A 79-year-old Chinese man was referred for nephrotic syndrome (proteinuria 4.4 g/day). In blood tests, serum high-density lipoprotein (HDL) cholesterol was undetectable, and the esterified cholesterol to total cholesterol ratio was very low. Lecithin: cholesterol acyltransferase (LCAT) activity was also undetectable. Since he had neither corneal opacity nor pathological mutations in the LCAT gene and anti-LCAT antibodies were detected in serum, a diagnosis of acquired LCAT deficiency was made. Renal biopsy revealed glomerulopathy associated with LCAT deficiency and membranous nephropathy (MN). Since the patient's proteinuria did not improve despite prescribing an angiotensin II receptor blocker (ARB), we suggested the prescription of prednisolone, but he returned to China due to the expiration of his residence visa for Japan. One year after the initial visit, his proteinuria had improved to 0.9 g/day without immunosuppressive therapy. However, his HDL cholesterol level was still low at around 3 mg/dL, indicating a discrepancy between remission of nephrotic syndrome and lack of improvement in lipid levels.Of the 11 patients with acquired LCAT deficiency reported to date, 4 with undetectable LCAT activity and MN on renal biopsy required immunosuppressive therapy to alleviate proteinuria. The present patient was prescribed only an ARB according to his preference, which happened to be consistent with the MN treatment guideline that states, "Wait 6 months for spontaneous remission while using maximal antiproteinuric therapy." The clinical course of acquired LCAT deficiency varies, and further case reports are needed to determine the necessity of immunosuppressive therapy.

Disruption of HDL antioxidant properties in children and adolescents with obesity.

Lecithin cholesterol acyltransferase (LCAT) plays a pivotal role in acyl-esterifying cholesterol intravascularly, but its function in metabolic dysfunction-associated steatotic liver disease (MASLD) or steatohepatitis (MASH) has remained uncertain both in murine models and humans for decades, which is largely attributable to the distinct differences in cholesterol metabolism between mice and humans. Previously, we created a novel golden Syrian hamster model deficient in LCAT activity. Herein, we explored the influence of LCAT on the development of MASLD and MASH. A cross-sectional clinical study of LCAT activity and free cholesterol (FC) levels in healthy and MASLD patients was performed. LCAT knockout (LCAT KO) hamsters were used to explore the characteristics of cholesterol homeostasis and MASLD and MASH development. Lipidomics, mRNA-seq, and qPCR were employed to investigate the underlying mechanisms involved. MASLD patients displayed reduced LCAT activity, elevated FC levels, and ratio of FC/TC. Serum FC levels were positively correlated with triglyceride (TG), total cholesterol (TC), and apoB100 levels. In hamsters, LCAT deficiency resulted in increased FC levels and decreased high-density lipoprotein levels. Apolipoprotein profiles revealed increased ApoB100/48 and apoE but decreased apoAI. Increases in serum FC levels were primarily observed in LCAT-deficient hamster. Interestingly, LCAT KO hamsters presented mild TG species deposition in the liver even when fed a chow diet indicated by lipidomics. These increased TG species included TG (16:0/18:1/18:2), TG (16:0/18:1/18:3), and TG (16:0/16:1/18:1). On a high-fat and high-cholesterol diet, LCAT-deficient hamsters developed severe liver ballooning, inflammation, and fibrosis. Using HepG2 cells and primary hepatocytes confirmed that FC increased intracellular lipogenesis and promoted inflammatory response, which was reversed by a NLRP3 inhibitor. In summary, LCAT deficiency in hamsters promotes liver lipid deposition and MASH progression, thus highlighting the therapeutic role of LCAT in MASLD and MASH.

Description of Case: A 26-year-old female was referred to cardiology with bilateral corneal opacifications of four years’ duration, with no change in her visual acuity. Her workup revealed a high-density lipoprotein cholesterol (HDL-C) level of less than 10 mg/dL and a low-density lipoprotein cholesterol (LDL-C) level of 182 mg/dL, prompting genetic evaluation for disorders of lipid metabolism. She was found to have a heterozygous mutation, c.440C>T (p.Thr147Ile), and variant of uncertain significance, c.715G>A (p.Gly239Ser) in the lecithin-cholesterol acyltransferase ( LCAT ) gene. Additional studies showed low-normal serum cholesterol esters and no evidence of hematologic abnormalities or renal dysfunction. Based on these findings and her corneal opacifications, a clinical diagnosis of partial LCAT deficiency, or Fish-Eye Disease (FED), was made. Given her lipid abnormalities and the increased risk of atherosclerosis associated with FED, a high-potency statin was prescribed. Her LDL-C decreased from 182 mg/dL to 124 mg/dL. Discussion: FED is an autosomal recessive disorder of lipid metabolism caused by mutations in the LCAT gene, resulting in partial loss of enzymatic activity. LCAT catalyzes the esterification of free cholesterol, a key step in reverse cholesterol transport; esterification is lost in HDL-C (i.e., alpha activity) and conserved in lipoproteins containing apolipoprotein B (i.e., beta activity). Consequently, FED is biochemically characterized by reduced HDL-C and plasma cholesterol esters and elevated LDL-C, very-low-density lipoprotein cholesterol, triglycerides, and/or plasma unesterified cholesterol. Clinically, these patients typically present with worsening corneal opacities and decreased visual acuity and are at increased risk of atherosclerosis due to preserved beta activity. In contrast, patients may have complete loss of LCAT activity and present with more severe sequelae, a disease known as familial LCAT deficiency (FLD). Absent LCAT activity leads to unesterified cholesterol accumulation, which disrupts red blood cell membranes and deposits in the renal mesangium, leading to hemolytic anemia and renal dysfunction. It is therefore important to promptly determine the degree of LCAT activity loss and manage patients accordingly. Measuring LCAT activity, both alpha and beta, is the best diagnostic test. FED should be treated primarily with lipid-lowering medications, whereas FLD requires monitoring for anemia and renal dysfunction.

Major depressive disorder (MDD) is associated with neuro-immune - metabolic - oxidative (NIMETOX) pathways. To examine the connections among NIMETOX pathways in outpatient MDD (OMDD) with and without metabolic syndrome (MetS); and to determine the prevalence of NIMETOX aberrations in a cohort ofOMDD patients. We included 67 healthy controls and 66OMDD patients and we assessed various NIMETOX pathways. We successfully identified a subgroup ofindividuals with aberrations in NIMETOX pathways, including diminished lecithin-cholesterol acyltransferase (LCAT), paraoxonase 1 (PON1) activity, and reverse cholesterol transport (RCT) activities, and elevated atherogenicity, differentially expressed immune networks, and advanced oxidation protein products (AOPP). A large part of the variance (around 44%) in atherogenicity indices was associated with AOPP, fasting blood glucose (FBG), PON1 activity, and immune activation. LCAT activity was positively correlated with PON1 activity and negatively with FBG, AOPP and immune activation. RCT was positively related with the PON1 R/R 192 genotype and negatively with FBG and immune activation. A larger part of the variance in the overall severity of OMDD (50.4%), suicidal behaviors (27.7%), and neuroticism (42.1%) was positively associated with adverse childhood experiences and NIMETOX pathways, including AOPP, immune-related neurotoxicity, FBG, insulin, and atherogenicity, and inversely with immune-related neuroprotection. Many OMDD patients (78.8%) show aberrations in NIMETOX pathways. The features ofOMDD, including severity of illness, neuroticism, and suicidal behaviors, are caused by intertwined NIMETOX pathways that may exert additional effects depending on whether MetS is present or not.

Cardiovascular disease (CVD), particularly atherosclerotic cardiovascular disease (ASCVD), is the leading cause of death worldwide, driven by factors like oxidative stress, inflammation, and lipid metabolism disorders. Although phenolic compounds such as Tyrosol (Tyr) and Hydroxytyrosol (HTyr) found in extra virgin olive oil (EVOO) have shown promising antioxidant and anti-inflammatory effects, their specific roles in modulating oxidative stress biomarkers and high-density lipoprotein (HDL) functionality in elderly populations, especially in those with prior myocardial infarction, are not fully understood. This study aimed to investigate the effects of EVOO phenolic compounds on oxidative stress biomarkers and HDL functionality, and related metabolic outcomes in both healthy and post-myocardial infarction (post-MI) elderly individuals. This pilot randomized clinical trial study included healthy and post-MI participants aged 65-85 years. Participants in each group were randomly assigned to consume 25 mL per day of one of three types of olive oils: high phenolic (HTyr/Tyr) extra virgin olive oil (HP-EVOO), extra virgin olive oil (EVOO), or refined olive oil (ROO) for a period of 26 weeks. Blood samples were collected at baseline and post-intervention to assess key biomarkers. Plasma levels of (poly)phenols, malondialdehyde (MDA), total antioxidant capacity (FRAP), lecithin-cholesterol acyltransferase activity (LCAT), and serum paraoxonase-1 (PON-1) activity were measured. A total of 34 individuals completed the study (mean age: 74 years). Baseline characteristics, including sex, age, body mass index (BMI), weight, blood pressure, and inflammatory markers like C-reactive protein (CRP) levels, did not differ significantly between the two groups. A significant increase in both FRAP levels and PON-1 activity was observed in post-MI participants following HP-EVOO consumption compared to baseline (p = 0.014). No significant changes were observed in MDA levels, LCAT activity, or plasma (poly)phenols. These results indicate that HP-EVOO may enhance antioxidant capacity, particularly FRAP and PON-1 activity, in elderly post-MI individuals. The observed differences between groups suggest that underlying cardiometabolic status may influence the response to olive oil phenolic compounds. Further studies are needed to explore the long-term cardiovascular effects.

Serum levels of advanced glycation end products negatively correlates with activity of Paraoxonase1 and Lecithin-Cholesterol Acyltransferase in diabetic retinopathy; A cross-sectional case-control study.

Lecithin:cholesterol acyltransferase (LCAT) is a high-density lipoprotein (HDL) modifying protein that profoundly affects the composition and function of HDL subspecies. The cholesterol esterification activity of LCAT is dramatically increased by apolipoprotein A-I (APOA1) on HDL, but the mechanism remains unclear. Using site-directed mutagenesis, cross-linking, mass spectrometry, electron microscopy, protein engineering, and molecular docking, we identified two LCAT binding sites formed by helices 4 and 6 from two antiparallel APOA1 molecules in HDL. Although the reciprocating APOA1 “belts” form two ostensibly symmetrical binding locations, LCAT can adopt distinct orientations at each site, as shown by our 9.8 Å cryoEM envelope. In one case, LCAT membrane binding domains align with the APOA1 belts and, in the other, the HDL phospholipids. By introducing disulfide bonds between the APOA1 helical domains, we demonstrated that LCAT does not require helical separation during its reaction cycle. This indicates that LCAT, anchored to APOA1 belts, accesses substrates and deposits products through interactions with the planar lipid surface. This model of the LCAT/APOA1 interaction provides insights into how LCAT and possibly other HDL-modifying factors engage the APOA1 scaffold, offering potential strategies to enhance LCAT activity in individuals with genetic defects.

BackgroundAlthough preβ1-high-density lipoprotein (preβ1-HDL) promotes cholesterol efflux, high fasting preβ1-high-density lipoprotein levels after breakfast are reduced in patients with poorly controlled type 2 diabetes.ObjectiveThis study investigated whether preβ1-high-density lipoprotein binds to triglyceride (TG)-rich lipoproteins (TGRLs) in the postprandial state and is released during lipolysis.MethodsWe measured preβ1-high-density lipoprotein concentrations, lecithin-cholesterol acyltransferase (LCAT) activity, and LCAT-dependent preβ1-high-density lipoprotein conversion before and after breakfast in patients with diabetes. We also performed in vitro studies using TGRLs. Preβ1-high-density lipoprotein was quantified by enzyme-linked immunosorbent assay and native two-dimensional gradient gel (N-2D-gel) electrophoresis.ResultsBefore breakfast, the diabetes group had higher preβ1-high-density lipoprotein concentrations than the healthy controls; after breakfast, levels in the two groups were similar. Neither LCAT mass nor the LCAT-dependent preβ1-high-density lipoprotein conversion rate changed after breakfast. Mixing of fasting plasma with chylomicrons or very-low-density lipoprotein (VLDL) reduced the preβ1-high-density lipoprotein level by 15% ± 4% and 45% ± 10%, respectively. N-2D-gel electrophoresis showed that preβ1-high-density lipoprotein was generated by bacteria-derived TG lipase only from postprandial VLDL of patients with type 2 diabetes.ConclusionPreβ1-high-density lipoprotein binds to TGRLs in the postprandial state and is released during lipolysis, implying that postprandial hyperlipidemia impairs reverse cholesterol transport in patients with poorly controlled type 2 diabetes.

Lecithin cholesterol acyltransferase (LCAT) is a crucial enzyme in high-density lipoprotein (HDL) metabolism that is often dysregulated in cancers, affecting tumor growth and therapy response. We extensively studied LCAT expression in various malignancies, linking it to clinical outcomes and genetic/epigenetic alterations. We analyzed LCAT expression in multiple cancers and used the Cox regression model to correlate it with patient survival metrics, including overall survival (OS), disease-specific survival (DSS), and progression-free interval (PFI). We also examined the copy number variations (CNVs), single-nucleotide variations (SNVs), DNA methylation, and N6-methyladenosine (m6A) modifications of LCAT and their connections to tumor immune responses and drug sensitivity. LCAT expression varies among cancers and correlates with patient outcomes. Low expression is linked to poor prognosis in low-grade glioma (LGG) and liver hepatocellular carcinoma (LIHC), while high expression is associated with better outcomes in adrenocortical carcinoma (ACC) and colon adenocarcinoma (COAD). In kidney renal papillary cell carcinoma (KIRP) and uterine corpus endometrial carcinoma (UCEC), LCAT CNV and methylation levels are prognostic markers. LCAT interacts with m6A modifiers and immune molecules, suggesting a role in immune evasion and as a biomarker for immunotherapy response. LCAT expression correlates with chemotherapeutic drug IC50 values, indicating potential for predicting treatment response. In ACC and COAD, LCAT may promote tumor growth, while in LGG and LIHC, it may inhibit progression. LCAT expression and activity regulation could be a new cancer therapy target. As a key molecule linking lipid metabolism, immune modulation, and tumor progression, the potential of LCAT in cancer therapy is significant. Our findings provide new insights into the role of LCAT in cancer biology and support the development of personalized treatment strategies.

A low-dose prebiotic fiber supplement reduces lipopolysaccharide-binding protein concentrations in a subgroup of young, healthy adults consuming low-fiber diets.

Ketosis is one of the most important metabolic disorders occurring in dairy cows after calving, which is caused by a negative energy balance during the peripartum period or around parturition. The current study focused on the diagnostic significance of the clinical scoring system, with serum lipid profiles, mainly lecithin cholesterol acyltransferase (LCAT) and apolipoprotein B-100 (ApoB-100), as recovery indicators in ketotic dairy cattle using the hormonal-steroids-carbohydrate therapeutic protocol. The study also discussed the correlation coefficient between serum apo-B100 and serum non-esterified fatty acids (NEFAs) in pretreated and post-treated ketotic cattle. In this study, 50 ketotic cattle from various dairy farms. The ketotic cows were subjected to a hormonal-steroids-carbohydrate therapeutic regimen extended for a continuous 5 days, including mainly insulin, dexamethasone, and carbohydrate replacement therapy (Glucose solution 50% alternative with dextrose solution 50%) with drenching of propylene glycol. and vitamin B12 injection. Insulin was administered simultaneously with both of glucose and glucocorticoid (Dexamethasone) and alternatively with a 50% dextrose solution. All animals were undergoing thorough clinical and biochemical investigations including mainly clinical scoring system, serum lipid profiles, and serum enzyme activities (Aspartate aminotransferase; AST) in days 0, 7, 14, 21, and 30. The ketotic dairy cattle needed a maximum 30-day follow-up period post-therapy to restore their physiological status for clinical scoring data (7 days needed) and most serum lipid indices [14 days needed, i.e., apoB-100, β-hydroxy butyric acid, NEFA, glucose, cholesterol, and AST]. A 30-day post-therapy as a follow-up period was urgently required to restore their reference values of serum LCAT. The results of this study indicated that serum LCAT activity and ApoB-100 were the most sensitive indicators of the efficacy of therapy and the restoration of the physiological status. The study revealed a significant negative correlation between serum NEFA and apoB-100 in ketotic cattle. The results of this study indicated that serum LCAT activity and ApoB-100 were the most sensitive indicators of the efficacy of therapy and the restoration of the physiological status. This could be seen by an obvious improvement in serum lipid profiles, mainly LCAT and apoB-100, and clinical findings as well as clinical coring data. The study identified a significant negative correlation between NEFA and apoB-100 in ketotic cattle. Exposure of diseased ketotic dairy cattle to this specific therapeutic strategy had a great impact on their recovery from ketosis and improved their health and productivity status. The current study concluded the diagnostic significance of the clinical scoring system (Appetite score, rumen filling score, manure digestion score, and manure condition score), and serum lipid profiles, mainly LCAT and apoB-100, as recovery indicators in ketotic dairy cattle using hormonal-steroids-carbohydrates therapeutic protocol.

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.

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.

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&lt;0.001). Conclusion: CSL112 altered HDL composition and increased HDL functionality by promoting multiple steps of the reverse cholesterol transport pathway.

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.

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

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.

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.