (causal) risk factors, a number of potentially important new factors has emerged. In this review we briefly summarize the evidence of the relation between atherosclerosis and the currently recognized causal risk factors, namely, age, smoking, LDL cholesterol, HDL cholesterol, hypertension, and diabetes. More emphasis has been put on description of the emerging entities such as atherogenic profile of plasma lipoproteins with discussion of LDL and HDL subclasses, Lp(a), homocysteine, and, last but not least, on the role of infection and inflammation in atherogenesis. Whenever possible, we tried to summarize the relevant lines of evidence such as epidemiological, pathological, genetic, and clinical trial data linking the specific factor with atherosclerosis.

Atherogenic lipoprotein profile in families with and without history of early myocardial infarction.

In this study we compared several parameters characterizing differences in the lipoprotein profile between members of families with a positive or negative family history of coronary artery disease (CAD). In addition to regular parameters such as the body mass index (BMI), total plasma cholesterol (TC), low density (LDL-C) and high density (HDL-C) cholesterol and triglycerides (TG) we estimated the fractional esterification rate of cholesterol in apoB lipoprotein-depleted plasma (FER(HDL)) which reflects HDL and LDL particle size distribution. A prevalence of smaller particles for the atherogenic profile of plasma lipoproteins is typical. Log (TG/HDL-C) as a newly established atherogenic index of plasma (AIP) was calculated and correlated with other parameters. The cohort in the study consisted of 29 young (< 54 years old) male survivors of myocardial infarction (MI), their spouses and at least one offspring (MI group; n=116). The control group consisted of 29 apparently healthy men with no family history of premature CAD in three generations, their spouses and at least one offspring (control group; n=124). MI families had significantly higher BMI than the controls, with the exception of spouses. Plasma TC did not significantly differ between MI and the controls. MI spouses had significantly higher TG. Higher LDL-C had MI survivors only, while lower HDL-C had both MI survivors and their spouses compared to the controls. FER(HDL) was significantly higher in all the MI subgroups (probands 25.85+/-1.22, spouses 21.55+/-2.05, their daughters 16.93+/-1.18 and sons 19.05+/-1.33 %/h) compared to their respective controls (men 20.80+/-1.52, spouses 14.70+/-0.98, daughters 13.23+/-0.74, sons 15.7+/-0.76 %/h, p<0.01 to p<0.05). Log(TG/HDL-C) ranged from negative values in control subjects to positive values in MI probands. High correlation between FER(HDL) and Log (TG/HDL-C) (r=0.80, p<0.0001) confirmed close interactions among TG, HDL-C and cholesterol esterification rate. The finding of significantly higher values of FER(HDL) and Log (TG/HDL-C) indicate higher incidence of atherogenic lipoprotein phenotype in members of MI families. The possibility that, in addition to genetic factors, a shared environment likely contributes to the familial aggregation of CAD risk factors is supported by a significant correlation of the FER(HDL) values within spousal pairs (control pairs: r=0.51 p<0.01, MI pairs: r=0.41 p<0.05).

[The new atherogenic plasma index reflects the triglyceride and HDL-cholesterol ratio, the lipoprotein particle size and the cholesterol esterification rate: changes during lipanor therapy]. / Nový aterogenní index plazmy (AIP) odpovídá pomeru triglyceridu a HDL-cholesterolu, velikosti cástic lipoproteinu a esterifikacní rychlosti cholesterolu: zmeny po lécbe lipanorem.

The new atherogenic plasma index (AIP) is a logarithmic transformation of the ratio of the molar triglyceride (TG) concentration and high density lipoprotein cholesterol (HDL-C). AIP correlates closely with the size of LDL particles (r = 0.8) and esterification rate of plasma cholesterol devoid of apo B lipoproteins (FERHDL), r = 0.9 which are considered at present the most sensitive indicators of the atherogenic plasma profile. AIP was recommended by the authors, based on analysis of results of 11 previous studies (1156 subjects) where FERHDL and plasma lipid parameters were investigated in different groups of people who differed as to the atherogenic risk. The AIP index was moreover used for evaluation of a clinical study comprising 609 patients with hyperlipidaemia, who were treated for three months with ciprofibrate (Lipanor). The mean AIP values of non-risk groups (plasma from umbilical blood, children, healthy women etc.) equalled zero or were lower, while with an increasing atherogenic risk (men, women after the menopause) AIP reached positive values, incl. high positive values in risk groups (plasma of diabetic subjects, patients with HLP, patients with positive angiography, myocardial infarction etc.). In all groups women had lower AIP values as compared with males. In patients after Lipanor therapy the AIP declined (from 0.58 +/- 0.17 to 0.33_0.18 in men, from 0.50 +/- 0.18 to 0.21 +/- 0.19 in women). If we consider AIP values from negative ones to 0.15 as "safe" from the aspect of atherogenicity, before Lipanor treatment these "safe" levels were recorded in 1.5% men and in 5.2% women and after treatment in 32% men and 48% women. The results indicate, that AIP which reflects the plasma lipoprotein profile quantifies the relations between TG and HDL-C and thus can be an objective indicator of the atherogenic risk and effectiveness of treatment and it is useful because it can be assessed in any surgery.

Effect of labeling of plasma lipoproteins with [(3)H]cholesterol on values of esterification rate of cholesterol in apolipoprotein B-depleted plasma.

The fractional esterification rate of cholesterol in apolipoprotein B (apoB)-depleted plasma (FER(HDL)) is a good indicator of particle size distribution in high density lipoprotein (HDL) and low density lipoprotein (LDL). However, there has been a discrepancy in the absolute values of FER(HDL) published by different laboratories. Because the main difference between the methods was in the labeling of lipoproteins with [(3)H]cholesterol we investigated the effect of using Corning immunoplates and paper discs as carriers of the labeled unesterified cholesterol. We found that Corning plates trap some (3)H-labeled free cholesterol, which is released during incubation at 37 degrees C. This means that this additional (3)H-labeled free cholesterol is exposed to lecithin: cholesterol acyltransferase (LCAT) for a shorter time and artificially decreases FER(HDL). Using paper discs discarded before incubation as carriers of the (3)H-labeled free cholesterol results in complete labeling of HDL and thus yields higher values of FER(HDL).

Effect of ciprofibrate on lipoprotien metabolism and oxidative stress parameters in patients with type 2 diabetes mellitus and atherogenic lipoprotein phenotype.

The effect of ciprofibrate therapy on plasma lipids and lipoproteins, HDL and LDL subfraction profile, fractional esterification rate of HDL cholesterol (FER(HDL)) and the resistance of LDL and serum lipids to oxidation was studied in 24 males with type 2 diabetes and atherogenic lipoprotein phenotype (ALP). We also examined the effect of ciprofibrate therapy on oxidative DNA damage in peripheral lymphocytes. No differences in glucose, HbA1C and BMI levels were found after three months of ciprofibrate therapy. Ciprofibrate significantly decreased total cholesterol and triglyceride levels by 5.5% and 50% (p = 0.05; 0.001, respectively) and increased HDL-cholesterol levels by 8.5% (p = 0.05). FER(HDL) and LDL subfraction profile were also favorably affected. However, no effect on HDL subclasses was found. There were no statistically significant differences in lipid resistance to oxidation measured in serum and in LDL (lag time and Vmax) before and after therapy. No significant effect of ciprofibrate was found on oxidative DNA damage. The evaluation of the relationship between oxidative damage of purines with lag time in LDL and maximal rate of serum lipid oxidation showed significant correlations after therapy (r = -0.58; 0.47, p = 0.01; 0.05, respectively), but only trends before starting ciprofibrate treatment. Type 2 diabetes mellitus represents a complex metabolic disorder expressed in glucose and lipoprotein disturbances and increased oxidative stress. Ciprofibrate therapy favorably affected major features of lipid abnormalities of diabetic patients, but the level of oxidative stress assessed by in vitro and in vivo methods was not changed. The evaluation of expected logical correlations between the parameters of lipoprotein metabolism, lipid resistance in serum and LDL, and oxidative DNA damage showed that those correlations were more relevant and significant after ciprofibrate treatment and were not related with glucose homeostasis.

Advances in understanding of the role of lecithin cholesterol acyltransferase (LCAT) in cholesterol transport.

We review the structure and function of lecithin cholesterol acyl transferase (LCAT), the advances in the studies of molecular genetics of LCAT and its deficiency states as well as the developments in assessment of LCAT activity particularly the concept of measurement of fractional esterification rate of plasma cholesterol in the absence of apoB lipoproteins (FER(HDL)) as an indication of atherogenic risk. We discuss LCAT reaction from two points of view: one that is consistent with the general belief in LCAT antiatherogenic potential and another, namely, a proposed concept of potentially opposing roles of LCAT in normal and dyslipidemic plasmas. While other plasma lipoproteins can (in addition to HDL) provide unesterified cholesterol (UC) for LCAT reaction, HDL may play an unique role in trafficking of newly formed cholesteryl esters (CE) rather than as a primary acceptor of cellular cholesterol. Thus, the plasma HDL, specifically the larger (HDL2b) particles, direct the efflux of most of (LCAT produced) CE to its specific catabolic sites rather than to potentially atherogenic VLDLs and back to LDLs.

High-density lipoprotein subclasses and esterification rate of cholesterol in children: effect of gender and age.

Since the development of coronary heart disease (CAD) is affected by a specific pattern of plasma high density lipoprotein (HDL) effects it may be useful to know whether this occurs already in childhood. In this study we evaluated particle size distribution of HDL by gradient gel electrophoresis and the determination of cholesterol esterification rate (FER(HDL)) in plasma depleted of apo B lipoproteins in 221 children (108 boys and 113 girls) aged 4 months to 20 years. Total plasma- (TC), low-density lipoprotein- (LDL-C) and HDL- (HDL-C) cholesterol, HDL unesterified cholesterol (HDL-UC) and plasma triglycerides (TG) were also measured. There were no significant gender and age differences with respect to the plasma TC, LDL-TC and TG but concentration of HDL-TC increased with age. Post-pubertal girls had significantly higher relative concentrations of HDL2b compared to boys (30.4% vs 17.2%), while HDL3b,c was lower in post-pubertal girls (8.7% vs. 16.5%). FER(HDL) correlated inversely with HDL2b and positively with HDL3b,c particles and was significantly higher in boys of the post-pubertal group compared to girls (16.9%/h vs 12.5%/h). While in girls there was a positive correlation between age and HDL-C, HDL-UC and the relative concentration of HDL2b no significant correlation were observed in boys. In girls the increase in TC showed a significant correlation with a simultaneous increase in HDL-C, HDL-UC and HDL2b. In boys TC correlated significantly with changes in TG only. When HDL2b and HDL3b,c cholesterol levels are calculated from HDL-C concentration and per cent distribution the differences between males and females are further emphasized. These data indicate that HDL particle size distribution is age- and gender-dependent.

Fractional esterification rate of HDL particles in patients with type 2 diabetes. Relation to coronary heart disease risk factors.

OBJECTIVE: To study the fractional esterification rate of cholesterol on HDL particles (FERHDL) in adults with type 2 diabetes and assess its correlation with serum lipids and other coronary heart disease (CHD) risk factors. RESEARCH DESIGN AND METHODS: FERHDL was measured in 90 adult (57 men, 33 women) patients by an isotopic assay method involving several steps, including preparation of VLDL- and LDL-depleted plasma, labeling of the sample with a trace amount of tritiated cholesterol, separation of free and esterified cholesterol fractions by chromatography post incubation, and subsequent counting of radioactivity in the individual fractions. RESULTS: Male patients have higher FERHDL values than their female counterparts. When HDL cholesterol was controlled for in a multivariate regression analysis, the sex factor was not significant. There was a significant positive correlation between FERHDL and plasma total cholesterol (r = 0.32), triglycerides (r = 0.82), apolipoprotein B (apo B; r = 0.48), insulin (r = 0.46), BMI (r = 0.31), and waist-to-hip ratio (WHR; r = 0.50). There was a negative correlation between FERHDL and HDL cholesterol (r = -0.76) and apolipoprotein AI (r = -0.60). When both HDL cholesterol and triglycerides were controlled for, the only significant correlation was between FERHDL and BMI. CONCLUSIONS: Non-insulin-requiring type 2 diabetic patients have FERHDL, which correlated positively with triglycerides and negatively with HDL cholesterol. The positive correlation of FERHDL with serum insulin, WHR, total cholesterol, and apo B, but not that with BMI, loses its significance when HDL cholesterol and triglycerides are controlled. The sex difference between men and women in FERHDL also loses its significance when HDL cholesterol is controlled.

Ciprofibrate treatment in patients with atherogenic lipoprotein phenotype: effects on HDL quality, LDL susceptibility to oxidation and DNA damage.

OBJECTIVES: This study was conducted to examine a complex effect of ciprofibrate therapy in patients with atherogenic lipoprotein phenotype. METHODS: Effects of ciprofibrate were studied on HDL subpopulations, HDL ability to esterify cholesterol (FER(HDL)), susceptibility of LDL to oxidation as well as on in vivo oxidative DNA damage in peripheral lymphocytes, measured as strand breaks (SBs) by the comet assay. RESULTS: Ciprofibrate treatment significantly decreased total cholesterol, and triglycerides, and increased HDL-cholesterol. The FER(HDL) showed a significant reduction (29.5+/-7.4 to 23+/-7.5% x h(-1), P=0.0001). The relative concentrations of HDL subclasses did not differ between baseline and after treatment. Ciprofibrate induced a significant increase in LDL oxidation lag time (93+/-7 to 102=11 min, P=0.02) and a decrease in DNA strand breaks (34.0+/-16.2 to 17.8+/-7.5, P=0.02). A significant correlation between maximal rate of diene production and strand breaks was found (r=0.55, P=0.01). These findings may be explained by an improvement of LDL resistance to oxidation, resulting in a decrease in oxidatively modified LDL's cytotoxic effect. CONCLUSION: Ciprofibrate treatment favourably affected the quality of plasma HDL, probably by the improvement of triglyceride rich lipoprotein metabolism and/or LDL subpopulation profile, increased LDL resistance to oxidation, and decreased the level of DNA damage in peripheral lymphocytes.

Understanding the mechanism of LCAT reaction may help to explain the high predictive value of LDL/HDL cholesterol ratio.

Traditionally, lecithin:cholesterol acyltransferase (LCAT) role in the reverse cholesterol transport (RCT) has been considered "antiatherogenic" as the cholesterol esterification is the prerequisite for the formation of mature high density lipoprotein (HDL) particles and may create a gradient necessary for the flow of unesterified cholesterol (UC) from tissues to plasma. However, newer data suggest that a higher esterification rate is not necessarily protective. Here we review the available data on the role of LCAT in RCT and propose that the LCAT-mediated esterification of plasma cholesterol promotes RCT only in the presence of sufficient concentrations of HDL2 while this reaction may be atherogenic in the presence of high concentration of plasma low density lipoprotein (LDL) cholesterol Thus, the "protective" or potentially "atherogenic" role of LCAT depends on the quality of HDL and concentration of LDL. This hypothesis is consistent with the known high predictive value of LDL/HDL cholesterol ratio.

Measurement of fractional esterification rate of cholesterol in plasma depleted of apoprotein B containing lipoprotein: methods and normal values.

The distribution of differently sized HDL particles in the plasma can be assessed by measurement of the fractional rate of cholesterol esterification (FERHDL). We have characterized the isotopic assay and compared it to the enzymatic measurement of the decrease in HDL free cholesterol (mass assay). The normal values of FERHDL were established in 116 apparently healthy individuals. The isotopic assay is particularly sensitive to changes in the incubation temperature above 37 degrees C. The reproducibility of the assay in aliquots of plasma stored at -20 degrees C and -70 degrees C for 3 months and even up to 2 years was high. Intraindividual variability of FERHDL is low. In the subjects in whom FERHDL was measured over a 3-month and 2-5 years' period, FERHDL showed a low variability (97.5 +/- 2.6% and 101 +/- 6.0% respectively in a paired t-test). Comparison of the isotopic assay and the mass assay revealed that the isotopic assay was much more reproducible. Normal values of FERHDL and the HDL subspecies distribution (using gradient gel electrophoresis) were established in 63 men and 56 women. The average values of FERHDL were significantly higher in men (16.8 +/- 4.5%/h) than in women (10.6 +/- 3.6%/h) and correlated well with the distribution of the HDL subspecies. FERHDL radioassay as a highly reproducible method for the assessment of HDL subspecies distribution which may be suitable for both retrospective and prospective studies of diseases of atherogenous origin.