Cholesterol Esterification Rate Research Articles

Investigating plasma and brain cholesterol esterification in patients with amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease, with metabolic alterations, abnormal cholesterol and lipid levels in the bloodstream and central nervous system (CNS). Similar to plasma, cholesterol in the cerebrospinal fluid (CSF) is carried by lipoproteins known as "HDL-like particles," due to their close similarity in density and composition to plasma HDL. Lecithin cholesterol acyltransferase (LCAT) is a key enzyme in HDL metabolism, catalysing cholesterol esterification in both plasma and CSF, thus facilitating HDL maturation. This study aimed to investigate cholesterol esterification in plasma and CSF and to characterize HDL subclass distribution in patients with ALS. The study included 20 ALS patients and 20 controls, in whom lipoprotein profile and cholesterol esterification were evaluated in both plasma and CSF. Plasma lipid levels were similar between patients and controls; however, the amount of discoidal preβ-HDL was significantly reduced in ALS patients compared to controls (8.5±4.9% vs 13.6±4.1%, p<0.0001). A significant increase in CSF unesterified cholesterol levels was observed in ALS patients compared to controls (0.22±0.07 mg/dL vs 0.15±0.04 mg/dL, p<0.01), leading to an increased unesterified/total cholesterol ratio in ALS patients (0.52±0.12 vs 0.40±0.12, respectively). While plasma cholesterol esterification remained unchanged in ALS patients, the cholesterol esterification rate was significantly reduced in their CSF (0.12±0.08 vs 2.41±1.98, p<0.01), consistent with the previous data. In conclusion, these results suggest a hampered cholesterol esterification in the CSF of ALS patients. Whether this defect is related to the severity or progression of the disease remains to be defined.

Abstract 4138633: Infusion of human apolipoprotein A-I (CSL112) promotes several aspects of reverse cholesterol transport

Background: High-density lipoprotein (HDL)-cholesterol is inversely correlated with cardiovascular risk, but increasing its circulating concentration is insufficient to prevent adverse cardiovascular outcomes. Instead, the emerging paradigm is on increasing the function of HDL and its major protein constituent apolipoprotein A-I (apoA-I), to increase reverse cholesterol transport. Objective: To investigate the effect of apoA-I [human] (CSL112) infusion on HDL protein composition, and provide further insights into the mechanism of action of CSL112 administered post-acute myocardial infarction (AMI). Methods: A mass spectrometry (MS)-based proteomic approach was used to evaluate changes in HDL protein composition in patients (n=50) from the AEGIS-I (ApoA-I Event Reducing in Ischemic Syndromes I) study who received either placebo or CSL112 post AMI. HDL was immuno-isolated from patient plasma using anti-apoA-I antibodies. Cholesterol esterification rate (CER) was measured to determine lecithin-cholesterol acyl transferase (LCAT) activity. Cholesterol efflux capacity (CEC) and hepatocyte uptake were assessed using patient serum in ex vivo cell-based assays. Results: CSL112 induced extensive rearrangement of HDL proteins at 4 hours post-infusion. Levels of apolipoproteins A2, B, C, and E as well as the acute phase proteins serum amyloid A1 and A4 were significantly reduced. By contrast, apoA-I, apoM, and LCAT significantly increased. Elevated apoA-I and LCAT levels on HDL were associated with an increase in CEC, plasma HDL-C levels, and CER in CSL112-treated patients. Furthermore, enhanced CEC strongly correlated with cholesterol uptake by hepatic cells (r=0.95 p<0.001). Conclusion: CSL112 altered HDL composition and increased HDL functionality by promoting multiple steps of the reverse cholesterol transport pathway.

Cholesterol esterification is hampered in alzheimer’s disease and cholesteryl esters composition is consequently altered

Introduction and Aim: Several epidemiological studies indicate a strong inverse association between the risk of developing Alzheimer’s disease (AD) and plasma HDL-C levels. The mechanism by which plasma HDL influence the pathogenesis and progression of AD is still unsolved and since cholesterol esterification is a crucial step in HDL metabolism it could be involved. The purpose of this study was to evaluate cholesterol esterification and HDL subclasses in plasma and cerebrospinal fluid (CSF) of Alzheimer’s Disease (AD) patients. Methods: The study enrolled 70 AD patients and 74 cognitively-normal controls comparable for age and sex. Lipids and lipoprotein profile, cholesterol esterification, and cholesterol efflux capacity (CEC) were evaluated in plasma and CSF using assays set for measurement in plasma, which were appropriately modified for CSF. Results: AD patients have normal plasma lipids, but significantly reduced unesterified cholesterol and unesterified/total cholesterol ratio. Lecithin:cholesterol acyltransferase (LCAT) activity and cholesterol esterification rate (CER), two measures of the efficiency of the esterification process, were reduced by 29% and 16%, respectively, in plasma of AD patients. Plasma HDL subclass distribution in AD patients was comparable to that of controls, but the content of small discoidal preβ-HDL particles was significantly reduced. In agreement with the reduced preβ-HDL particles, cholesterol efflux capacity mediated by the transporters ABCA1 and ABCG1 was reduced in AD patients’ plasma. The CSF unesterified to total cholesterol ratio was increased in AD patients, and CSF CER and CEC from astrocytes were significantly reduced in AD patients. In the AD group, a significant positive correlation was observed between plasma unesterified cholesterol and unesterified/total cholesterol ratio with Aβ1-42 CSF content. Conclusions: Taken together data indicate that cholesterol esterification is hampered in plasma and CSF of AD patients, and that plasma cholesterol esterification biomarkers (unesterified cholesterol and unesterified/total cholesterol ratio) are significantly associated to disease biomarkers (i.e., CSF Aβ1-42).

Apolipoprotein E isoforms differentially affect LCAT-dependent cholesterol esterification

Background and aimsLCAT esterifies cholesterol in both HDL (α-activity) and apoB-containing lipoproteins (β-activity). The main activator of LCAT β-activity is apoE, which in humans exists in 3 main different isoforms (E2, E3 and E4). Here, to gather insights into the potential role of LCAT in apoB-containing lipoprotein metabolism, we investigated the ability of apoE isoforms to promote LCAT-mediated cholesterol esterification. MethodsWe evaluated the plasma cholesterol esterification rate (CER) in 311 individuals who express functional LCAT and either apoE2, apoE3, or apoE4 and in 28 individuals who also carried LCAT mutations causing selective loss of LCAT α-activity (Fish-Eye Disease (FED)-causing mutations). The association of carrier status with CER was determined using an adjusted linear regression model. The kinetic of LCAT activity towards reconstituted HDLs (rHDLs) containing each apoE isoform was determined using the Michaelis-Menten model. ResultsPlasma CER was ∼20% higher in apoE2 carriers compared to apoE3 carriers, and ∼30% higher in apoE2 carriers compared to apoE4 carriers. After adjusting for age, sex, total cholesterol, HDL-C, apoA-I, apoB, chronic kidney disease diagnosis, zygosity, and LCAT concentration, CER remained significantly different among carriers of the three apoE isoforms. The same trend was observed in carriers of FED-causing mutations. rHDLs containing apoE2 were associated with a lower affinity but higher maximal esterification rate, compared to particles containing apoE3 or apoE4. ConclusionThe present results suggest that the apoE2 isoform is associated with a higher LCAT-mediated cholesterol esterification. This observation may contribute to the characterization of the peculiar functional properties of apoE2.

Plasma and cerebrospinal fluid cholesterol esterification is hampered in Alzheimer’s disease

ObjectiveThe purpose of this study was to evaluate cholesterol esterification and HDL subclasses in plasma and cerebrospinal fluid (CSF) of Alzheimer’s disease (AD) patients.MethodsThe study enrolled 70 AD patients and 74 cognitively normal controls comparable for age and sex. Lipoprotein profile, cholesterol esterification, and cholesterol efflux capacity (CEC) were evaluated in plasma and CSF.ResultsAD patients have normal plasma lipids but significantly reduced unesterified cholesterol and unesterified/total cholesterol ratio. Lecithin:cholesterol acyltransferase (LCAT) activity and cholesterol esterification rate (CER), two measures of the efficiency of the esterification process, were reduced by 29% and 16%, respectively, in the plasma of AD patients. Plasma HDL subclass distribution in AD patients was comparable to that of controls but the content of small discoidal preβ-HDL particles was significantly reduced. In agreement with the reduced preβ-HDL particles, cholesterol efflux capacity mediated by the transporters ABCA1 and ABCG1 was reduced in AD patients’ plasma. The CSF unesterified to total cholesterol ratio was increased in AD patients, and CSF CER and CEC from astrocytes were significantly reduced in AD patients. In the AD group, a significant positive correlation was observed between plasma unesterified cholesterol and unesterified/total cholesterol ratio with Aβ1-42 CSF content.ConclusionTaken together our data indicate that cholesterol esterification is hampered in plasma and CSF of AD patients and that plasma cholesterol esterification biomarkers (unesterified cholesterol and unesterified/total cholesterol ratio) are significantly associated to disease biomarkers (i.e., CSF Aβ1-42).

Two novel variants in the lecithin:cholesterol acyltransferase gene resulted in classic LCAT deficiency

Background and aimsWe report the first two cases of familial lecithin:cholesterol acyltransferase (LCAT) deficiency in Croatia with classical clinical and biochemical features. Patients and methodsA 30-year-old man with nephrotic syndrome, corneal opacities, hepatosplenomegaly, anemia, low high-density lipoprotein (HDL)-cholesterol levels and arterial hypertension (blood pressure >200/100 mmHg) was admitted to our department. At admission, he had an elevated creatinine serum level (233 μmol/L), proteinuria of 12 g in 24-h urine (g/24 h), 3–7 erythrocytes in urine sediment and notable anemia (hemoglobin level 90 g/l). His HDL-cholesterol was significantly low (0.42 mmol/L). Besides chronic kidney disease (CKD), other secondary causes of hypertension were ruled out. The patient was previously diagnosed with membranous nephropathy and treated unsuccessfully with immunosuppressive agents (steroids, cyclosporine, cyclophosphamide). Re-evaluation of histopathological findings of kidney biopsy revealed massive deposition of lipid material in the glomerular basal membrane and in the mesangial region. His 4-year younger brother was also evaluated due to corneal opacities and new-onset arterial hypertension. Nephrotic range proteinuria with preserved global renal function was determined. He also had very low HDL-cholesterol levels. ResultsKidney biopsies from both patients were consistent with LCAT deficiency. The disease was confirmed by measurement of LCAT enzyme activity, plasma cholesterol esterification rate, and genetic testing. Two novel missense variants in the LCAT gene (c.496G > A and c.1138T > C) were found. ConclusionsTo our knowledge, the presented cases are the first reported cases of genetic LCAT deficiency in Croatia. Given the clinical presentation, the complete lack of LCAT activity and cholesterol esterification rate, diagnosis of familial LCAT deficiency was made.

Hesperetin inhibits foam cell formation and promotes cholesterol efflux in THP-1-derived macrophages by activating LXR\u03b1 signal in an AMPK-dependent manner

Cholesterol efflux from macrophages is the first step of reverse cholesterol transport (RCT), whose increase inhibits cholesterol accumulation and foam cell formation to suppress atherogenesis. Hesperetin has been reported to exert several protective effects on cardiovascular diseases, while little is known about the role of hesperetin and its underlying mechanism in macrophage foam cell formation. In this study, we sought to investigate the potential effects of hesperetin on foam cell formation and cholesterol efflux by using human macrophages, focusing on liver X receptor alpha (LXRα) and AMPK. We found that hesperetin treatment reduced foam cell formation, intracellular cholesterol levels and the cholesterol esterification rate, and increased cholesterol efflux in THP-1 macrophages. Hesperetin increased the levels of LXRα protein and its targets, including ABCA1, ABCG1, SR-BI, and phosphorylated-AMPK. Meanwhile, the hesperetin-induced increase in LXRα expression was further increased by the AMPK agonist and inhibited by an AMPK inhibitor. Meanwhile, hesperetin increased the levels of LXRα mRNA and its target genes, all of which were decreased in cells transfected with the AMPKα1/α2 small interfering RNA (siRNA). Furthermore, the hesperetin-induced inhibition of foam cell formation and promotion of cholesterol efflux were decreased by transfection of AMPKα1/α2 siRNA. In conclusions, We are the first to report that hesperetin activate AMPK in THP-1-derived macrophages. This activation upregulats LXRα and its targets, including ABCA1, ABCG1 and SR-BI, which significantly inhibits foam cell formation and promotes cholesterol efflux. Our results highlight the therapeutic potential of hesperetin to possibly reduce foam cell formation. This new mechanism might contribute the anti-atherogenic effects of hesperetin.

Activation of Naturally Occurring Lecithin:Cholesterol Acyltransferase Mutants by a Novel Activator Compound.

Lecithin:cholesterol acyltransferase (LCAT) is a unique plasma enzyme able to esterify cholesterol, and it plays an important role in HDL maturation and promotion of reverse cholesterol transport. Familial LCAT deficiency (FLD; OMIM number 245900) is a rare recessive disease that results from loss-of-function mutations in the LCAT gene and has no cure. In this study, we assessed the in vitro efficacy of a novel small-molecule LCAT activator. Cholesterol esterification rate (CER) and LCAT activity were tested in plasma from six controls and five FLD homozygous carriers of various LCAT mutations at different doses of the compound (0.1, 1, and 10 µg/ml). In control plasma, the compound significantly increased both CER (P < 0.001) and LCAT activity (P = 0.007) in a dose-dependent manner. Both CER and LCAT activity increased by 4- to 5-fold, reaching maximum activation at the dose of 1 µg/ml. Interestingly, Daiichi Sankyo compound produced an increase in CER in two of the five tested LCAT mutants (Leu372--Arg and Val309--Met), while LCAT activity increased in three LCAT mutants (Arg147--Trp, Thr274--Ile and Leu372--Arg); mutant Pro254--Ser was not activated at any of the tested doses. The present findings form the basis for personalized therapeutic interventions in FLD carriers and support the potential LCAT activation in secondary LCAT defects. SIGNIFICANCE STATEMENT: We characterized the pharmacology of a novel small-molecule LCAT activator in vitro on a subset of naturally occurring LCAT mutants. Our findings form the basis for personalized therapeutic interventions for familial LCAT deficiency carriers, who can face severe complications and for whom no cure exists.

Association of lecithin-cholesterol acyltransferase activity and low-density lipoprotein heterogeneity with atherosclerotic cardiovascular disease risk: a longitudinal pilot study

BackgroundLecithin-cholesterol acyltransferase (LCAT) is believed to be involved in reverse cholesterol transport, which is known to play a key role in suppression of atherosclerosis. However, recent investigations have demonstrated that higher LCAT activity, measured in terms of the serum cholesterol esterification rate by an endogenous substrate method, is associated with increased formation of triglyceride (TG)-rich lipoproteins (TRLs), leading to a decrease in the low-density lipoprotein (LDL) particle size. The purpose of this hospital-based longitudinal study was to clarify the causal relationship between changes in the LCAT activity and changes in the LDL-particle size.MethodsThe subjects were a total of 335 patients, derived from our previous study cohort, with one or more risk factors for atherosclerotic cardiovascular disease (ASCVD). For this study, we measured the LDL-particle size (relative LDL migration [LDL-Rm value]) by polyacrylamide gel electrophoresis in the subjects, along with the changes in the LCAT activity, at the end of a follow-up period of at least 1 year.ResultsThe results revealed that the absolute change (Δ) in the LDL-particle size increased significantly as the quartile of Δ LCAT activity increased (p = 0.01). A multi-logistic regression adjusted-analysis revealed that Δ LCAT activity in the fourth quartile as compared to that in the first quartile was independently predictive of an increased LDL-particle size (odds ratio [95% confidence interval]: 2.03 [1.02/4.04], p = 0.04). Moreover, the ∆ LCAT activity was also positively correlated with ∆ TRL-related markers (i.e., TG, remnant particle-like cholesterol [RLP-C], apolipoprotein B, apolipoprotein C-2, and apolipoprotein C-3).ConclusionsThe results lend support to the hypothesis that increased LCAT activity may be associated with increased formation of TRLs, leading to a reduction in the LDL-particle size in patients at a high risk for ASCVD. To reduce the risk of ASCVD, it may be important to focus not only on the quantitative changes in the serum LDL-cholesterol levels, but also on the LCAT activity.Trial registrationUMIN (https://upload.umin.ac.jp/cgi-bin/ctr/ctr_reg_list.cgi) Study ID: UMIN000033228 retrospectively registered 2 July 2018.

Impact of serum cholesterol esterification rates on the development of diabetes mellitus in a general population

sBackgroundLecithin:cholesterol acyltransferase (LCAT) plays an important role in cholesterol esterification in serum. Serum LCAT activity is elevated in patients with serum high triglyceride and low high-density lipoprotein-cholesterol (HDL-C) concentrations, both of which are related to metabolic syndrome and subsequent diabetes mellitus, referred to as lipotoxicity. We hypothesized that increased serum LCAT activity could predict future risk of diabetes mellitus in a general Japanese population.MethodsWe prospectively studied 1496 individuals aged 20–86 years without histories of diabetes mellitus at baseline. Serum lipid concentrations, glucose parameters, and LCAT activity measured as the serum cholesterol esterification rate, were evaluated.ResultsDuring 11 years of follow-up, 46 newly diagnosed patients with diabetes mellitus were reported. After adjustment for plasma glycosylated hemoglobin A1c (HbA1c) levels, the relative risks (RRs) for the development of diabetes mellitus were 5.45 [95% confidence interval (95% CI) 2.37–12.55; P < 0.001] for body-mass index, 0.22 (95% CI, 0.09–0.53; P = 0.001) for HDL-C, 4.81 (95% CI, 1.96–11.77; P = 0.001) for triglyceride, and 4.64 (95% CI, 1.89–11.41; P = 0.001) for LCAT activity. After adjustment for HbA1c, total cholesterol, triglyceride, HDL-C, phospholipid, and free fatty acid levels, the RR of LCAT activity for future risk of diabetes mellitus remained significant (RR, 4.93; 95% CI,1.32–18.41; P = 0.018). In this analysis, we found a significant association between LCAT activity and risk of diabetes mellitus in men but not in women.ConclusionIncreased serum cholesterol esterification rate is a potent predictor for future diabetes mellitus.

Elevated level of lecithin:cholesterol acyltransferase (LCAT) is associated with reduced coronary atheroma burden

Background and aimsLecithin:cholesterol acyltransferase (LCAT), a key enzyme in high-density lipoprotein (HDL) metabolism and reverse cholesterol transport (RCT), has been associated with atheroprotection. However, its relation to plaque characteristics has not been confirmed to date. We aimed to determine the relationship between plasma LCAT mass concentration and plaque burden in a multi-center imaging study. MethodsTwo hundred sixty-seven patients with angiographically proven coronary artery disease (CAD) underwent intravascular ultrasonography (IVUS) imaging. Ninety-six patients without CAD served as controls for biochemistry assessments. ResultsPlasma LCAT mass concentration was higher in CAD patients as compared to controls (8.94 ± 2.51 μg/mL vs. 7.89 ± 2.99 μg/mL, p = 0.003), while cholesterol esterification rate (CER) was downregulated (253.6 ± 83.9 μM/2 h vs. 315.3 ± 115.0 μM/2 h, p<0.0001). Both parameters correlated inversely with total atheroma volume (r = −0.14, p = 0.027 and r = −0.14, p = 0.024, respectively), while only LCAT mass was found to be a significant predictor of atheroma volume (β-coefficient −0.18, p = 0.0047) when tested in a stepwise linear regression model against known CAD risk factors as predictor variables. Accordingly, patients with LCAT mass in the highest quartile had significantly less atheroma burden than those in the lower quartiles (39.7 ± 10.7% vs. 45.4 ± 10.4%, p = 0.0014 for highest vs. lowest quartile of LCAT mass). ConclusionsPlasma LCAT mass concentration is upregulated in CAD patients and inversely related to plaque volume, suggesting atheroprotective effects. LCAT mass concentration outperformed LCAT activity in risk prediction models for atheroma burden, suggesting that LCAT mass is a key variable in atheroprotection. Further studies assessing LCAT as a therapeutic target in cardiovascular disease are warranted.

Fractional esterification rate of cholesterol in high-density lipoprotein associates with risk of coronary heart disease

BackgroundFractional esterification rate of cholesterol in high-density lipoprotein (FERHDL) has been found to be closely correlated with atherosclerotic dyslipidemia, especially lipoprotein distributions, and is a potentially useful predictor for coronary heart disease (CHD). The associations of FERHDL, measured by the simple and precise HPLC method, with angiographically defined CHD and its related risk factors in Chinese patients were evaluated.MethodsTwo hundred and fifty eight Chinese patients who had indications for angiography were enrolled in this study. Coronary angiograms were obtained by the standard techniques. FERHDL was determined by the HPLC method. Cholesterol levels in serum HDL, LDL and subfractions were measured by ultracentrifugation/HPLC method. Associations between FERHDL and CHD and CHD risk factors were analyzed.ResultsFERHDL was correlated with almost all the CHD risk factors. Compared with the non-CHD group, the CHD patients had higher values of FERHDL (20.9 ± 7.9%/h vs 17.7 ± 7.1%/h, p = 0.001). FERHDL was found to be independently and positively correlated with log TG (β = 0.386, P < 0.001) and log (LDLb-C) (β = 0.165, P = 0.020), respectively, and negatively correlated with log (HDL2-C)(β = −0.351, P < 0.001). Logistic regression analysis demonstrated that age, diabetes mellitus, smoking and FERHDL (OR = 1.056–1.080, p < 0.05) were independent risk factors for CHD.ConclusionFERHDL significantly correlated with both HDL2-C and LDLb-C, and therefore, is the predictor of lipoprotein distributions. In addition, after correcting for the presence of classic risk factors, FERHDL was independently associated with the presence of angiographically defined CHD.

Atherogenic Impact of Lecithin-Cholesterol Acyltransferase and Its Relation to Cholesterol Esterification Rate in HDL (FERHDL) 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.

Persistent changes in lipoprotein lipids after a single infusion of ascending doses of MDCO-216 (apoA-IMilano/POPC) in healthy volunteers and stable coronary artery disease patients

Background and aimsEffects of single ascending doses of MDCO-216 on plasma lipid and lipoprotein levels were assessed in human healthy volunteers and in patients with stable coronary artery disease (CAD). MethodsMDCO-216 was infused at a single dose of 5, 10, 20, 30 or 40 mg/kg over 2 h and blood was collected at 2, 4, 8, 24, 48, 168 and 720 h after start of infusion (ASOI). Lipoprotein lipids were assessed by FLPC and by 1H NMR. ResultsPlasma concentrations of free cholesterol (FC) displayed a rapid and dose-dependent rise, peaking at 8 h, but remaining above baseline until 48 h ASOI, whereas levels of esterified cholesterol (CE) increased at lower doses but not at higher doses, and even decreased below baseline at the highest dose. Plasma cholesterol esterification rate (CER) decreased with a first nadir between 4 and 8 h and a second nadir at 48 h ASOI. Taken over all subjects receiving MDCO-216, the increase in FC at 8 h correlated inversely with the drop in CER at 4 h but positively with the increase in basal and scavenger receptor class B type I (SR-BI)-mediated cholesterol efflux capacities at 2 h ASOI.Upon FPLC analysis, FC was found to increase first in high density lipoproteins (HDL) and very low density lipoproteins (VLDL) and later (at 48 or 168 h ASOI) in low density lipoproteins (LDL). CE initially decreased in LDL and HDL but after 24 h started to increase in VLDL and LDL whereas HDL-CE was still below baseline at 48 h. Phospholipids (PL) showed the same pattern as FC. Triglycerides (TG) also rose rapidly, most prominently in VLDL, but also in LDL and HDL. Apolipoprotein E (Apo-E) in VLDL increased at 4–8 h but returned to baseline at 24 h ASOI.1H NMR analysis showed a rapid and dose-dependent increase in HDL particle size, peaking at 2 h and returning to baseline at 24 h, and a small increase in HDL particle concentration. After infusion of the 40 mg/kg dose, LDL and VLDL-particles also increased in number and size. ConclusionsA single administration of MDCO-216 caused rapid changes in lipid levels and lipoprotein composition, some of which persisted for at least 7 days.

Mechanism and Physiologic Significance of the Suppression of Cholesterol Esterification in Human Interstitial Fluid

Cholesterol esterification in high density lipoproteins (HDLs) by lecithin:cholesterol acyltransferase (LCAT) promotes unesterified cholesterol (UC) transfer from red cell membranes to plasma in vitro. However, it does not explain the transfer of UC from most peripheral cells to interstitial fluid in vivo, as HDLs in afferent peripheral lymph are enriched in UC. Having already reported that the endogenous cholesterol esterification rate (ECER) in lymph is only 5% of that in plasma, we have now explored the underlying mechanism. In peripheral lymph from 20 healthy men, LCAT concentration, LCAT activity (assayed using an optimized substrate), and LCAT specific activity averaged, respectively, 11.8, 10.3, and 84.9% of plasma values. When recombinant human LCAT was added to lymph, the increments in enzyme activity were similar to those when LCAT was added to plasma. Addition of apolipoprotein AI (apo AI), fatty acid-free albumin, Intralipid, or the d < 1.006 g/ml plasma fraction had no effect on ECER. During incubation of lymph plus plasma, the ECER was similar to that observed with buffer plus plasma. When lymph was added to heat-inactivated plasma, the ECER was 11-fold greater than with lymph plus buffer. Addition of discoidal proteoliposomes of apo AI and phosphatidycholine (PC) to lymph increased ECER 10-fold, while addition of apo AI/PC/UC disks did so by only six-fold. We conclude that the low ECER in lymph is due to a property of the HDLs, seemingly substrate inhibition of LCAT by excess cell-derived UC. This is reversed when lymph enters plasma, consequent upon redistribution of UC from lymph HDLs to plasma lipoproteins.

Nicotinic Acid Accelerates HDL Cholesteryl Ester Turnover in Obese Insulin-Resistant Dogs.

AimNicotinic acid (NA) treatment decreases plasma triglycerides and increases HDL cholesterol, but the mechanisms involved in these change are not fully understood. A reduction in cholesteryl ester transfer protein (CETP) activity has been advanced to explain most lipid-modulating effects of NA. However, due to the central role of CETP in reverse cholesterol transport in humans, other effects of NA may have been hidden. As dogs have no CETP activity, we conducted this study to examine the specific effects of extended-release niacin (NA) on lipids and high-density lipoprotein (HDL) cholesteryl ester (CE) turnover in obese Insulin-Resistant dogs with increase plasma triglycerides.MethodsHDL kinetics were assessed in fasting dogs before and four weeks after NA treatment through endogenous labeling of cholesterol and apolipoprotein AI by simultaneous infusion of [1,2 13C2] acetate and [5,5,5 2H3] leucine for 8 h. Kinetic data were analyzed by compartmental modeling. In vitro cell cholesterol efflux of serum from NA-treated dogs was also measured.ResultsNA reduced plasma total cholesterol, low-density lipoprotein cholesterol, HDL cholesterol, triglycerides (TG), and very-low-density lipoprotein TG concentrations (p < 0.05). The kinetic study also showed a higher cholesterol esterification rate (p < 0.05). HDL-CE turnover was accelerated (p < 0.05) via HDL removal through endocytosis and selective CE uptake (p < 0.05). We measured an elevated in vitro cell cholesterol efflux (p < 0.05) with NA treatment in accordance with a higher cholesterol esterification.ConclusionNA decreased HDL cholesterol but promoted cholesterol efflux and esterification, leading to improved reverse cholesterol transport. These results highlight the CETP-independent effects of NA in changes of plasma lipid profile.

Modification of lipoprotein and glucose metabolism, vascular inflammatory biomarkers and neuropathy after weight loss following bariatric surgery

Modification of lipoprotein and glucose metabolism, vascular inflammatory biomarkers and neuropathy after weight loss following bariatric surgery

Association of lecithin-cholesterol acyltransferase activity measured as a serum cholesterol esterification rate and low-density lipoprotein heterogeneity with cardiovascular risk: a cross-sectional study.

The cholesterol-esterifying enzyme, lecithin-cholesterol acyltransferase (LCAT), is believed to play a key role in reverse cholesterol transport. However, recent investigations have demonstrated that higher LCAT activity levels increase the formation of triglyceride (TG)-rich lipoproteins (TRLs) and atherogenesis. We hypothesized that higher LCAT activity measured as a serum cholesterol esterification rate by the endogenous substrate method might increase the formation of TRLs and thereby alter low-density lipoprotein (LDL) heterogeneity. The estimated LDL particle size [relative LDL migration (LDL-Rm)] was measured by polyacrylamide gel electrophoresis with the LipoPhor system (Joko, Tokyo, Japan) in 538 consecutive patients with at least risk factor for atherosclerosis. Multivariate regression analysis after adjustments for traditional risk factors identified elevated TRL-related marker (TG, remnant-like particle cholesterol, apolipoprotein C-II, and apolipoprotein C-III) levels as independent predictors of smaller-sized LDL particle size, both in the overall subject population and in the subset of patients with serum LDL cholesterol levels of <100mg/dL. Area under the receiver operating characteristic curve of the LCAT activity (0.79; sensitivity 60%; specificity 84.8%) was observed for the evaluation of the indicators of an LDL-Rm value of ≥0.40, which suggests the presence of large amounts of small-dense LDL. The results lend support to the hypothesis that increased LCAT activity may be associated with increased formation of TRLs, leading to a reduction in LDL particle size. Therefore, to reduce the risk of atherosclerotic cardiovascular disease, it may be of importance to pay attention not only to a quantitative change in the serum LDL-C, but also to the LCAT activity which is possibly associated with LDL heterogeneity.

Cholesterol and lipoprotein metabolism: Early Career Committee contribution.

Cholesterol and lipoprotein metabolism: Early Career Committee contribution.

Acquired lecithin:cholesterol acyltransferase deficiency as a major factor in lowering plasma HDL levels in chronic kidney disease.

It has been suggested that a low plasma high-density lipoprotein cholesterol (HDL-C) level contributes to the high cardiovascular disease risk of patients with chronic kidney disease (CKD), especially those undergoing haemodialysis (HD). The present study was conducted to gain further understanding of the mechanism(s) responsible for the low HDL-C levels in patients with CKD and to separate the impact of HD from that of the underlying CKD. Plasma lipids and lipoproteins, HDL subclasses and various cholesterol esterification parameters were measured in a total of 248 patients with CKD, 198 of whom were undergoing HD treatment and 40 healthy subjects. Chronic kidney disease was found to be associated with highly significant reductions in plasma HDL-C, unesterified cholesterol, apolipoprotein (apo)A-I, apoA-II and LpA-I:A-II levels in both CKD cohorts (with and without HD treatment). The cholesterol esterification process was markedly impaired, as indicated by reductions in plasma lecithin:cholesterol acyltransferase (LCAT) concentration and activity and cholesterol esterification rate, and by an increase in the plasma preβ-HDL content. HD treatment was associated with a further lowering of HDL levels and impaired plasma cholesterol esterification. The plasma HDL-C level was highly significantly correlated with LCAT concentration (R=0.438, P<0.001), LCAT activity (R=0.243, P<0.001) and cholesterol esterification rate (R=0.149, P=0.031). Highly significant correlations were also found between plasma LCAT concentration and levels of apoA-I (R=0.432, P<0.001), apoA-II (R=0.275, P<0.001), LpA-I (R= 0.326, P<0.001) and LpA-I:A-II (R=0.346, P< 0.001). Acquired LCAT deficiency is a major cause of low plasma HDL levels in patients with CKD, thus LCAT is an attractive target for therapeutic intervention to reverse dyslipidaemia, and possibly lower the cardiovascular disease risk in these patients.