Lecithin:cholesterol Acyltransferase Research Articles

Insulin resistance in childhood obesity: The role of dietary habits and their association with novel markers of cardiovascular disease

Background Childhood obesity presents numerous comorbidities such as insulin resistance (IR) and dyslipidemia, and could be associated with alterations in novel markers of cardiovascular (CV) risk like: (1) the activities of associated enzymes such as lipoprotein associated phospholipase A2 (Lp-PLA2) and paraoxonase 1 (PON 1), (2) reverse cholesterol transport (RCT), which comprises cellular cholesterol efflux (CCE), in addition to lecithin:cholesterol acyltransferase (LCAT) and cholesteryl ester transfer protein (CETP) activities, and (3) high density lipoprotein (HDL) antioxidant capacity. Moreover, IR could worsen these cardiometabolic alterations. The objective of the present study was to characterize the effect of IR on novel CV markers in a pediatric population with obesity. Methods Twenty-five obese children and adolescents with IR, and 25 without IR took part in the study. Anthropometric parameters, Tanner stage and dietary habits were registered. Glucose, insulin, non-esterified fatty acid (NEFA), lipid, and high sensitivity C reactive protein (hsCRP) levels, plus Lp-PLA2, LCAT, CETP and PON 1 activities, as well as CCE and HDL antioxidant capacity were measured. A cutoff point of 3.16 in Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) determined the presence of IR. Results No differences were observed in age, sex and Tanner stage. Expectedly, the group with IR displayed higher insulin and NEFA levels (p < 0.05). They also presented increased Lp-PLA2 and decreased PON activities (p < 0.05). Importantly, these differences were associated with dietary habits (p < 0.05). Conclusion IR present in pediatric obesity associated with vascular specific inflammation and reduced PON 1 activity, in addition to alterations in glucose metabolism, thus increasing CV risk in adulthood. These proatherogenic disturbances were conditioned by dietary habits.

A Case–Control Study on the Usefulness of Serum Lecithin: Cholesterol Acyltransferase Activity as a Predictor of Retained Placenta in Close-Up Dairy Cows

The purpose of this study was to investigate the usefulness of the activity of lecithin:cholesterol acyltransferase (LCAT), the enzyme responsible for esterification of cholesterol in plasma, as a predictor of retained placenta (RP) in close-up cows, compared with the non-esterified fatty acids (NEFA) concentration. This study was conducted as a case–control study between February 2010 and February 2016, on a single farm with approximately 200 Holstein parous cows in Hokkaido, Japan. Of the 1187 dairy cattle that calved, 835 dairy cattle were enrolled that underwent routine regular health examinations including blood sampling, body condition score (BCS) and the rumen fill score (RFS) at the close-up stage between 2 and 21 days before their expected calving dates. Of these, 27 cows that were multiparous and had RP were designated as the RP group. The controls were 60 clinically healthy cows that did not develop RP and were matched for the sampling period and parity with the RP group. The LCAT activity and NEFA concentration were significantly (p < 0.01) lower and higher, respectively, in the RP group than in controls. There was no significant difference in cholesteryl esters, free cholesterol concentrations and BCS between the two groups. However, RFS was significantly (p < 0.01) lower in the RP group than in the controls. Cows with LCAT activity of <450 U were 3.6 times more likely to develop RP than those with higher values, whereas those with NEFA levels above 0.4 mEq/L were 5.4 times more likely to. The area under the curve of receiver operator characteristic curves showed that LCAT activity was as efficient as the NEFA concentration in the diagnostic prediction of RP, suggesting it to be a useful predictor. Logistic regression analysis with LCAT or NEFA and RFS as explanatory variables resulted in a model with higher predictive accuracy than with each alone, indicating RFS to be a possible factor in predicting RP.

Ajuga iva extract lowers plasma cholesterol and improves lipoprotein profile and lecithin: cholesterol acyltransferase (LCAT) activity in rats fed high cholesterol diet

The purpose of the study was to investigate the therapeutic and preventive effects of Ajuga iva (L) Schreber (Labiatae) (Ai) extract on hypercholesterolemic model rats. For this aim, male Wistar rats were fed a high‑cholesterol (1%) diet to establish a hypercholesterolemia model supplemented or not with aqueous extract of Ajuga Iva (Ai) (5 g/kg diet) for 4 weeks. Ai lowered plasma total cholesterol (TC) (18%) with a reduction in cholesteryl esters (CE) (29%). Low VLDL-TC and high HDL2-TC were observed in Ai group. TC/HDL’s -C ratio was 1.64-fold lower, whereas HDL’s-C/ LDL-HDL1-C was 1.82-fold higher in Ai treated rats. Triacylglycerols (TG) were reduced in plasma and in VLDL but increased in HDL2 and HDL3 with Ai supplementation. Rats exposed to Ai diet lowered VLDL-unesterified cholesterol (UC), LDL-HDL1-amount and LDL-HDL1-CE but increased HDL3-CE. Low levels of liver phospholipids (PL) and high CE concentrations were observed in Ai group. In aorta, TC was decreased by 37% with Ai. Feeding Ai diet decreased HDL3-PL and increased HDL2-CE and plasma LCAT activity. Moreover, Ai administration (5 g/kg for 4 weeks) improved liver and kidney function, as demonstrated by decreased plasma aspartate aminotransferase (AST) activity and creatinine, and resulted in an increase of urinary and sodium excretion. We conclude that, in addition to its Strong C and TG-lowering effect, Ai improves effectively the atherogenic lipoproteins profile by reducing the LDL-HDL1 amount and increasing the HDL-cholesterol. Furthermore, Ai increases the reverse cholesterol transport by enhancement of cholesterol: acyltransferase (LCAT) activity. These beneficial effects are considered potential mechanisms through which Ai acts as a protective agent against cholesterol-induced damage, ensuring cardiovascular safety.

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.

Gliflozins, sucrose and flavonoids are allosteric activators of lecithin-cholesterol acyltransferase

Lecithin-cholesterol acyltransferase (LCAT) serves as a pivotal enzyme in preserving cholesterol homeostasis via reverse cholesterol transport, a process closely associated with the onset of atherosclerosis. Impaired LCAT function can lead to severe LCAT deficiency disorders for which no pharmacological treatment exists. LCAT-based therapies, such as small molecule positive allosteric modulators (PAMs), against LCAT deficiencies and atherosclerosis hold promise, although their efficacy against atherosclerosis remains challenging. Herein we utilized a quantitative in silico metric to predict the activity of novel PAMs and tested their potencies with in vitro enzymatic assays. As predicted, sodium-glucose cotransporter 2 (SGLT2) inhibitors (gliflozins), sucrose and flavonoids activate LCAT. This has intriguing implications for the mechanism of action of gliflozins, which are commonly used in the treatment of type 2 diabetes, and for the endogenous activation of LCAT. Our results underscore the potential of molecular dynamics simulations in rational drug design.

Novel pathogenic variant in the LCAT gene in a compound heterozygous patient with fish-eye disease and a mild phenotype

Background and ObjectiveLow HDL-cholesterol and corneal opacity are associated with fish-eye disease (FED), familial LCAT deficiency (FLD), ApoAI deficiency, and Tangier disease. The differential diagnosis is made by clinical and biochemical tests. Measuring the LCAT activity is the ideal way to distinguish conditions caused by LCAT gene variants (FED and FLD) from the other two diseases. However, this is not accessible from all clinics. The CE/TC ratio, which is below the reference range in most cases with LCAT gene variants, has been proposed as an alternative. We report a case of compound heterozygous FED with a CE/TC ratio within the reference range. MethodsLCAT activity assays and genetic analyses were performed using patients’ blood samples. Identified LCAT gene variants were examined by an in vitro expression assay. ResultsThe proband showed approximately 20% LCAT α-activity relative to the normolipidemic controls, whereas a patient with a typical FED-causing variant (p.Thr147Ile) showed only 3% activity. We identified compound heterozygous variants (c.101C>T/c.460A>G) resulting in a p.Pro34Leu/p.Asn154Asp amino acid residue substitution in the LCAT gene of the proband. The former variant has been reported previously, but the latter was newly identified. An in vitro expression assay demonstrated that the LCAT α-activity of the p.Asn154Asp variant significantly decreased regarding the wild type, but it was relatively well preserved compared to the typical FED-causing variants (p.Pro34Leu and p.Thr147Ile). ConclusionThese results suggest that the residual 20% LCAT α-activity is sufficient to normalize CE/TC, but not sufficient to prevent the development of corneal opacity in FED.

Effects of dietary interventions and intermittent fasting on HDL function in obese individuals with T2DM: a randomized controlled trial

BackgroundCardiovascular disease represents a significant risk factor for mortality in individuals with type 2 diabetes mellitus (T2DM). High-density lipoprotein (HDL) is believed to play a crucial role in maintaining cardiovascular health through its multifaceted atheroprotective effects and its capacity to enhance glycemic control. The impact of dietary interventions and intermittent fasting (IF) on HDL functionality remains uncertain. The objective of this study was to assess the effects of dietary interventions and IF as a strategy to safely improve glycemic control and reduce body weight on functional parameters of HDL in individuals with T2DM.MethodsBefore the 12-week intervention, all participants (n = 41) of the INTERFAST-2 study were standardized to a uniform basal insulin regimen and randomized to an IF or non-IF group. Additionally, all participants were advised to adhere to dietary recommendations that promoted healthy eating patterns. The IF group (n = 19) followed an alternate-day fasting routine, reducing their calorie intake by 75% on fasting days. The participants’ glucose levels were continuously monitored. Other parameters were measured following the intervention: Lipoprotein composition and subclass distribution were measured by nuclear magnetic resonance spectroscopy. HDL cholesterol efflux capacity, paraoxonase 1 (PON1) activity, lecithin cholesterol acyltransferase (LCAT) activity, and cholesterol ester transfer protein (CETP) activity were assessed using cell-based assays and commercially available kits. Apolipoprotein M (apoM) levels were determined by ELISA.ResultsFollowing the 12-week intervention, the IF regimen significantly elevated serum apoM levels (p = 0.0144), whereas no increase was observed in the non-IF group (p = 0.9801). ApoM levels correlated with weight loss and fasting glucose levels in the IF group. Both groups exhibited a robust enhancement in HDL cholesterol efflux capacity (p < 0.0001, p = 0.0006) after 12 weeks. Notably, only the non-IF group exhibited significantly elevated activity of PON1 (p = 0.0455) and LCAT (p = 0.0117) following the 12-week intervention. In contrast, the changes observed in the IF group did not reach statistical significance.ConclusionsA balanced diet combined with meticulous insulin management improves multiple metrics of HDL function. While additional IF increases apoM levels, it does not further enhance other aspects of HDL functionality.Trial registrationThe study was registered at the German Clinical Trial Register (DRKS) on 3 September 2019 under the number DRKS00018070.Graphical

Impaired HDL antioxidant and anti-inflammatory functions are linked to increased mortality in acute heart failure patients

AimsAcute heart failure (AHF) is typified by inflammatory and oxidative stress responses, which are associated with unfavorable patient outcomes. Given the anti-inflammatory and antioxidant properties of high-density lipoprotein (HDL), this study sought to examine the relationship between impaired HDL function and mortality in AHF patients. The complex interplay between various HDL-related biomarkers and clinical outcomes remains poorly understood. MethodsHDL subclass distribution was quantified by nuclear magnetic resonance spectroscopy. Lecithin–cholesterol acyltransferase (LCAT) activity, cholesterol ester transfer protein (CETP) activity, and paraoxonase (PON-1) activity were assessed using fluorometric assays. HDL-cholesterol efflux capacity (CEC) was assessed in a validated assay using [3H]-cholesterol-labeled J774 macrophages. ResultsAmong the study participants, 74 (23.5 %) out of 315 died within three months after hospitalization due to AHF. These patients exhibited lower activities of the anti-oxidant enzymes PON1 and LCAT, impaired CEC, and lower concentration of small HDL subclasses, which remained significant after accounting for potential confounding factors. Smaller HDL particles, particularly HDL3 and HDL4, exhibited a strong association with CEC, PON1 activity, and LCAT activity. ConclusionsIn patients with AHF, impaired HDL CEC, HDL antioxidant and anti-inflammatory function, and impaired HDL metabolism are associated with increased mortality. Assessment of HDL function and subclass distribution could provide valuable clinical information and help identify patients at high risk.

Low LCAT activity is linked to acute decompensated heart failure and mortality in patients with CKD

Chronic kidney disease (CKD) is often associated with decreased activity of lecithin-cholesterol acyltransferase (LCAT), an enzyme essential for HDL maturation. This reduction in LCAT activity may potentially contribute to an increased risk of cardiovascular mortality in patients with CKD. The objective of this study was to investigate the association between LCAT activity in patients with CKD and the risk of adverse outcomes. We measured serum LCAT activity and characterized lipoprotein profiles using nuclear magnetic resonance spectroscopy in 453 non-dialysis CKD patients from the CARE FOR HOMe study. LCAT activity correlated directly with smaller HDL particle size, a type of HDL potentially linked to greater cardiovascular protection. Over a mean follow-up of 5.0 ± 2.2 years, baseline LCAT activity was inversely associated with risk of death (standardized HR 0.62, 95% CI 0.50–0.76; P < 0.001) and acute decompensated heart failure (ADHF) (standardized HR 0.67, 95% CI 0.52–0.85; P = 0.001). These associations remained significant even after adjusting for other risk factors. Interestingly, LCAT activity was not associated with the incidence of atherosclerotic cardiovascular events or kidney function decline during the follow-up. To conclude, our findings demonstrate that low LCAT activity is independently associated with all-cause mortality and ADHF in patients with CKD, and is directly linked to smaller, potentially more protective HDL subclasses.

Rescue of Familial Lecithin:Cholesterol Acyltranferase Deficiency Mutations with an Allosteric Activator.

Lecithin:cholesterol acyltransferase (LCAT) deficiencies represent severe disorders characterized by aberrant cholesterol esterification in plasma, leading to life-threatening conditions. This study investigates the efficacy of Compound 2, a piperidinyl pyrazolopyridine allosteric activator that binds the membrane-binding domain of LCAT, in rescuing the activity of LCAT variants associated with disease. The variants K218N, N228K, and G230R, all located in the cap and lid domains of LCAT, demonstrated notable activity restoration in response to Compound 2. Molecular dynamics simulations and structural modeling indicate that these mutations disrupt the lid and membrane binding domain, with Compound 2 potentially dampening these structural alterations. Conversely, variants such as M252K and F382V in the cap and α/β-hydrolase domain, respectively, exhibited limited or no rescue by Compound 2. Future research should prioritize in vivo investigations that would validate the therapeutic potential of Compound 2 and related activators in familial LCAT deficiency patients with mutations in the cap and lid of the enzyme. SIGNIFICANCE STATEMENT: Lecithin:cholesterol acyltranferase (LCAT) catalyzes the first step of reverse cholesterol transport, namely the esterification of cholesterol in high density lipoprotein particles. Somatic mutations in LCAT lead to excess cholesterol in blood plasma and, in severe cases, kidney failure. In this study, we show that recently discovered small molecule activators can rescue function in LCAT-deficient variants when the mutations occur in the lid and cap domains of the enzyme.

Lecithin-cholesterol acyltransferase is a potential tumor suppressor and predictive marker for hepatocellular carcinoma metastasis

BACKGROUND Hepatocellular carcinoma (HCC) is a major cause of cancer mortality worldwide, and metastasis is the main cause of early recurrence and poor prognosis. However, the mechanism of metastasis remains poorly understood. AIM To determine the possible mechanism affecting HCC metastasis and provide a possible theoretical basis for HCC treatment. METHODS The candidate molecule lecithin-cholesterol acyltransferase (LCAT) was screened by gene microarray and bioinformatics analysis. The expression levels of LCAT in clinical cohort samples was detected by quantitative real-time polymerase chain reaction and western blotting. The proliferation, migration, invasion and tumor-forming ability were measured by Cell Counting Kit-8, Transwell cell migration, invasion, and clonal formation assays, respectively. Tumor formation was detected in nude mice after LCAT gene knockdown or overexpression. The immunohistochemistry for Ki67, E-cadherin, N-cadherin, matrix metalloproteinase 9 and vascular endothelial growth factor were performed in liver tissues to assess the effect of LCAT on HCC. Gene set enrichment analysis (GSEA) on various gene signatures were analyzed with GSEA version 3.0. Three machine-learning algorithms (random forest, support vector machine, and logistic regression) were applied to predict HCC metastasis in The Cancer Genome Atlas and GEO databases. RESULTS LCAT was identified as a novel gene relating to HCC metastasis by using gene microarray in HCC tissues. LCAT was significantly downregulated in HCC tissues, which is correlated with recurrence, metastasis and poor outcome of HCC patients. Functional analysis indicated that LCAT inhibited HCC cell proliferation, migration and invasion both in vitro and in vivo . Clinicopathological data showed that LCAT was negatively associated with HCC size and metastasis (HCC size ≤ 3 cm vs 3-9 cm, P &lt; 0.001; 3-9 cm vs &gt; 9 cm, P &lt; 0.01; metastatic-free HCC vs extrahepatic metastatic HCC, P &lt; 0.05). LCAT suppressed the growth, migration and invasion of HCC cell lines via PI3K/AKT/mTOR signaling. Our results indicated that the logistic regression model based on LCAT, TNM stage and the serum level of α-fetoprotein in HCC patients could effectively predict high metastatic risk HCC patients. CONCLUSION LCAT is downregulated at translational and protein levels in HCC and might inhibit tumor metastasis via attenuating PI3K/AKT/mTOR signaling. LCAT is a prognostic marker and potential therapeutic target for HCC.

Proteomic Profiling of HDL in Newly Diagnosed Breast Cancer Based on Tumor Molecular Classification and Clinical Stage of Disease.

The association between high-density lipoprotein (HDL) cholesterol and breast cancer (BC) remains controversial due to the high complexity of the HDL particle and its functionality. The HDL proteome was determined in newly diagnosed BC classified according to the molecular type [luminal A or B (LA or LB), HER2, and triple-negative (TN)] and clinical stage of the disease. Women (n = 141) aged between 18 and 80 years with BC, treatment-naïve, and healthy women [n = 103; control group (CT)], matched by age and body mass index, were included. Data-independent acquisition (DIA) proteomics was performed in isolated HDL (D = 1.063-1.21 g/mL). Results: Paraoxonase1, carnosine dipeptidase1, immunoglobulin mMu heavy chain constant region (IGHM), apoA-4, and transthyretin were reduced, and serum amyloid A2 and tetranectin were higher in BC compared to CT. In TNBC, apoA-1, apoA-2, apoC-2, and apoC-4 were reduced compared to LA, LB, and HER2, and apoA-4 compared to LA and HER2. ComplementC3, lambda immunoglobulin2/3, serpin3, IGHM, complement9, alpha2 lysine rich-glycoprotein1, and complement4B were higher in TNBC in comparison to all other types; complement factor B and vitamin D-binding protein were in contrast to LA and HER2, and plasminogen compared to LA and LB. In grouped stages III + IV, tetranectin and alpha2-macroglobulin were reduced, and haptoglobin-related protein; lecithin cholesterol acyltransferase, serum amyloid A1, and IGHM were increased compared to stages I + II. Conclusions: A differential proteomic profile of HDL in BC based on tumor molecular classification and the clinical stage of the disease may contribute to a better understanding of the association of HDL with BC pathophysiology, treatment, and outcomes.

Longitudinal proteomics of leptin treatment in humans with acute and chronic energy deficiency-induced hypoleptinemia reveal novel, mainly immune-related, pleiotropic effects

BackgroundLeptin is known for its metabolic, immunomodulatory and neuroendocrine properties, but the full spectrum of molecules downstream of leptin and relevant underlying mechanisms remain to be fully clarified. Our objective was to identify proteins and pathways influenced by leptin through untargeted proteomics in two clinical trials involving leptin administration in lean individuals. MethodsWe performed untargeted liquid chromatography-tandem mass spectrometry serum proteomics across two studies a) Short-term randomized controlled crossover study of lean male and female humans undergoing a 72-h fast with concurrent administration of either placebo or high-dose leptin; b) Long-term (36-week) randomized controlled trial of leptin replacement therapy in human females with acquired relative energy deficiency and hypoleptinemia. We explored longitudinal proteomic changes and run adjusted mixed models followed by post-hoc tests. We further attempted to identify ontological pathways modulated during each experimental condition and/or comparison, through integrated qualitative pathway and enrichment analyses. We also explored dynamic longitudinal relationships between the circulating proteome with clinical and hormonal outcomes. Results289 and 357 unique proteins were identified per each respective study. Short-term leptin administration during fasting markedly upregulated several proinflammatory molecules, notably C-reactive protein (CRP) and cluster of differentiation (CD) 14, and downregulated lecithin cholesterol acyltransferase and several immunoglobulin variable chains, in contrast with placebo, which produced minimal changes. Quantitative pathway enrichment further indicated an upregulation of the acute phase response and downregulation of immunoglobulin- and B cell-mediated immunity by leptin. These changes were independent of participants' biological sex. In the long term study, leptin likewise robustly and persistently upregulated proteins of the acute phase response, and downregulated immunoglobulin-mediated immunity. Leptin also significantly and differentially affected a wide array of proteins related to immune function, defense response, coagulation, and inflammation compared with placebo. These changes were more notable at the 24-week visit, coinciding with the highest measured levels of serum leptin. We further identified distinct co-regulated clusters of proteins and clinical features during leptin administration indicating robust longitudinal correlations between the regulation of immunoglobulins, immune-related molecules, serpins (including cortisol and thyroxine-binding globulins), lipid transport molecules and growth factors, in contrast with placebo, which did not produce similar associations. ConclusionsThese high-throughput longitudinal results provide unique functional insights into leptin physiology, and pave the way for affinity-based proteomic analyses measuring several thousands of molecules, that will confirm these data and may fully delineate underlying mechanisms.

The role of pharmacological interventions in managing hyperlipidemia: A closer look at different drugs

Hyperlipidemia is a medical condition characterized by an increase in plasma lipids, including triglycerides, cholesterol, cholesterol esters, phospholipids, and plasma lipoproteins, which is a leading risk factor for cardiovascular diseases. The pathophysiology of hyperlipidemia is influenced by endothelial damage to blood vessels, leading to a loss of nitric oxide, increased inflammation, and lipid accumulation in the deepest layer of the endothelial wall. Lipid-lowering drugs like statins can reduce LDL levels by 25-60%, but they have negative impacts on clinical outcomes. Lipoprotein metabolism involves various enzymes, and atherosclerosis accumulates fat, cholesterol, and calcium in artery linings, creating fibrous plaques that reduce blood flow and oxygen supply, leading to heart damage and death. Lipoprotein metabolism involves various enzymes, including lipoprotein lipase (LPL), hepatic lipase (HL), lecithin cholesterol acyl transferase (LCAT), cholesterol ester transfer protein (CETP), microsomal triglyceride protein (MTP), and acyl Co-A transferase (ACAT). Atherosclerosis accumulates fat, cholesterol, and calcium in artery linings, creating fibrous plaques. This leads to reduced blood flow and oxygen supply, causing heart damage and death. Reducing LDL and total cholesterol can significantly lower the incidence of strokes. Reducing LDL and total cholesterol can significantly lower the incidence of strokes. Traditional antihyperlipidemic medicines have negative effects, and herbal treatments like onion, garlic, guggul, and Asparagus racemosus have been shown to have anti-diabetic and antihyperlipidemic properties.

Lecithin-cholesterol acyltransferase and paraoxonase-1 levels in atherosclerotic cardiovascular disease patients in Nigeria.

Recent evidence has linked changes in plasma lecithin-cholesterol acyltransferase (LCAT) and paraoxonase-1 (PON-1) levels with increased risk for development of premature atherosclerotic cardiovascular disease (ASCVD) in different populations. However, studies on this in Nigeria and sub-Saharan Africa are scarce. This study assessed the association between reduced plasma LCAT and PON-1 levels and an increased risk of ASCVD, and their potential as biomarkers for ASCVD. Atherosclerotic cardiovascular disease patients and healthy controls were randomly selected for this cross-sectional case-control study from the Lagos State University Teaching Hospital, Ikeja, Lagos, Nigeria, between March 2022 and March 2023. Plasma LCAT and PON-1 were determined by sandwich enzyme-linked immunosorbent assay, while the lipid profile was measured by spectrophotometry. A total of 153 ASCVD patients (mean age: 52.92 ± 10.24 years) and 50 healthy controls (mean age: 46.96 ± 11.05 years) were included in the analyses. Stastistically significant increases were observed in the mean body weight, hip circumference, waist circumference, waist-to-hip ratio, body mass index, diastolic and systolic blood pressure (all p ≤ 0.001), and pulse rate (p = 0.003) compared to the control values. Statistically significant increases were also observed in the mean plasma total cholesterol, triglycerides, low-density lipoprotein cholesterol, and non-high-density lipoprotein cholesterol (all p ≤ 0.001). In contrast, the mean plasma high-density lipoprotein cholesterol, LCAT, and PON-1 (p ≤ 0.001) were notably reduced compared to the control values. The present study provides supportive evidence that changes in plasma LCAT and PON-1 could predispose individuals to risk of premature ASCVD. Plasma LCAT and PON-1 may serve as independent markers or complement other established cardiovascular disease markers to discriminate the risk of ASCVD when it is unclear.

ALKBH5 regulates chicken adipogenesis by mediating LCAT mRNA stability depending on m6A modification

BackgroundPrevious studies have demonstrated the role of N6-methyladenosine (m6A) RNA methylation in various biological processes, our research is the first to elucidate its specific impact on LCAT mRNA stability and adipogenesis in poultry.ResultsThe 6 100-day-old female chickens were categorized into high (n = 3) and low-fat chickens (n = 3) based on their abdominal fat ratios, and their abdominal fat tissues were processed for MeRIP-seq and RNA-seq. An integrated analysis of MeRIP-seq and RNA-seq omics data revealed 16 differentially expressed genes associated with to differential m6A modifications. Among them, ELOVL fatty acid elongase 2 (ELOVL2), pyruvate dehydrogenase kinase 4 (PDK4), fatty acid binding protein 9 (PMP2), fatty acid binding protein 1 (FABP1), lysosomal associated membrane protein 3 (LAMP3), lecithin-cholesterol acyltransferase (LCAT) and solute carrier family 2 member 1 (SLC2A1) have ever been reported to be associated with adipogenesis. Interestingly, LCAT was down-regulated and expressed along with decreased levels of mRNA methylation methylation in the low-fat group. Mechanistically, the highly expressed ALKBH5 gene regulates LCAT RNA demethylation and affects LCAT mRNA stability. In addition, LCAT inhibits preadipocyte proliferation and promotes preadipocyte differentiation, and plays a key role in adipogenesis.ConclusionsIn conclusion, ALKBH5 mediates RNA stability of LCAT through demethylation and affects chicken adipogenesis. This study provides a theoretical basis for further understanding of RNA methylation regulation in chicken adipogenesis.

Differentiation between descending thoracic aortic diseases using machine learning and plasma proteomic signatures

BackgroundDescending thoracic aortic aneurysms and dissections can go undetected until severe and catastrophic, and few clinical indices exist to screen for aneurysms or predict risk of dissection.MethodsThis study generated a plasma proteomic dataset from 75 patients with descending type B dissection (Type B) and 62 patients with descending thoracic aortic aneurysm (DTAA). Standard statistical approaches were compared to supervised machine learning (ML) algorithms to distinguish Type B from DTAA cases. Quantitatively similar proteins were clustered based on linkage distance from hierarchical clustering and ML models were trained with uncorrelated protein lists across various linkage distances with hyperparameter optimization using fivefold cross validation. Permutation importance (PI) was used for ranking the most important predictor proteins of ML classification between disease states and the proteins among the top 10 PI protein groups were submitted for pathway analysis.ResultsOf the 1,549 peptides and 198 proteins used in this study, no peptides and only one protein, hemopexin (HPX), were significantly different at an adjusted p < 0.01 between Type B and DTAA cases. The highest performing model on the training set (Support Vector Classifier) and its corresponding linkage distance (0.5) were used for evaluation of the test set, yielding a precision-recall area under the curve of 0.7 to classify between Type B from DTAA cases. The five proteins with the highest PI scores were immunoglobulin heavy variable 6–1 (IGHV6-1), lecithin-cholesterol acyltransferase (LCAT), coagulation factor 12 (F12), HPX, and immunoglobulin heavy variable 4–4 (IGHV4-4). All proteins from the top 10 most important groups generated the following significantly enriched pathways in the plasma of Type B versus DTAA patients: complement activation, humoral immune response, and blood coagulation.ConclusionsWe conclude that ML may be useful in differentiating the plasma proteome of highly similar disease states that would otherwise not be distinguishable using statistics, and, in such cases, ML may enable prioritizing important proteins for model prediction.

Systematic evaluation of lecithin:cholesterol acyltransferase binding sites in apolipoproteins via peptide based nanodiscs: regulatory role of charged residues at positions 4 and 7.

Lecithin:cholesterol acyltransferase (LCAT) exhibits α-activity on high-density and β-activity on low-density lipoproteins. However, the molecular determinants governing LCAT activation by different apolipoproteins remain elusive. Uncovering these determinants would offer the opportunity to design and explore advanced therapies against dyslipidemias. Here, we have conducted coarse-grained and all-atom molecular dynamics simulations of LCAT with nanodiscs made with α-helical amphiphilic peptides either derived from apolipoproteins A1 and E (apoA1 and apoE) or apoA1 mimetic peptide 22A that was optimized to activate LCAT. This study aims to explore what drives the binding of peptides to our previously identified interaction site in LCAT. We hypothesized that this approach could be used to screen for binding sites of LCAT in different apolipoproteins and would provide insights to differently localized LCAT activities. Our screening approach was able to discriminate apoA1 helixes 4, 6, and 7 as key contributors to the interaction with LCAT supporting the previous research data. The simulations provided detailed molecular determinants driving the interaction with LCAT: the formation of hydrogen bonds or salt bridges between peptides E4 or D4 and LCAT S236 or K238 residues. Additionally, salt bridging between R7 and D73 was observed, depending on the availability of R7. Expanding our investigation to diverse plasma proteins, we detected novel LCAT binding helixes in apoL1, apoB100, and serum amyloid A. Our findings suggest that the same binding determinants, involving E4 or D4 -S236 and R7-D73 interactions, influence LCAT β-activity on low-density lipoproteins, where apoE and or apoB100 are hypothesized to interact with LCAT.

Lutein and Zeaxanthin Enhance, Whereas Oxidation, Fructosylation, and Low pH Damage High-Density Lipoprotein Biological Functionality.

High-density lipoproteins (HDLs) are key regulators of cellular cholesterol homeostasis but are functionally altered in many chronic diseases. The factors that cause HDL functional loss in chronic disease are not fully understood. It is also unknown what roles antioxidant carotenoids play in protecting HDL against functional loss. The aim of this study was to measure how various disease-associated chemical factors including exposure to (1) Cu2+ ions, (2) hypochlorous acid (HOCL), (3) hydrogen peroxide (H2O2), (4) sialidase, (5) glycosidase, (6) high glucose, (7) high fructose, and (8) acidic pH, and the carotenoid antioxidants (9) lutein and (10) zeaxanthin affect HDL functionality. We hypothesized that some of the modifications would have stronger impacts on HDL particle structure and function than others and that lutein and zeaxanthin would improve HDL function. HDL samples were isolated from generally healthy human plasma and incubated with the corresponding treatments listed above. Cholesterol efflux capacity (CEC), lecithin-cholesterol acyl transferase (LCAT) activity, and paraoxonase-1 (PON1) activity were measured in order to determine changes in HDL functionality. Median HDL particle diameter was increased by acidic pH treatment and reduced by HOCl, high glucose, high fructose, N-glycosidase, and lutein treatments. Acidic pH, oxidation, and fructosylation all reduced HDL CEC, whereas lutein, zeaxanthin, and sialidase treatment improved HDL CEC. LCAT activity was reduced by acidic pH, oxidation, high fructose treatments, and lutein. PON1 activity was reduced by sialidase, glycosidase, H2O2, and fructose and improved by zeaxanthin and lutein treatment. These results show that exposure to oxidizing agents, high fructose, and low pH directly impairs HDL functionality related to cholesterol efflux and particle maturation, whereas deglycosylation impairs HDL antioxidant capacity. On the other hand, the antioxidants lutein and zeaxanthin improve or preserve both HDL cholesterol efflux and antioxidant activity but have no effect on particle maturation.

Estrogen Induces LCAT to Maintain Cholesterol Homeostasis and Suppress Hepatocellular Carcinoma Development.

Hepatocellular carcinoma (HCC) is an aggressive disease that occurs predominantly in men. Estrogen elicits protective effects against HCC development. Elucidation of the estrogen-regulated biological processes that suppress HCC could lead to improved prevention and treatment strategies. Here, we performed transcriptomic analyses on mouse and human liver cancer and identified lecithin cholesterol acyltransferase (LCAT) as the most highly estrogen-upregulated gene and a biomarker of favorable prognosis. LCAT upregulation inhibited HCC in vitro and in vivo and mediated estrogen-induced suppression of HCC in an ESR1-dependent manner. LCAT facilitated high-density lipoprotein cholesterol production and uptake via the LDLR and SCARB1 pathways. Consistently, high HDL-C levels corresponded to a favorable prognosis in HCC patients. The enhanced HDL-C absorption induced by LCAT impaired SREBP2 maturation, which ultimately suppressed cholesterol biosynthesis and dampened HCC cell proliferation. HDL-C alone inhibited HCC growth comparably to the cholesterol-lowering drug lovastatin, and SREBF2 overexpression abolished the inhibitory activity of LCAT. Clinical observations and cross-analyses of multiple databases confirmed the correlation of elevated LCAT and HDL-C levels to reduced cholesterol synthesis and improved HCC patient prognosis. Furthermore, LCAT deficiency mimicked whereas LCAT overexpression abrogated the tumor growth-promoting effects of ovariectomy in HCC-bearing female mice. Most importantly, HDL-C and LCAT delayed the development of subcutaneous tumors in nude mice, and HDL-C synergized with lenvatinib to eradicate orthotopic liver tumors. Collectively, this study reveals that estrogen upregulates LCAT to maintain cholesterol homeostasis and to dampen hepatocarcinogenesis. LCAT and HDL-C represent potential prognostic and therapeutic biomarkers for targeting cholesterol homeostasis as a strategy for treating HCC. Significance: Estrogen mediates the sex differences in hepatocellular carcinoma development by reducing cholesterol biosynthesis through activation of an LCAT/HDL-C axis, providing strategies for improving liver cancer prevention, prognosis, and treatment.