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Background The functionality of high-density lipoproteins (HDL) is a better cardiovascular risk predictor than HDL concentrations. One of the key elements of HDL functionality is its apolipoprotein composition. Lecithin-cholesterol acyl transferase (LCAT) and cholesterol-ester transfer protein (CETP) are enzymes involved in HDL-mediated reverse cholesterol transport. This study assessed the concentration and activity of LCAT and CETP in HDL subspecies defined by their content of apolipoproteins E (apoE) and C-III (apoC-III) in humans. Methods Eighteen adults (ten women and eight men, mean age 55.6, BMI 26.9 Kg/m 2 , HbA1c 5.4%) were studied. HDL from each participant were isolated and divided into four subspecies containing respectively: No apoE and no apoC-III (E-C-), apoE but not apoC-III (E + C-), apoC-III but no apoE (E-C+) and both apoE and apoC-III (E + C+). The concentration and enzymatic activity of LCAT and CETP were measured within each HDL subspecies using immunoenzymatic and fluorometric methods. Additionally, the size distribution of HDL in each apolipoprotein-defined fraction was determined using non-denaturing electrophoresis and anti-apoA-I western blotting. Results HDL without apoE or apoC-III was the predominant HDL subtype. The size distribution of HDL was very similar in all the four apolipoprotein-defined subtypes. LCAT was most abundant in E-C- HDL (3.58 mg/mL, 59.6% of plasma LCAT mass), while HDL with apoE or apoC-III had much less LCAT (19.8, 12.2 and 8.37% of plasma LCAT respectively for E + C-, E-C+ and E + C+). LCAT mass was lower in E + C- HDL relative to E-C- HDL, but LCAT activity was similar in both fractions, signaling a greater activity-to-mass ratio associated with the presence of apoE. Both CETP mass and CETP activity showed only slight variations across HDL subspecies. There was an inverse correlation between plasma LCAT activity and concentrations of both E-C+ pre-beta HDL ( r  = − 0.55, P  = 0.017) and E-C- alpha 1 HDL ( r  = − 0.49, P  = 0.041). Conversely, there was a direct correlation between plasma CETP activity and concentrations of E-C+ alpha 1 HDL ( r  = 0.52, P  = 0.025). Conclusions The presence of apoE in small HDL is correlated with increased LCAT activity and esterification of plasma cholesterol. These results favor an interpretation that LCAT and apoE interact to enhance anti-atherogenic pathways of HDL.

The aim of this work was to determine lipoprotein metabolism alterations in macrosomic newborns and to see whether these lipoprotein abnormalities are parallel or not to those found in their obese or nonobese mothers. Serum lipids, apo A-I, apo B100, lipoproteins (VLDL, LDL, HDL2, and HDL3), and LCAT activity were investigated in obese and nonobese mothers and cord blood of their macrosomic or appropriate-for-gestational-age (AGA) newborns. Serum and VLDL triglyceride concentrations were higher in obese mothers of AGA newborns than in nonobese mothers. Serum triglyceride, VLDL, and apo B100 levels were higher, while serum apo A-I and HDL2 cholesterol concentrations were lower in obese mothers of macrosomic newborns than in the other groups. In their macrosomic newborns, serum lipid, lipoprotein, apo B100, and apo A-I levels were higher as compared with those of other newborns. Macrosomic newborns of nonobese mothers had lipoprotein profiles similar to those in AGA newborns. LCAT activity was similar in both mother groups and in both newborn groups. In conclusion, maternal obesity and fetal macrosomia were associated with lipoprotein abnormalities consistent with high atherogenic risk.

The effects of liver transplantation involving livingrelated donors were investigated in 20 pediatric cases in terms of protein and lipid metabolism using the extent of cholesterol esterification and the levels of total cholesterol, lecithine-cholesterol acyltransferase, apolipoprotein A-I, cholinesterase, and rapid turnover proteins as parameters. Cholesterol esterification increased from preoperative values of 39%±4% to 67%±1% (mean±SEM, n=17) at 3 weeks after liver transplantation in successful cases but decreased from the preoperative value of 45%±10% to 26%±6% (n=3) at 3 weeks in unsuccessful cases. Cholinesterase, transferrin, and prealbumin levels remained low after 3 weeks even in successful cases. Patients who had partial liver transplantations from living-related donors showed rapid recovery of cholesterol esterification. However, patients with graft livers required an extensive period before normalization of protein metabolism occurred, indicating the necessity for long-term follow-up of recipient development.

Background An early detection tool for EOC was constructed from analysis of biomarker expression data from serum collected during the UKCTOCS. Methods This study included 49 EOC cases (19 Type I and 30 Type II) and 31 controls, representing 482 serial samples spanning seven years pre-diagnosis. A logit model was trained by analysis of dysregulation of expression data of four putative biomarkers, (CA125, phosphatidylcholine-sterol acyltransferase, vitamin K-dependent protein Z and C-reactive protein); by scoring the specificity associated with dysregulation from the baseline expression for each individual. Results The model is discriminatory, passes k -fold and leave-one-out cross-validations and was further validated in a Type I EOC set. Samples were analysed as a simulated annual screening programme, the algorithm diagnosed cases with >30% PPV 1–2 years pre-diagnosis. For Type II cases (~80% were HGS) the algorithm classified 64% at 1 year and 28% at 2 years tDx as severe. Conclusions The panel has the potential to diagnose EOC one-two years earlier than current diagnosis. This analysis provides a tangible worked example demonstrating the potential for development as a screening tool and scrutiny of its properties. Limits on interpretation imposed by the number of samples available are discussed.

Background Cardiovascular 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. Methods Before 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. Results Following 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. Conclusions A 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 registration The study was registered at the German Clinical Trial Register (DRKS) on 3 September 2019 under the number DRKS00018070. Graphical Abstract

This study aimed to assess the prevalence of genetic variants responsible for extreme levels of high-density lipoprotein cholesterol (HDL-C) and evaluate the adequacy of current thresholds for genetic testing of HDL-related dyslipidemia. Using data from the Tromsø Study, a population-based cohort in Northern Norway, we identified 210 individuals with HDL-C levels ≤ 0.5 mmol/L or ≥ 3.0 mmol/L. Six HDL-related genes (ABCA1, APOA1, CETP, LCAT, PLTP, SCARB1) were sequenced in these participants. We classified variants according to ACMG guidelines, incorporating functional assays and UK Biobank data for additional phenotype-genotype associations. We identified 38 variants of interest across six HDL-related genes, of which 10 were considered potentially causative, found in 14 individuals. Genetic causes were detected in 33.3% of individuals with low HDL-C and 5.05% of those with high HDL-C. Sex-specific analyses showed that using HDL-C thresholds aligned with population distributions improved detection of individuals with pathogenic variants, particularly among women with high HDL-C and men with low HDL-C. These findings suggest that current uniform thresholds may overlook clinically relevant cases and that incorporating sex-specific HDL-C distributions could enhance the identification of individuals with suspected genetic HDL disorders. Genetic testing for HDL-related dyslipidemia is underutilized, with many individuals not meeting the current extreme HDL-C threshold criteria. Revised sex-specific thresholds for genetic testing will improve the identification of pathogenic variants and provide more accurate diagnoses of HDL-related disorders. Continued research is essential to refine our understanding of HDL genetics and its clinical implications.

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.

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.

Background This study aimed to identify molecular markers that influence liver metastasis in colorectal cancer (CRC) and assess their clinical relevance. Methods Proteomic analysis compared differential protein expression between CRC patients with liver metastasis (CRLM) and those without (CRNLM). Bioinformatics and survival analyses identified key proteins and validated them using the TCGA database for expression and clinical significance. Clinical and pathological data, along with tissue samples from our center, were used to create tissue microarrays for immunohistochemistry. Logistic regression assessed odds ratios (OR) for molecular markers linked to liver metastasis post-CRC surgery. Stable LCAT knockdown and overexpression CRC cell lines were constructed, and Transwell assays assessed the impact LCAT on cell migration. Nile red staining of these cells validated the effect LCAT on lipid metabolism in CRC cells. Results Proteomic analysis identified 383 differentially expressed proteins between the CRLM and CRNLM groups (212 upregulated, 171 downregulated). Enrichment analysis linked these proteins to steroid and alcohol metabolism, inflammation, lipoproteins, and HDL particles, with key pathways in cholesterol and retinol metabolism. Lecithin cholesterol acyltransferase (LCAT), an important enzyme in this process, showed higher expression in CRC tissues, with increased LCAT linked to poorer 5-year OS, DSS, and PFI. LCAT expression also increased with tumor stage. Among 119 patients with CRC, preoperative complications, tumor staging, and LCAT scores differed significantly between patients with and without liver metastasis within 3 years post-surgery. LCAT and postoperative CEA levels were independent risk factors for liver metastasis (LCAT OR, 10.221; P  = 0.002; CEA OR, 1.296; P  = 0.014). Western blotting confirmed significantly higher LCAT expression in CRC tissues with liver metastasis. Transwell assays showed that LCAT overexpression enhanced migratory ability, while knockdown inhibited it. Nile red staining revealed increased lipid droplet accumulation in LCAT-overexpressing CRC cells, which was reduced by LCAT knockdown. Conclusion LCAT, which is involved in lipid metabolism, is an independent risk factor for liver metastasis following CRC surgery, suggesting its potential as a therapeutic target.

Background High density lipoproteins (HDL) have many cardioprotective roles; however, in subjects with type 2 diabetes (T2D) these cardioprotective properties are diminished. Conversely, increased fruit and vegetable (F&V) intake may reduce cardiovascular disease risk, although direct trial evidence of a mechanism by which this occurs in subjects with T2D is lacking. Therefore, the aim of this study was to examine if increased F&V consumption influenced the carotenoid content and enzymes associated with the antioxidant properties of HDL in subjects with T2D. Methods Eighty obese subjects with T2D were randomised to a 1- or ≥6-portion/day F&V diet for 8-weeks. Fasting serum was collected pre- and post-intervention. HDL was subfractionated into HDL 2 and HDL 3 by rapid ultracentrifugation. Carotenoids were measured in serum, HDL 2 and HDL 3 by high performance liquid chromatography. The activity of paraoxonase-1 (PON-1) was measured in serum, HDL 2 and HDL 3 by a spectrophotometric assay, while the activity of lecithin cholesterol acyltransferase (LCAT) was measured in serum, HDL 2 and HDL 3 by a fluorometric assay. Results In the ≥6- vs. 1-portion post-intervention comparisons, carotenoids increased in serum, HDL 2 and particularly HDL 3 , (α-carotene, p = 0.008; β-cryptoxanthin, p = 0.042; lutein, p = 0.012; lycopene, p = 0.016), as did the activities of PON-1 and LCAT in HDL 3 (p = 0.006 and 0.044, respectively). Conclusion To our knowledge, this is the first study in subjects with T2D to demonstrate that increased F&V intake augmented the carotenoid content and influenced enzymes associated with the antioxidant properties of HDL. We suggest that these changes would enhance the cardioprotective properties of this lipoprotein. Clinical trial registration ISRCTN21676269