Frank G. Perton

High plasma lecithin: cholesterol acyltransferase activity does not predict low incidence of cardiovascular events: Possible attenuation of cardioprotection associated with high HDL cholesterol

The cholesterol esterifying enzyme, lecithin:cholesterol acyltransferase (LCAT), is crucial in high density lipoprotein (HDL) metabolism. The role of LCAT activity on incident cardiovascular disease (CVD) is unknown. We determined the association of incident CVD with plasma LCAT activity, and evaluated whether LCAT may modify the cardioprotective effect of higher HDL cholesterol. In a community-based prospective nested case-control study (PREVEND cohort), an exogenous substrate assay was used to measure plasma LCAT activity in 116 men who developed CVD (cases) and in 111 male controls. Plasma LCAT activity was 5% higher in cases (P=0.027) in association with higher total cholesterol, non-HDL cholesterol and triglycerides. Age-adjusted incident CVD was increased with higher LCAT activity (continuous variable: hazard ratio (HR) 1.23; 95% CI 1.01-1.49, P=0.037; upper quartile vs. lowest 3 quartiles: HR 1.60; 95% CI 1.07-2.39, P=0.021). This relationship was not significant after adjustment for lipids. Compared to subjects with HDL cholesterol above the median and lower LCAT activity (lowest 3 quartiles) the age-adjusted cardiovascular risk was elevated in subjects with similarly higher HDL cholesterol and higher LCAT activity (HR 2.38; 95% CI 1.27-4.49, P=0.007), lower HDL cholesterol and lower LCAT activity (HR 2.58; 95% CI 1.64-4.49, P<0.001) and lower HDL cholesterol and higher LCAT activity (HR 2.76; 95% CI 1.58-4.83, P<0.001). These HRs were unchanged after non-HDL cholesterol and triglyceride adjustment. In conclusion, high plasma LCAT activity does not predict reduced CVD risk, and may attenuate cardioprotection associated with higher HDL cholesterol.

Plasma Lecithin: Cholesterol Acyltransferase Activity Is Elevated in Metabolic Syndrome and Is an Independent Marker of Increased Carotid Artery Intima Media Thickness

CONTEXT Lecithin:cholesterol acyltransferase (LCAT), which esterifies free cholesterol to cholesteryl esters, is required for normal plasma lipoprotein structure and is instrumental in high density lipoprotein (HDL) remodeling, but the relationship of variation in plasma LCAT activity with subclinical atherosclerosis is unclear. OBJECTIVES The aim of the study was to determine the effect of the metabolic syndrome (MetS) on plasma LCAT activity and its relationship with carotid artery intima media thickness (IMT). SETTING The study was conducted at the vascular laboratory of a university medical center. METHODS In 74 subjects with MetS and 90 subjects without MetS (National Cholesterol Education Program Adult Treatment Panel III criteria), mean carotid artery IMT, plasma lipids, LCAT activity (exogenous substrate method), high-sensitive C-reactive protein, and homeostasis model assessment insulin resistance (HOMA(ir)) were documented. RESULTS IMT was greater (P = 0.01) and plasma LCAT activity was higher (P < 0.001) in subjects with MetS compared to subjects without MetS. Similar increases in IMT and LCAT were found in MetS subjects without type 2 diabetes mellitus. Multiple linear regression analysis demonstrated that plasma LCAT activity was independently and positively related to HOMA(ir), plasma triglycerides, non-HDL cholesterol, and HDL cholesterol (all P < 0.001). After adjustment for age and sex, IMT was positively associated with LCAT activity (P < 0.01), independently of the presence of MetS (or alternatively of plasma lipids), HOMA(ir), and high-sensitive C-reactive protein. CONCLUSIONS Plasma LCAT activity is elevated in MetS and may be a marker of subclinical atherosclerosis. Our findings do not support the contention that strategies to elevate LCAT are necessarily beneficial for cardioprotection.

Increased LCAT activity and hyperglycaemia decrease the antioxidative functionality of HDL

Eur J Clin Invest 2012; 42 (5): 487–495

High plasma cholesteryl ester transfer but not CETP mass predicts incident cardiovascular disease: a nested case-control study.

OBJECTIVE The relationship of cardiovascular disease (CVD) with plasma cholesteryl ester transfer protein (CETP) levels is controversial. We determined whether plasma cholesteryl ester transfer (CET), reflecting CETP-mediated transfer of cholesteryl esters from endogenous HDL towards apolipoprotein B-lipoproteins, predicts incident CVD. METHODS A prospective nested case-control study was carried out in 114 men who developed CVD and 105 controls. Participants did not use lipid lowering drugs at baseline. Plasma CET was assayed using an isotope method. RESULTS Plasma CET was 19% higher (P=0.030), whereas CETP mass was unaltered (P=0.30) in cases vs. controls. Plasma CET predicted CVD (age-adjusted hazard ratio (HR): 1.20 (95% CI 1.02-1.46, P=0.028), but incident CVD was unrelated to CETP mass (HR: 0.88 (95% CI 0.73-1.07), P=0.20). Plasma CET still predicted CVD after additional adjustment for total cholesterol/HDL cholesterol, triglycerides and non-lipid risk markers (HR: 1.22 (95% CI 1.02-1.46, P=0.031). CONCLUSION Plasma CET rather than CETP mass may be a determinant of cardiovascular risk.

Hepatic lipid accumulation in apolipoprotein C-I-deficient mice is potentiated by cholesteryl ester transfer protein

The impact of apolipoprotein C-I (apoC-I) deficiency on hepatic lipid metabolism was addressed in mice in the presence or the absence of cholesteryl ester transfer protein (CETP). In addition to the expected moderate reduction in plasma cholesterol levels, apoCIKO mice showed significant increases in the hepatic content of cholesteryl esters (+58%) and triglycerides (+118%) and in biliary cholesterol concentration (+35%) as compared with wild-type mice. In the presence of CETP, hepatic alterations resulting from apoC-I deficiency were enforced, with up to 58% and 302% increases in hepatic levels of cholesteryl esters and triglycerides in CETPTg/apoCIKO mice versus CETPTg mice, respectively. Biliary levels of cholesterol, phospholipids, and bile acids were increased by 88, 77, and 20%, respectively, whereas total cholesterol, HDL cholesterol, and triglyceride concentrations in plasma were further reduced in CETPTg/apoCIKO mice versus CETPTg mice. Finally, apoC-I deficiency was not associated with altered VLDL production rate. In line with the previously recognized inhibition of lipoprotein clearance by apoC-I, apoC-I deficiency led to decreased plasma lipid concentration, hepatic lipid accumulation, and increased biliary excretion of cholesterol. The effect was even greater when the alternate reverse cholesterol transport pathway via VLDL/LDL was boosted in the presence of CETP.

Plasma lecithin:cholesterol acyltransferase activity modifies the inverse relationship of C-reactive protein with HDL cholesterol in nondiabetic men

Lecithin:cholesterol acyltransferase (LCAT) is instrumental in high-density lipoprotein (HDL) maturation, but high LCAT levels do not predict low cardiovascular risk. LCAT may affect antioxidative or anti-inflammatory properties of HDL. We determined the relationship of plasma high-sensitivity C-reactive protein (CRP) with LCAT activity and evaluated whether LCAT activity modifies the decreasing effect of HDL cholesterol (HDL-C) on CRP, as an estimate of its anti-inflammatory properties. Plasma HDL-C, apolipoprotein (apo) A-I and LCAT activity (exogenous substrate method) were measured in 260 nondiabetic men without cardiovascular disease. CRP was correlated inversely with HDL-C and apo A-I, and positively with LCAT activity (P<0.01 to 0.001). Multivariate regression analysis demonstrated that age- and smoking-adjusted plasma CRP levels were associated negatively with HDL-C (beta=-0.224, P<0.001) and positively with LCAT activity (beta=0.119, P=0.034), as well as with the interaction between HDL-C and LCAT activity (beta=0.123, P=0.026). There was also an interaction between apo A-I and LCAT activity on CRP (beta=0.159, P=0.005). These relationships remained similar after adjustment for apo B-containing lipoproteins. In conclusion, the inverse relationship of HDL-C with CRP is attenuated by LCAT activity at higher HDL-C levels. It is hypothesized that LCAT could mitigate HDLs anti-inflammatory or antioxidative properties at higher HDL-C concentrations.

Carotid intima media thickness is related positively to plasma pre ß-high density lipoproteins in non-diabetic subjects

BACKGROUND Lipid-poor or lipid-free high density lipoprotein (HDL) particles, designated pre ß-HDL, stimulate removal of cell-derived cholesterol to the extracellular compartment, which is an initial step in the reverse cholesterol transport pathway. Pre ß-HDL levels may be elevated in subjects with established cardiovascular disease. We determined the relationship of carotid intima media thickness (IMT), a marker of subclinical atherosclerosis, with pre ß-HDL in subjects without clinically manifest cardiovascular disease. METHODS IMT and plasma pre ß-HDL, assayed by crossed immuno-electrophoresis, were determined in 70 non-diabetic subjects (aged 56±9 years; non-smokers only; 27 women). RESULTS IMT was correlated positively with pre ß-HDL, both expressed as plasma apolipoprotein (apo) A-I concentration (r=0.271, p=0.023) and as% of apo A-I (r=0.341, p=0.004). In contrast, IMT was correlated inversely with HDL cholesterol (r=-0.253, p=0.035). IMT was also related positively to pre ß-HDL after adjustment for age, sex, systolic blood pressure (in apoA-I concentration, ß=0.203, p=0.043; in% of plasma apoA-I, ß=0.235, p=0.023). IMT remained associated with pre ß-HDL after additional adjustment for either body mass index, plasma glucose, cholesterol, triglycerides, HDL cholesterol, apoA-I and apoB. CONCLUSION Subclinical atherosclerosis may relate to higher plasma pre ß-HDL independently of apoA-I and HDL cholesterol levels.

Alterations in plasma lecithin : cholesterol acyltransferase and myeloperoxidase in acute myocardial infarction: Implications for cardiac outcome

BACKGROUND The cholesterol esterifying enzyme, lecithin:cholesterol acyltransferase (LCAT), plays a key role in HDL maturation and remodeling. Myeloperoxidase (MPO) may compromise LCAT enzymatic activity. We tested the extent to which plasma LCAT activity is altered in acute myocardial infarction (MI) in conjunction with abnormal MPO levels. We also assessed the impact of LCAT and MPO on newly developed major adverse cardiovascular events (MACE). METHODS Two-hundred one consecutive patients referred for acute chest pain of whom 134 had MI (95 with ST-elevation) participated. Forty-five new MACE were ascertained during 1203 (range 13-1745) days of follow-up among 185 patients. Plasma LCAT activity was measured using an exogenous substrate assay. MPO mass was assayed by chemiluminescent microparticle immunoassay. RESULTS Plasma LCAT activity was decreased by 15%, coinciding with 7-fold increased MPO levels in acute MI patients vs. patients with non-cardiac chest pain (p < 0.001 for both; correlation: r = -0.343, p < 0.001). MI at admission was associated independently with both lower plasma LCAT activity and higher MPO (age- and sex-adjusted odds ratio per 1 SD increment: 0.46 (95% CI, 0.31-0.68), p < 0.001 and 7.58 (95% CI, 3.34-17.11), p < 0.001, respectively). In an analysis with LCAT and MPO together these associations were modestly attenuated. MPO mass (hazard ratio: 1.59 (95% CI, 1.15-2.19), p = 0.004), but not LCAT activity (hazard ratio: 0.87 (95% CI, 0.65-1.19), p = 0.39), predicted newly manifest MACE. CONCLUSION In acute MI patients, plasma LCAT activity is decreased coinciding with increased MPO levels. Higher MPO but not lower LCAT activity prospectively predicts adverse cardiac outcome.

Increased large VLDL particles confer elevated cholesteryl ester transfer in diabetes

Plasma cholesteryl ester transfer (CET), reflecting transfer of cholesteryl esters from high density lipoproteins (HDL) towards apolipoprotein B‐containing lipoproteins, may promote atherosclerosis development, and is elevated in Type 2 diabetes mellitus (T2DM). We determined the extent to which the relationship of plasma CET with very low density lipoprotein (VLDL) and low density lipoprotein (LDL) subfractions is modified in T2DM.

Downregulation of cholesteryl ester transfer protein by glucocorticoids: A randomised study on HDL

High density lipoprotein (HDL) cholesterol is not decreased in hypercortisolism despite high triglycerides, which may be ascribed to effects on the cholesteryl ester transfer protein (CETP) pathway. We explored if CETP mRNA expression is modulated by glucocorticoid treatment in vitro. Effects of doubling the hydrocortisone (HCT) replacement dose on plasma CETP activity, and HDL characteristics were tested in patients with secondary adrenal insufficiency.