Lecithin:cholesterol Acyltransferase Activity Research Articles

High-density lipoprotein functionality in systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is a heterogeneous disease which is characterized with excessive inflammation and autoantibodies, macrophage and complement activation, and subsequently immunologically mediated tissue damage. In spite of improved treatments of SLE, these patients experience premature atherosclerosis and the rate of mortality among them remains high. Autoantibodies and circulating immune complexes might contribute to the pathogenesis of atherosclerosis by injuring the endothelium, as well as inducing pro-inflammatory and pro-adhesive endothelial cell phenotypes, as well as altering the metabolism of lipoproteins involved in atherogenesis. Hence, high levels of atherogenic lipoproteins (like low-density lipoprotein (LDL) and very low-density lipoprotein (VLDL)) and low levels of high-density lipoprotein (HDL-C) are important risk factors for atherosclerotic cardiovascular complications in SLE patients but these traditional risk factors fail to fully explain the increased risk of cardiovascular disease (CVD) in these patients. The exact mechanism by which inflammation decreases HDL levels is not defined, but decreases in apoA-I production and lecithin cholesterol acyltransferase (LCAT) activity, as well as increased serum amyloid A (SAA), endothelial lipase and secretory phospholipase A2 activity (PLA2) could all contribute. In addition, during inflammation multiple changes in HDL structure occur, leading to alterations in HDL function which may be implicated in the CVD complications of SLE. Therefore, this review will aim to identify the mechanisms implicated in HDL dysfunction which occurs in SLE patients.

Lecithin–cholesterol acyltransferase (LCAT) activity is lower in patients with type 2 diabetes in the presence of metabolic syndrome

Backgrounds: Metabolic syndrome can facilitate the development of diabetes mellitus and has gained a negative reputation for its adverse effects on the general health of the population and its tendency to increase the risk of cardiovascular diseases. Cardiovascular complications may be mediated by the alteration of certain enzyme activities and pathways. Lecithin-Cholesterol Acyltransferase (LCAT) may have a potential role in the prevention of atherosclerosis as a rate-limiting enzyme in reverse cholesterol transport. In this study, LCAT activity was compared among patients with type 2 diabetes in the presence or absence of metabolic syndrome.Methods: In the present study, 55 patients with type 2 diabetes with metabolic syndrome (DM+MS group), 25 patients with type 2 diabetes without metabolic syndrome (DM-MS group), and a control group of 43 subjects without type 2 diabetes (HC group) were compared based on their anthropometric parameters, lipid profiles, glycemic indices, and LCAT activity.Results: LCAT activity was lower among participants of the DM+MS group (70.22±7.88) in comparison with the both HC group (89.51±3.59) and the DM-MS group (76.73±7.25) (respectively P<0.001, P=0.021). There was no significant difference in the fasting blood glucose levels, as evidenced by the HbA1c and HOMA-IR measurements between the DM+MS group and the DM-MS group. BMI was significantly higher in the DM+MS group compared to the DM-MS group (P=0.031). In patients with type 2 diabetes mellitus and metabolic syndrome, there was a negative correlation between LCAT activity and BMI (r=-0.275, P=0.048). There was also a negative correlation between LCAT activity and HbA1c in the DM-MS group (r=-0.606, P=0.008) and the DM+MS group (r=-0.421, P=0.002).Conclusion: LCAT activity was lower among patients with type 2 diabetes compared to subjects without type 2 diabetes and it had a greater reduction in the presence of metabolic syndrome. LCAT activity also had a negative correlation with BMI in patients with type 2 diabetes mellitus and metabolic syndrome compared to patients with type 2 diabetes that did not have metabolic syndrome.Keywords: Lecithin-Cholesterol Acyltransferase (LCAT), Metabolic syndrome, Diabetes mellitus, type 2, BMI

Temporal Dynamics of High-Density Lipoprotein Proteome in Diet-Controlled Subjects with Type 2 Diabetes.

We examined the effect of mild hyperglycemia on high-density lipoprotein (HDL) metabolism and kinetics in diet-controlled subjects with type 2 diabetes (T2D). 2H2O-labeling coupled with mass spectrometry was applied to quantify HDL cholesterol turnover and HDL proteome dynamics in subjects with T2D (n = 9) and age- and BMI-matched healthy controls (n = 8). The activities of lecithin–cholesterol acyltransferase (LCAT), cholesterol ester transfer protein (CETP), and the proinflammatory index of HDL were quantified. Plasma adiponectin levels were reduced in subjects with T2D, which was directly associated with suppressed ABCA1-dependent cholesterol efflux capacity of HDL. The fractional catabolic rates of HDL cholesterol, apolipoprotein A-II (ApoA-II), ApoJ, ApoA-IV, transthyretin, complement C3, and vitamin D-binding protein (all p < 0.05) were increased in subjects with T2D. Despite increased HDL flux of acute-phase HDL proteins, there was no change in the proinflammatory index of HDL. Although LCAT and CETP activities were not affected in subjects with T2D, LCAT was inversely associated with blood glucose and CETP was inversely associated with plasma adiponectin. The degradation rates of ApoA-II and ApoA-IV were correlated with hemoglobin A1c. In conclusion, there were in vivo impairments in HDL proteome dynamics and HDL metabolism in diet-controlled patients with T2D.

Lipase C, Hepatic Type -250A/G (rs2070895) Variant Enhances Carotid Atherosclerosis in Normolipidemic and Asymptomatic Individuals from Brazil.

The common genetic variant in the promoter region of the hepatic lipase gene [LIPC -250G/A(rs2070895)] has an ambiguous association with cardiovascular disease. In this context, our study was performed to identify the relationships between the rs2070895 with carotid atherosclerosis, plasma lipids, and parameters of reverse cholesterol transport. A total of 285 normolipidemic and asymptomatic participants from an initial sample of 598,288 individuals (inclusion criteria: LDL-C ≤130 mg/dL and triglycerides ≤150 mg/dL; age: 20-75 years, both genders; confirmation of clinical, anthropometric and laboratory data; attended all visits; DNA was achieved to perform genetic analysis) were enrolled and the rs2070895 variant was genotyped by TaqMan® OpenArray® Plataform. Carotid intima-media thickness and the screening of atherosclerotic plaques were determined by B-mode ultrasonography. The rs2070895 genotype frequencies were 0.44, 0.41, and 0.15 (GG, GA, and AA, respectively). Logistic regression analysis showed that the risk of having plaques was increased in participants carrying the AA or AG genotypes (OR = 3.90; 95% CI = 1.54-10.33), despite an increase in high-density lipoprotein cholesterol levels, HDL diameter and apolipoprotein A-I, as compared to the GG genotype. Hepatic lipase and endogenous lecithin cholesterol acyl transferase activities were reduced (38% and 19%, respectively) and lipoprotein lipase was increased by 30% (AA vs GG). Our results provide evidence that the AA or AG genotypes of the rs2070895 were associated with carotid atherosclerosis in apparently healthy participants, probably as a consequence of reduced reverse cholesterol transport and accumulation of HDL subfraction 2 rich in triglycerides and depleted in cholesteryl esters that could become dysfunctional.

Study of LCAT and some biochemical parameters in cardiovascular patient

The Clinical study included individuals (m23ales and females aged 25-75y) with cardiovascular disease. The activity of Lecithin: cholesterol acyl transferase (LCAT) and glutathione peroxidase(GPx) was estimated, in addition to the level of apolipoprotein AI (apo AI), apolipoprotein B100 (apoB100), total cholesterol (TC), triglyceride (TG), high density lipoprotein-cholesterol (HDL-c), low density lipoprotein-cholesterol (LDL-c), glutathione (GSH), peroxy nitrate (PN), malondialdehyde (MDA), glucose and certain elements (Zn, Cu, Mg and Co) in blood serum. The results showed that there was a significant decrease in the activity of LCAT and GPx, and the level of apoAI, HDL-c, GSH, Zn and Mg. on the other hand, it was shown that there was a significant increase in the level of apoB100, TC, TG, LDL-c, PN, Glu, Cu and Co but on unsignificant change in the level of MDA for both male and females.

Structural analysis of lecithin:cholesterol acyltransferase bound to high density lipoprotein particles

Lecithin:cholesterol acyltransferase (LCAT) catalyzes a critical step of reverse cholesterol transport by esterifying cholesterol in high density lipoprotein (HDL) particles. LCAT is activated by apolipoprotein A-I (ApoA-I), which forms a double belt around HDL, however the manner in which LCAT engages its lipidic substrates and ApoA-I in HDL is poorly understood. Here, we used negative stain electron microscopy, crosslinking, and hydrogen-deuterium exchange studies to refine the molecular details of the LCAT–HDL complex. Our data are consistent with LCAT preferentially binding to the edge of discoidal HDL near the boundary between helix 5 and 6 of ApoA-I in a manner that creates a path from the lipid bilayer to the active site of LCAT. Our results provide not only an explanation why LCAT activity diminishes as HDL particles mature, but also direct support for the anti-parallel double belt model of HDL, with LCAT binding preferentially to the helix 4/6 region.

Atorvastatin Improves Hepatic Lipid Metabolism and Protects Renal Damage in Adenine-Induced Chronic Kidney Disease in Sprague-Dawley Rats.

Objective Chronic kidney disease (CKD), including nephrotic syndrome, is a major cause of cardiovascular morbidity and mortality. The literature indicates that CKD is associated with profound lipid disorders largely due to the dysregulation of lipoprotein metabolism which further aggravates the progression of kidney disease. The present study sought to determine the efficacy of atorvastatin treatment on hepatic lipid metabolism and renal tissue damage in CKD rats. Methods Serum, hepatic and faecal lipid contents and the expression and enzyme activity of molecules involved in cholesterol and triglyceride metabolism, along with kidney function, were determined in untreated adenine-induced CKD, atorvastatin-treated CKD (10 mg/kg/day oral for 24 days) and control rats. Key Findings CKD resulted in metabolic dyslipidaemia, renal insufficiency, hepatic lipid accumulation, upregulation of 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase, acyl-CoA cholesterol acyltransferase-2 (ACAT2) and the downregulation of LDL receptor protein, VLDL receptor, hepatic lipase, lipoprotein lipase (LPL), lecithin–cholesterol acyltransferase (LCAT) and scavenger receptor class B type 1 (SR-B1). CKD also resulted in increased enzymatic activity of HMG-CoA reductase and ACAT2 together with decreased enzyme activity of lipase and LCAT. Atorvastatin therapy attenuated dyslipidaemia, renal insufficiency, reduced hepatic lipids, HMG-CoA reductase and ACAT2 protein abundance and raised LDL receptor and lipase protein expression. Atorvastatin therapy decreased the enzymatic activity of HMG-CoA reductase and increased enzymatic activity of lipase and LCAT. Conclusions Atorvastatin improved hepatic tissue lipid metabolism and renal function in adenine-induced CKD rats.

Lipid Profile Rather Than the LCAT Mutation Explains Renal Disease in Familial LCAT Deficiency

Renal complications are the major cause of morbidity and mortality in patients with familial lecithin–cholesterol acyltransferase (LCAT) deficiency (FLD). We report three FLD patients, two of them siblings—only one of whom developed renal disease—and the third case being a young man with early renal disease. The aim of this study was to analyze the clinical characteristics and possible mechanisms associated with renal disease in these patients. Plasma lipid levels, LCAT activity, lipoprotein particle profile by NMR and FPLC, free and esterified cholesterol, presence of lipoprotein X (LpX) and DNA sequencing in the three FLD patients have been determined. The three cases presented clinical characteristics of FLD, although only one of the siblings developed renal disease, at 45 years of age, while the other patient developed the disease in his youth. Genetic analysis revealed new missense homozygous mutations, p.(Ile202Thr) in both siblings and p.(Arg171Glu) in the other patient. Lipoprotein particle analysis showed that the two patients with renal disease presented higher numbers of small very low-density lipoprotein (VLDL) and a higher concentration of triglycerides in VLDL. This study reports three new cases of LCAT deficiency, not previously described. Renal disease is not only dependent on LCAT deficiency, and could be due to the presence of VLDL particles, which are rich in triglycerides, free cholesterol and LpX.

Isopulegol Ameliorates Dyslipidemia by Modulating Adipokine Secretion in High Fat Diet / Streptozotocin Induced Diabetic Rats

The present study investigates the effect of isopulegol on adipokine secretion and dyslipidemia in high fat diet and streptozotocin (HFD/STZ) induced diabetic rats. Animals were made diabetic by feeding HFD for 4 wks followed by single intraperitoneal injection of STZ (35mg/kg b.w; 0.1M citrate buffer; pH 4.0). Diabetic rats showed increased levels of total cholesterol, triglycerides, free fatty acids, phospholipids, low density lipoprotein-C (LDL-C), very low density lipoprotein -C (VLDL-C) and decreased high density lipoprotein-C levels (HDL-C). Similarly, the activity of HMG-CoA reductase, was increased while lipoprotein lipase (LPL) and lecithin cholesterol acyl transferase (LCAT) activities were significantly decreased. Furthermore, the expression of sterol regulatory element binding protein-1C (SREBP-1C), adiponectin, peroxisome proliferator activated receptor gamma (PPARγ) were significantly down regulated, whereas leptin expression was upregulated in diabetic rats. Administration of isopulegol (100 mg/kg b.w) for 28 days significantly restored lipid levels in plasma and liver tissue by modulating adipokine secretion in diabetic treated rats. From this we conclude that isopulegol exhibited significant antihyperlipidemic effect in HFD/STZ induced diabetic rats. Keywords: Dyslipidemia, Diabetes mellitus, Adiponectin, Leptin, PPARγ, SREBP-1C

Metabolic and antioxidant effects of micro algae in diabetic rats: Implications for the prevention of human pathologies

Oxidative stress has been shown to play an important role during diabetes. Micro algae constitute a major field for the research of new bioactive molecules of interest for the health and care of the disease such as polyunsaturated fatty acids and carotenoids. Nannochloropsis gaditana is a genusmicroalgae that has anti-inflammatory, antioxidant and antidiabetic properties. The purpose of the present study was to investigate the effect of micro algae Nannochlorpsis gaditana supplementation on lipases activities and some markers of redox status in diabetic rats. Wistar rat received streptozotocin (STZ) and were feed with different diets for 2 months: standard diet and a diet supplemented with micro algae. After sacrifices the serum activity of lecithin cholesterol acyltransferase (LCAT) was determined as well as markers of erythrocyte lysates oxidative stress such as MDA, protein carbonyls, catalase, GSH and SOD. The adipose tissue, liver andpancreaswere also used to study the activity of lipases. We evidenced increased blood glucose and glycated hemoglobin in diabetic rats. Nannochloropsis gaditana supplementation lowered blood glucose andglycated hemoglobin. Significant decreases in hepatic and pancreatic lipoprotein lipase (LPL)and LCAT activities were recorded in diabetic rats compared to their controls. In parallel, an increase in the adipose hormone sensitive lipase (HSL) activity in adipose tissue was noted in diabetic rats, probably due to lack of insulin. The administration of micro algae in diabetic animals induced a modulation of lipase activities and LCAT. Regarding to the oxidant/antioxidant status in the erythrocyte lysates, we evidenced an imbalance of redox status in diabetic rats. Supplementation with the micro algae Nannochlorpsis gaditana attenuated oxidative stress in the diabetic rats by reducing lipid peroxidation markers such as MDA and protein carbonyls and increasing the activity of catalase, GSH and SOD, suggesting an important antioxidant defence. Our results suggest that Nannochlorpsis gaditana has antidiabetic and antioxidant activities that can reduce oxidative stress and correct metabolic alterations associated with diabetes.

Cactus young cladodes improves unbalanced glycemic control, dyslipidemia, prooxidant/antioxidant stress biomarkers and stimulate lecithin-cholesterol acyltransferase and paraoxonase activities in young rats after cafeteria diet exposure

PurposeThis paper aims to evaluate the protective potential of prickly pear cactus fresh cladodes (opuntia ficus indica (OFI)) on glycemic disorders, dyslipidemia, prooxidant/antioxidant stress biomarkers and reverse cholesterol transport (by evaluating the activity of lecithin-cholesterol acyltransferase (LCAT)) and paraoxonase (PON1) in rats prematurely exposed to cafeteria diet (CD).Design/methodology/approachSixteen young rats were divided into two groups fed CD containing 50 per cent of hyperlipidic diet (HLD) and 50 per cent of junk food mix supplemented or not with 50 g of fresh young cladodes of OFI to 100 g of CD, during 30 days.FindingsOFI cladodes supplementation decreased significantly body weight (p &lt; 0.001), food intake (p &lt; 0.05), adipose tissue weight (p &lt; 0.01), fasting glycemia and glycosylated hemoglobin (p &lt; 0.01), homeostasis model assessment (HOMA-IR) and insulinemia (p &lt; 0.001), levels of cholesterol (C) (p &lt; 0.05) and triacylglycerols (TG) (p &lt; 0.01) in serum and in very low-density lipoproteins (VLDL-Cp &lt; 0.05 and VLDL-TGp &lt; 0.01) and improves reverse cholesterol transport by increasing high-density lipoprotein cholesteryl-esters concentrations (p &lt; 0.001) and by stimulating LCAT activity. Moreover, they attenuated lipid peroxidation in VLDL and low-density lipoproteins by increasing atheroprotective activity of PON-1 and in liver and adipose tissue by enhancing enzymatic antioxidant defence.Social implicationsThe young cladodes of OFI because of their antiobesity benefits could constitute a novel functional ingredient in pharmaceutical and nutraceutical applications.Originality/valueYoung cladodes of OFI in rat precociously submitted to a hyperlipidic diet/junk food (cafeteria model) seem to prevent metabolic disorders associated with obesity.

Intravenous laser wavelength radiation effect on LCAT, PON1, catalase, and FRAP in diabetic rats.

The main purpose of this study is to evaluate the effect of intravenous irradiation of different low-level laser wavelengths on the activity of lecithin-cholesterol acyltransferase (LCAT), paraoxonase (PON1), catalase, and ferricreducing ability of plasma (FRAP) in diabetic rats. First, diabetes was induced in rats using streptozotocin (STZ). Enzymes' activity was measured in the blood samples and compared before and after intravenous laser blood irradiation. We used four continuous-wave lasers-IR (λ = 808nm), Red (λ = 638nm), Green (λ = 532nm), and Blue (λ = 450nm)-to compare the wavelength's effect on different enzymes' activity. Laser power was fixed at 0.01mW and laser energy was changed by 2-, 4-, 6-, and 8-min time of radiations.The enzymes' activity of blood samples was measured 2, 6, and 24h after radiation. The results show an increase in the activity of different enzymes when compare with diabetic non-radiated samples. More importantly, with a constant laser energy, the enzymes' activity increased with decreasing laser wavelength. It is important to note that with a constant laser energy, as the wavelength decreases, the photon energy increases and the number of photons decrease, while the enzyme's activity elevation increases. As a result, we can conclude that in intravenous low-level laser therapy, photon energy is more important than the number of photons even if their product, energy, is kept constant.

Allergic rhinitis is associated with complex alterations in high-density lipoprotein composition and function

Despite strong evidence that high-density lipoproteins (HDLs) modulate the immune response, the role of HDL in allergies is still poorly understood. Many patients with allergic rhinitis (AR) develop a late-phase response, characterized by infiltration of monocytes and eosinophils into the nasal submucosa. Functional impairment of HDL in AR-patients may insufficiently suppress inflammation and cell infiltration, but the effect of AR on the composition and function of HDL is not understood. We used apolipoprotein (apo) B-depleted serum as well as isolated HDL from AR-patients (n = 43) and non-allergic healthy controls (n = 20) for detailed compositional and functional characterization of HDL. Both AR-HDL and apoB-depleted serum of AR-patients showed decreased anti-oxidative capacity and impaired ability to suppress monocyte nuclear factor-κB expression and pro-inflammatory cytokine secretion, such as interleukin (IL)-4, IL-6, IL-8, tumor necrosis factor alpha and IL-1 beta. Sera of AR-patients showed decreased paraoxonase and cholesteryl-ester transfer protein activities, increased lipoprotein-associated phospholipase A2 activity, while lecithin-cholesterol acyltransferase activity and cholesterol efflux capacity were not altered. Surprisingly, apoB-depleted serum and HDL from AR-patients showed an increased ability to suppress eosinophil effector responses upon eotaxin-2/CCL24 stimulation. Mass spectrometry and biochemical analyses showed reduced levels of apoA-I and phosphatidylcholine, but increased levels of apoA-II, triglycerides and lyso-phosphatidylcholine in AR-HDL. The changes in AR-HDL composition were associated with altered functional properties. In conclusion, AR alters HDL composition linked to decreased anti-oxidative and anti-inflammatory properties but improves the ability of HDL to suppress eosinophil effector responses.

The association between lecithin-cholesterol acyltransferase activity and fatty liver index.

Background Non-alcoholic fatty liver disease is a frequent ailment with known complications, including those within the cardiovascular system. Associations between several indicators of high-density lipoprotein metabolism and function with clinical and laboratory parameters for the assessment of fatty liver index, a surrogate marker of non-alcoholic fatty liver disease, were evaluated. Methods The study comprised 130 patients classified according to fatty liver index values: fatty liver index &lt; 30, fatty liver index 30–59 (the intermediate group) and fatty liver index ⩾ 60. Lecithin–cholesterol acyltransferase and cholesteryl ester transfer protein activities were determined. Paraoxonase 1 concentration and its activity, paraoxonase 3 concentration and high-density lipoprotein subclass distribution were assessed. Results Increased lecithin–cholesterol acyltransferase activity correlated with increased fatty liver index ( P &lt; 0.001). Paraoxonase 3 concentration was lower in the fatty liver index ⩾ 60 group compared with the fatty liver index &lt; 30 group ( P &lt; 0.05). Cholesteryl ester transfer protein activity, paraoxonase 1 concentration and its activity did not significantly differ across the fatty liver index groups. The relative proportion of small-sized high-density lipoprotein 3 subclass was higher in the fatty liver index ⩾ 60 group compared with the other two fatty liver index groups ( P &lt; 0.01). Lecithin–cholesterol acyltransferase activity positively associated with the fatty liver index ⩾ 60 group and remained significant after adjustment for other potential confounders. Only the triglyceride concentration remained significantly associated with lecithin–cholesterol acyltransferase activity when the parameters that constitute the fatty liver index equation were examined. Conclusions Higher lecithin–cholesterol acyltransferase activity is associated with elevated fatty liver index values. Significant independent association between triglycerides and lecithin–cholesterol acyltransferase activity might indicate a role of hypertriglyceridaemia in alterations of lecithin–cholesterol acyltransferase activity in individuals with elevated fatty liver index.

The P274S Mutation of Lecithin-Cholesterol Acyltransferase (LCAT) and Its Clinical Manifestations in a Large Kindred

Lecithin-cholesterol acyltransferase (LCAT) catalyzes the maturation of high-density lipoprotein. Homozygosity for loss-of-function mutations causes familial LCAT deficiency (FLD), characterized by corneal opacities, anemia, and renal involvement. This study sought to characterize kidney biopsy findings and clinical outcomes in a family withFLD. Prospective observational study. 2 (related) index patients with clinically apparent FLD were initially identified. 110 of 122 family members who consented to genetic analysis were also studied. Demographic and laboratory parameters (including lipid profiles and LCAT activity) and full sequence analysis of the LCAT gene. Kidney histologic examination was performed with samples from 6 participants. Cardiovascular and renal events during a median follow-up of 12 years. Estimation of annual rate of decline in glomerular filtration rate. Analysis of variance, linear regression analysis, and Fine-Gray competing-risk survival analysis. 9 homozygous, 57 heterozygous, and 44 unaffected family members were identified. In all affected individuals, full sequence analysis of the LCAT gene revealed a mutation (c.820C>T) predicted to cause a proline to serine substitution at amino acid 274 (P274S). Homozygosity caused a complete loss of LCAT activity. Kidney biopsy findings demonstrated lipid deposition causing glomerular basement membrane thickening, mesangial expansion, and "foam-cell" infiltration of kidney tissue. Tubular atrophy, glomerular sclerosis, and complement fixation were associated with worse kidney outcomes. Estimated glomerular filtration rate deteriorated among homozygous family members at an average annual rate of3.56 mL/min/1.73 m2. The incidence of cardiovascularand renal complications was higher among homozygous family members compared with heterozygous and unaffected members. Mild thrombocytopenia was a common finding among homozygous participants. The presence of cardiovascular disease was mainly based on medical history. The P274S LCAT mutation was found to cause FLD with renal involvement. Tubular atrophy, glomerular sclerosis, and complement fixation were associated with a worse renal prognosis.

Atrial fibrillation is associated with alterations in HDL function, metabolism, and particle number.

Increased morbidity and mortality in atrial fibrillation (AF) are related to the pro-fibrotic, pro-thrombotic, and pro-inflammatory processes that underpin the disease. High-density lipoproteins (HDL) have anti-inflammatory, anti-oxidative, and anti-thrombotic properties. Functional impairment of HDL may, therefore, associate with AF initiation or progression. We studied indices of HDL quality and quantity of AF patients and healthy controls, including HDL-particle number, HDL cholesterol, apolipoprotein (apo) A-I levels, serum amyloid A (SAA) content and HDL-cholesterol efflux capacity, and paraoxonase activity of apoB-depleted serum. Serum samples were collected from AF patients (n = 91) before catheter ablation and from age- and sex-matched control subjects (n = 54). HDL-cholesterol efflux capacity was assessed in a validated assay using [3H]-cholesterol-labeled J774 macrophages. Lecithin-cholesterol acyltransferase (LCAT) and paraoxonase activities were assessed using fluorometric assays, SAA levels were determined by ELISA, and total and subclass HDL-particle number was assessed by nuclear magnetic resonance spectroscopy. ApoA-I levels were determined by immunoturbidimetry. HDL-cholesterol efflux capacity, HDL-particle number, apoA-I levels, and LCAT activity were markedly reduced in AF patients when compared to healthy individuals (all p < 0.001), whereas HDL-associated paraoxonase activity and SAA content were not altered (p = 0.578, p = 0.681). Notably, cholesterol efflux capacity, HDL-particle number, apoA-I levels as well as LCAT activity recovered following restoration of sinus rhythm (all p < 0.001). We identified marked alterations in HDL function, HDL maturation, and HDL-particle number in AF patients. Assessing HDL-particle number and function in AF may be used as a surrogate marker of AF onset and progression and may help identifying patients at high risk.

Recombinant LCAT (Lecithin:Cholesterol Acyltransferase) Rescues Defective HDL (High-Density Lipoprotein)-Mediated Endothelial Protection in Acute Coronary Syndrome.

Objective- Aim of this study was to evaluate changes in LCAT (lecithin:cholesterol acyltransferase) concentration and activity in patients with an acute coronary syndrome, to investigate if these changes are related to the compromised capacity of HDL (high-density lipoprotein) to promote endothelial nitric oxide (NO) production, and to assess if rhLCAT (recombinant human LCAT) can rescue the defective vasoprotective HDL function. Approach and Results- Thirty ST-segment-elevation myocardial infarction (STEMI) patients were enrolled, and plasma was collected at hospital admission, 48 and 72 hours thereafter, at hospital discharge, and at 30-day follow-up. Plasma LCAT concentration and activity were measured and related to the capacity of HDL to promote NO production in cultured endothelial cells. In vitro studies were performed in which STEMI patients' plasma was added with rhLCAT and HDL vasoprotective activity assessed by measuring NO production in endothelial cells. The plasma concentration of the LCAT enzyme significantly decreases during STEMI with a parallel significant reduction in LCAT activity. HDL isolated from STEMI patients progressively lose the capacity to promote NO production by endothelial cells, and the reduction is related to decreased LCAT concentration. In vitro incubation of STEMI patients' plasma with rhLCAT restores HDL ability to promote endothelial NO production, possibly related to significant modification in HDL phospholipid classes. Conclusions- Impairment of cholesterol esterification may be a major factor in the HDL dysfunction observed during acute coronary syndrome. rhLCAT is able to restore HDL-mediated NO production in vitro, suggesting LCAT as potential therapeutic target for restoring HDL functionality in acute coronary syndrome.

Plasma Levels of Preβ1-HDL Are Significantly Elevated in Non-Dialyzed Patients with Advanced Stages of Chronic Kidney Disease.

In chronic kidney disease (CKD), the level of high-density lipoprotein (HDL) decreases markedly, but there is no strong inverse relationship between HDL-cholesterol (HDL-C) and cardiovascular diseases. This indicates that not only the HDL-C level, but also the other quantitative changes in the HDL particles can influence the protective functionality of these particles, and can play a key role in the increase of cardiovascular risk in CKD patients. The aim of the present study was the evaluation of the parameters that may give additional information about the HDL particles in the course of progressing CKD. For this purpose, we analyzed the concentrations of HDL containing apolipoprotein A-I without apolipoprotein A-II (LpA-I), preβ1-HDL, and myeloperoxidase (MPO), and the activity of paraoxonase-1 (PON-1) in 68 patients at various stages of CKD. The concentration of HDL cholesterol, MPO, PON-1, and lecithin-cholesterol acyltransferase (LCAT) activity were similar in all of the analyzed stages of CKD. We did not notice significant changes in the LpA-I concentrations in the following stages of CKD (3a CKD stage: 57 ± 19; 3b CKD stage: 54 ± 15; 4 CKD stage: 52 ± 14; p = 0.49). We found, however, that the preβ1-HDL concentration and preβ1-HDL/LpA-I ratio increased along with the progress of CKD, and were inversely correlated with the estimated glomerular filtration rate (eGFR), even after adjusting for age, gender, triacylglycerols (TAG), HDL cholesterol, and statin therapy (β = −0.41, p < 0.001; β = −0.33, p = 0.001, respectively). Our results support the earlier hypothesis that kidney disease leads to the modification of HDL particles, and show that the preβ1-HDL concentration is significantly elevated in non-dialyzed patients with advanced stages of CKD.

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.

Changes in lecithin: cholesterol acyltransferase, cholesteryl ester transfer protein and paraoxonase-1 activities in patients with colorectal cancer

BackgroundPrevious studies revealed decreased level of high-density lipoprotein cholesterol (HDLC) as important factor for development of colorectal cancer (CRC). Quantity and structure of HDL particles depend on activities of lipid transfer proteins lecithin:cholesterol acyltransferase (LCAT) and cholesteryl ester transfer protein (CETP), but this topic is largely unexplored in CRC. The main objective of this study was to investigate activities of LCAT and CETP in patients with CRC. Additionally, we analyzed activity of paraoxonase-1 (PON-1), as a main carrier of HDL-antioxidant function. Materials and methodsNinety-nine CRC patients and 101 healthy individuals were included. LCAT and CETP activities were assessed by measuring rates of formation and transfer of cholesteryl esters. PON-1 paraoxonase and arylesterase activities were measured. ResultsLower levels of HDL-C (p < .001) were observed in cohort of patients, alongside with decreased LCAT (p < .050) and increased CETP activity (p < .050). Both PON-1 activities were diminished in CRC (p < .050 and p < .001 respectively). Univariate logistic regression singled out HDL-C level (OR = 0.218, p < .001), CETP activity (OR = 1.010, p < .01) and mass (OR = 0.994, p < .001) as possible markers of elevated CRC risk. CETP mass maintained its predictive significance when adjusted for traditional risk factors and level of oxidative stress (OR = 0.993, p < .001; OR = 0.982, p < .050, respectively). ConclusionOur results demonstrated increased CETP and decreased LCAT and PON-1 activities in CRC patients. In preliminary analysis CETP mass was identified as potential significant predictor of CRC development, suggesting that alterations in HDL-C levels, alongside with changes in HDL structure might have a role in carcinogenesis.