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Simple Summary: Retained placenta (RP) is one of the most periparturient diseases of dairy cows, in which the placenta is not expelled from the body within 24 h of calving. This condition increases the risk of other periparturient diseases and decreased milk production and reproductive efficiency. In order to reliably predict PR, this study focused on the activity of lecithin:cholesterol acyltransferase (LCAT) and compared its usefulness in the prepartum prediction of PR with the concentration of non-esterified fatty acids (NEFA). LCAT is an enzyme synthesized in the liver that converts free cholesterol to cholesteryl esters, which is known to be acutely related to and reduced by periparturient diseases. NEFA is a fatty acid that increases in the blood when animals are in negative energy balance and has been reported as a useful prepartum predictor of some perinatal diseases. This study was carried out at a single farm with approximately 200 Holstein parous cows from February 2010 to February 2016. Twenty-seven parous cows between 2 and 21 days (close-up stage) before their expected calving dates that developed RP (RP group) were assessed. They were compared with 60 clinically healthy cows (controls) that did not develop RP and were matched with the RP group for sampling period and parity. The results of this study were as follows: LCAT showed adequate discriminative ability of PR occurrence comparable to that of NEFA. However, LCAT or NEFA plus RFS showed higher discrimination ability than both alone. These results indicate that LCAT has a useful ability to predict the occurrence of RP. 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. [ABSTRACT FROM AUTHOR]

Introduction: Lecithin cholesterol acyltransferase (LCAT) plays a crucial role in acyl-esterifying cholesterol in plasma, which is essential for reverse cholesterol transport (RCT). Previous studies indicated that its activity on both α and β lipoproteins interpret its effects on lipoproteins for many controversial investigations of atherosclerosis. Objectives: To better understand the relationship between LCAT, diet-induced dyslipidemia and atherosclerosis, we developed a double knockout (LCAT−/−&LDLR−/−, DKO) hamster model to evaluate the specific role of LCAT independent of LDL clearance effects. Methods: Plasma triglyceride (TG), total cholesterol (TC), high-density lipoprotein-cholesterol (HDL-C), and free cholesterol (FC) levels were measured using biochemical reagent kits. FPLC was performed to analyze the components of lipoproteins. Apolipoprotein content was assessed using western blotting (WB). The hamsters were fed a high cholesterol/high fat diet (HCHFD) to induce atherosclerosis. Oil Red O staining was employed to detect plaque formation. Peritoneal macrophages were studied to investigate the effects of LCAT on cholesterol uptake and efflux. Results: On HCHFD, DKO hamsters exhibited significantly elevated levels of TG and FC, while HDL-C was nearly undetectable without affecting TC levels, as compared to low-density lipoprotein receptor (LDLR)-deficient (LDLR−/−, LKO) hamsters. Lipoprotein profiling revealed a marked increase in plasma chylomicron/very low-density lipoprotein (CM/VLDL) fractions, along with an unexpected reduction in LDL fraction in DKO hamsters. Furthermore, DKO hamsters displayed aggravated atherosclerotic lesions in the aorta, aortic root, and coronary artery relative to LKO hamsters, attributed to a pro-atherogenic lipoprotein profile and impaired cholesterol efflux in macrophages. Conclusions: Our study demonstrates the beneficial role of LCAT in inhibiting atherosclerotic development and highlights the distinctive lipid metabolism characteristics in hamsters with familial hypercholesterolemia.

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. [ABSTRACT FROM AUTHOR]

[Display omitted] • A hamster model lacking both LCAT and LDL receptor (DKO) was successfully constructed in the present study. • A significant reduction in plasma LDL-C and HDL-C levels with increased triglyceride and free cholesterol levels was observed in DKO hamsters on a regular chow diet. • Dyslipidemia contributed to HFD-induced atherosclerosis and fatty liver independent on LDL levels in DKO hamsters. • Lipid metabolism was impaired in primary peritoneal macrophages from DKO hamsters. Lecithin cholesterol acyltransferase (LCAT) plays a crucial role in acyl-esterifying cholesterol in plasma, which is essential for reverse cholesterol transport (RCT). Previous studies indicated that its activity on both α and β lipoproteins interpret its effects on lipoproteins for many controversial investigations of atherosclerosis. To better understand the relationship between LCAT, diet-induced dyslipidemia and atherosclerosis, we developed a double knockout (LCAT−/−&LDLR−/−, DKO) hamster model to evaluate the specific role of LCAT independent of LDL clearance effects. Plasma triglyceride (TG), total cholesterol (TC), high-density lipoprotein-cholesterol (HDL-C), and free cholesterol (FC) levels were measured using biochemical reagent kits. FPLC was performed to analyze the components of lipoproteins. Apolipoprotein content was assessed using western blotting (WB). The hamsters were fed a high cholesterol/high fat diet (HCHFD) to induce atherosclerosis. Oil Red O staining was employed to detect plaque formation. Peritoneal macrophages were studied to investigate the effects of LCAT on cholesterol uptake and efflux. On HCHFD, DKO hamsters exhibited significantly elevated levels of TG and FC, while HDL-C was nearly undetectable without affecting TC levels, as compared to low-density lipoprotein receptor (LDLR)-deficient (LDLR−/−, LKO) hamsters. Lipoprotein profiling revealed a marked increase in plasma chylomicron/very low-density lipoprotein (CM/VLDL) fractions, along with an unexpected reduction in LDL fraction in DKO hamsters. Furthermore, DKO hamsters displayed aggravated atherosclerotic lesions in the aorta, aortic root, and coronary artery relative to LKO hamsters, attributed to a pro-atherogenic lipoprotein profile and impaired cholesterol efflux in macrophages. Our study demonstrates the beneficial role of LCAT in inhibiting atherosclerotic development and highlights the distinctive lipid metabolism characteristics in hamsters with familial hypercholesterolemia. [ABSTRACT FROM AUTHOR]

Abstract Background Previous 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. Results The 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. Conclusions In 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.

Background: Previous 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. Results: The 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. Conclusions: In 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. [ABSTRACT FROM AUTHOR]

Genetic insights help us to investigate disease pathogenesis and risk. The ABCA1 protein encoded by ABCA1 is involved in transporting cholesterol across the cell membrane. Genetic variations in the ABCA1 gene are well documented; however, their role in the development of diabetic dyslipidemia still needs to be explored. This study aimed to identify the associations of rs757194699 (K1587Q) and rs2066714 (I883M) with dyslipidemia in type 2 diabetes and performed molecular simulations. In our case–control study, 330 individuals were divided equally into a diabetic dyslipidemia cases and a healthy controls. Allele-specific polymerase chain reaction and restriction fragment length polymorphism were performed to screen selected variants of the ABCA1 gene. Sanger sequencing was also performed to find genetic mutations in exon 5 of the ABCA1 gene. The C allele of rs757194699 was observed at a high frequency in cases compared to controls and followed the overdominant genetic model (p < 0.0001, OR:3.84; CI:1.67–8.82). The frequency of G allele of rs2066714 was significantly higher in cases compared to controls and followed the genetic model of codominant (p< 0.0001, OR: 39.61; CI:9.97–157.32), dominant (p < 0.0001,OR:59.59; CI:15.19–233.81), overdominant (p< 0.0001, OR:9.75; CI:3.16–30.11), and log-additive (p< 0.0001, OR:42.15; CI:11.08–160.40). In silico modeling and docking revealed that rs2066714 and rs757194699 produced deleterious conformational changes in the ABCA1 protein, resulting in alterations in the binding of the apoA1 protein. There were no genetic variations found in exon-5 in Sanger sequencing. The G allele of rs2066714 and C allele of rs757194699 in the ABCA1 gene were found to be risk alleles in the development of dyslipidemia in type 2 diabetes. These polymorphisms could alter the binding site of ABCA1 with apoA1 thus disturbs the reverse cholesterol transport. [ABSTRACT FROM AUTHOR]

Aims: Acute 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. Methods: HDL 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. Results: Among 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. Conclusions: In 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.

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

Sebastian Ciro Acosta,1 Lorena Díaz-Ordóñez,1,2 Juan David Gutierrez-Medina,1,3 Yisther Katherine Silva-Cuero,1,2 Luis Guillermo Arango-Vélez,4,5 Andrés Octavio García-Trujillo,4,5 Harry Pachajoa1,2,6 1Centro de Investigaciones en Anomalias Congenitas y Enfermedades Raras (CIACER), Universidad Icesi, Cali, Colombia; 2Departamento de Ciencias Basicas Medicas, Facultad de Salud, Universidad Icesi, Cali, Colombia; 3Centro de Investigaciones Clinicas, Fundacion Valle del Lili, Cali, Colombia; 4Servicio de Endocrinologia, Fundacion Valle del Lili, Cali, Colombia; 5Departamento de Medicina interna, Seccion de Endocrinologia, Universidad Icesi, Cali, Colombia; 6Genetic Division, Fundacion Valle del Lili, Cali, ColombiaCorrespondence: Lorena Díaz-Ordóñez, Centro de Investigaciones en Anomalias Congenitas y Enfermedades Raras (CIACER), Universidad Icesi, Street 18 Number 122-135, Cali, Valle del Cauca, 760031, Colombia, Tel +57 602 5552334, Email lldiaz@icesi.edu.coAbstract: Mutations in the lecithin-cholesterol acyltransferase (LCAT) gene, which catalyzes the esterification of cholesterol, result in two types of autosomal recessive disorders: Familial LCAT deficiency (FLD) and Fish Eye Disease (FED). While both phenotypes are characterized by corneal opacities and different forms of dyslipidemia, such as low levels of high-density lipoprotein-cholesterol (HDL-C), FLD exhibits more severe clinical manifestations like splenomegaly, anemia, and renal failure. We describe the first clinically and genetically confirmed case of FLD in Colombia which corresponds to a 46-year-old woman with corneal opacity, hypothyroidism, and dyslipidemia, who does not have any manifestations of renal failure, with two pathogenic heterozygous missense variants in the LCAT gene: LCAT (NM_000229.2):c.803G>A (p.Arg268His) and LCAT (NM_000229.2):c.368G>C (p.Arg123Pro). In silico analysis of the mutations predicted the physicochemical properties of the mutated protein, causing instability and potentially decreased LCAT function. These compound mutations highlight the clinical heterogeneity of the phenotypes associated with LCAT gene mutations.Keywords: eye, LCAT, cholesterol/trafficking, genomics, VLDL, lecithin cholesterol acyltransferase deficiency, LCAT deficiency, alpha-LCAT deficiency, fish eye disease

Mutations in the lecithin-cholesterol acyltransferase (LCAT) gene, which catalyzes the esterification of cholesterol, result in two types of autosomal recessive disorders: Familial LCAT deficiency (FLD) and Fish Eye Disease (FED). While both phenotypes are characterized by corneal opacities and different forms of dyslipidemia, such as low levels of high-density lipoprotein-cholesterol (HDL-C), FLD exhibits more severe clinical manifestations like splenomegaly, anemia, and renal failure. We describe the first clinically and genetically confirmed case of FLD in Colombia which corresponds to a 46-year-old woman with corneal opacity, hypothyroidism, and dyslipidemia, who does not have any manifestations of renal failure, with two pathogenic heterozygous missense variants in the LCAT gene: LCAT (NM_000229.2):c.803G>A (p.Arg268His) and LCAT (NM_000229.2):c.368G>C (p.Arg123Pro). In silico analysis of the mutations predicted the physicochemical properties of the mutated protein, causing instability and potentially decreased LCAT function. These compound mutations highlight the clinical heterogeneity of the phenotypes associated with LCAT gene mutations. [ABSTRACT FROM AUTHOR]

Case summaryAn indoor-only 6-year-old spayed female domestic cat was evaluated for a history of stertorous respiration. Skull radiographs revealed increased soft tissue density within the caudal aspect of the left nasal cavity. CT and rhinoscopy revealed a mass lesion in the choana, plus a smaller lesion, nearly completely occluding flow through the nasal passages. Rhinoscopy was used to collect a biopsy specimen from a fleshy, tan-yellow mass visualized in the caudal nasopharynx. Histopathology was diagnostic for Cryptococcus species infection and systemic antifungal therapy with fluconazole was initiated. Following a series of discordant results, serum samples were submitted to a veterinary diagnostic laboratory that utilized a cryptococcal antigen latex agglutination system with pretreatment of serum with pronase. Twenty-three months after the initial diagnosis, the cat's serum cryptococcal antigen titer declined to 1:5 and the cat has responded well to continuing treatment.Relevance and novel informationThis case illustrates challenges associated with discordant test results for cryptococcal antigen among laboratories. Discordancies may be due to differences in assay design, or the underlying disease state itself, or whether serum is pre-treated with pronase; with some tests relying on the training and experience of the operator if the cryptococcal antigen detection test requires a subjective interpretation. It also resolves some confusion in the literature related to the assay types available and terminology used to describe them, and emphasizes the importance of considering cryptococcosis as an important differential for cats with upper respiratory signs, without nasal discharge, even if the cat is kept exclusively indoors.

High-density lipoproteins (HDL) play a critical role in cholesterol homeostasis. Apolipoprotein E (APOE), particularly the E4 allele, is a significant risk factor for Alzheimer's disease but is also a key HDL-associated protein involved in lipid transport in both the periphery and central nervous systems. The objective was to determine the influence of the APOE genotype on HDL function and size in the context of Alzheimer's disease. HDL from 194 participants (non-demented controls, mild cognitive impairment, and Alzheimer's disease dementia) were isolated from the plasma. The HDL cholesterol efflux capacity (CEC), lecithin-cholesterol acyltransferase (LCAT) activity, and particle diameter were measured. Neuropsychological test scores, clinical dementia rating, and magnetic resonance imaging scores were used to determine if cognition is associated with HDL function and size. HDL CEC and LCAT activity were reduced in APOE3E4 carriers compared to APOE3E3 carriers, regardless of diagnosis. In APOE3E3 carriers, CEC and LCAT activity were lower in patients. In APOE3E4 patients, the average particle size was lower. HDL LCAT activity and particle size were positively correlated with the neuropsychological scores and negatively correlated with the clinical dementia rating. We provide evidence for the first time of APOE genotype-specific alterations in HDL particles in Alzheimer's disease and an association between HDL function, size, and cognitive function.

Microorganisms can takeover critical metabolic pathways in host cells to fuel their replication. This interaction provides an opportunity to target host metabolic pathways, in addition to the pathogen-specific ones, in the development of antimicrobials. Host-directed therapy (HDT) is an emerging strategy of anti-infective therapy, which targets host cell metabolism utilized by facultative and obligate intracellular pathogens for entry, replication, egress or persistence of infected host cells. This review provides an overview of the host lipid metabolism and links it to the challenges in the development of HDTs for viral and bacterial infections, where pathogens are using important for the host lipid enzymes, or producing their own analogous of lecithin-cholesterol acyltransferase (LCAT) and lipoprotein lipase (LPL) thus interfering with the human host’s lipid metabolism.

Low HDL-cholesterol (HDL-C) concentrations are a typical trait of the dyslipidemia associated with chronic kidney disease (CKD). In this condition, plasma HDLs are characterized by alterations in structure and function, and these particles can lose their atheroprotective functions, e.g., the ability to promote cholesterol efflux from peripheral cells, anti-oxidant and anti-inflammatory proprieties and they can even become dysfunctional, i.e., exactly damaging. The reduction in plasma HDL-C levels appears to be the only lipid alteration clearly linked to the progression of renal disease in CKD patients. The association between the HDL system and CKD development and progression is also supported by the presence of genetic kidney alterations linked to HDL metabolism, including mutations in the APOA1, APOE, APOL and LCAT genes. Among these, renal disease associated with LCAT deficiency is well characterized and lipid abnormalities detected in LCAT deficiency carriers mirror the ones observed in CKD patients, being present also in acquired LCAT deficiency. This review summarizes the major alterations in HDL structure and function in CKD and how genetic alterations in HDL metabolism can be linked to kidney dysfunction. Finally, the possibility of targeting the HDL system as possible strategy to slow CKD progression is reviewed.

Objective; To construct lecithin ⁃ cholesterolacyl transferase（LCAT）knock ⁃in mice by CRISPR/Cas9 ⁃ mediated gene editing and to obtain liver⁃specific overexpression of Lcat mice by mating with liver⁃specific Cre⁃expressing transgenic mice. Providing an animal model for the study of the mechanism of the Lcat gene in the development of liver⁃related metabolic diseases. Methods; Lcat knock ⁃in mice were constructed by CRISPR/Cas9 technology；Liver ⁃ specific Cre⁃ expressing transgenic mice were mated with Lcat knock ⁃in mice to obtain liver ⁃specific overexpressing Lcat mice；Genotyping mice by PCR；Quantitative real ⁃time PCR（qPCR）and Western blot（WB）techniques were used to verify the expression of Lcat gene in C57BL/6 mice. Results; The PCR results showed that the liver⁃specific overexpression of Lcat gene in mice was successfully constructed；the qPCR results showed that the Lcat gene was specifically highly expressed in the liver, and the liver of knock ⁃in mice showed higher Lcat expression；the WB results showed that LCAT protein was more highly expressed in the liver of liver⁃specific Lcat knock⁃in mice. Conclusion; Liver⁃specific overexpression of Lcat gene mice were successfully constructed, providing a platform for exploring the function of the Lcat gene at animal level in liver⁃related metabolic diseases and the associated pathogenesis. [ABSTRACT FROM AUTHOR]

Background and Aim: The role of lecithin: cholesterol acyltransferase (LCAT) and oxidized low‐density lipoprotein (ox‐LDL) in endometrial cancer (EC) or EC with concurrent type 2 diabetes is still unclear. This study investigated the LCAT activity, ox‐LDL, and lipid profile in EC patients with or without type 2 diabetes and compared them with healthy individuals and patients with type 2 diabetes alone. Methods: In this cross‐sectional, case–control study, 93 female participants were recruited. The participants were divided into four groups, including EC with type 2 diabetes (n = 19), EC without type 2 diabetes (n = 17), type 2 diabetes (n = 31), and healthy controls (n = 26). Sociodemographic information, the LCAT activity, triglyceride (TG), total cholesterol, high‐density lipoprotein cholesterol (HDL‐C), low‐density lipoprotein cholesterol (LDL‐C), and ox‐LDL levels were collected. One‐way analysis of variance and analysis of covariance, Student's t‐test, Mann–Whitney U‐test, and χ2‐test were used to compare demographic features and laboratory results among studied groups. Regression analyses were also performed to evaluate the interaction effect between EC and type 2 diabetes on serum LCAT activity. Results: The LCAT activity was significantly lower, and ox‐LDL levels were significantly higher in all patient groups compared to the healthy controls (p < 0.001). EC patients had significantly lower LCAT activity and higher ox‐LDL levels than type 2 diabetes and healthy groups (p < 0.05). Higher levels of TG and lower levels of HDL‐C were observed in all patient groups compared to the healthy group (all p < 0.001). Patients with EC and concomitant type 2 diabetes had significantly lower serum LDL‐C levels than healthy and type 2 diabetes groups (p < 0.05). Conclusions: The combination of EC and type 2 diabetes had a subadditive effect on LCAT activity and ox‐LDL level. The lowest LCAT activity and the highest ox‐LDL levels were observed in patients with EC and concurrent type 2 diabetes. Key points: The lecithin: cholesterol acyltransferase (LCAT) activity, oxidized low‐density lipoprotein (ox‐LDL) levels, and lipid profile were evaluated among four groups.The groups were endometrial cancer (EC), type 2 diabetes, EC and concurrent type 2 diabetes, and healthy controls.LCAT and high‐density lipoprotein decreased, and ox‐LDL increased in all three disease groups.The accompaniment of EC and type 2 diabetes significantly increased oxidative stress.The EC group had lower LCAT activity and higher ox‐LDL levels than the type 2 diabetes group. [ABSTRACT FROM AUTHOR]

Abstract Background The dysregulation of CD5L has been reported in hepatocellular carcinoma (HCC). However, its functions in HCC were controversial. In this study, we aimed to identify CD5L-associated pathways and markers and explore their values in HCC diagnosis, prognosis and treatment. Methods HCC datasets with gene expression profiles and clinical data in TCGA and ICGC were downloaded. The immune/stroma cell infiltrations were estimated with xCell. CD5L-associated pathways and CD5L-associated genes (CD5L-AGs) were identified with gene expression comparisons and gene set enrichment analysis (GSEA). Cox regression, Kaplan–Meier survival analysis, and least absolute shrinkage and selection operator (LASSO) regression analysis were performed. The correlations of the key genes with immune/stroma infiltrations, immunoregulators, and anti-cancer drug sensitivities in HCC were investigated. At protein level, the key genes dysregulations, their correlations and prognostic values were validated in clinical proteomic tumor analysis consortium (CPTAC) database. Serum CD5L and LCAT activity in 50 HCC and 30 normal samples were evaluated and compared. The correlations of serum LCAT activity with alpha-fetoprotein (AFP), albumin (ALB) and high-density lipoprotein (HDL) in HCC were also investigated. Results Through systemic analyses, 14 CD5L-associated biological pathways, 256 CD5L-AGs and 28 CD5L-associated prognostic and diagnostic genes (CD5L-APDGs) were identified. A risk model consisting of LCAT and CDC20 was constructed for HCC overall survival (OS), which could discriminate HCC OS status effectively in both the training and the validation sets. CD5L, LCAT and CDC20 were shown to be significantly correlated with immune/stroma cell infiltrations, immunoregulators and 31 anti-cancer drug sensitivities in HCC. At protein level, the dysregulations of CD5L, LCAT and CDC20 were confirmed. LCAT and CDC20 were shown to be significantly correlated with proliferation marker MKI67. In serum, no significance of CD5L was shown. However, the lower activity of LCAT in HCC serum was obvious, as well as its significant positive correlations ALB and HDL concentrations. Conclusions CD5L, LCAT and CDC20 were dysregulated in HCC both at mRNA and protein levels. The LCAT-CDC20 signature might be new predicator for HCC OS. The associations of the three genes with HCC microenvironment and anti-cancer drug sensitivities would provide new clues for HCC immunotherapy and chemotherapy.

A specific feature of dyslipidemia in pregnancy is increased high-density lipoprotein (HDL) cholesterol concentration, which is probably associated with maternal endothelium protection. However, preeclampsia is most often associated with low HDL cholesterol, and the mechanisms behind this change are scarcely explored. We aimed to investigate changes in HDL metabolism in risky pregnancies and those complicated by late-onset preeclampsia. We analyze cholesterol synthesis (cholesterol precursors: desmosterol, 7-dehydrocholesterol, and lathosterol) and absorption markers (phytosterols: campesterol and β-sitosterol) within HDL particles (NCSHDL), the activities of principal modulators of HDL cholesterol's content, and major HDL functional proteins levels in mid and late pregnancy. On the basis of the pregnancy outcome, participants were classified into the risk group (RG) (70 women) and the preeclampsia group (PG) (20 women). HDL cholesterol was lower in PG in the second trimester compared to RG (p < 0.05) and followed by lower levels of cholesterol absorption markers (p < 0.001 for campesterolHDL and p < 0.05 for β-sitosterolHDL). Lowering of HDL cholesterol between trimesters in RG (p < 0.05) was accompanied by a decrease in HDL phytosterol content (p < 0.001), apolipoprotein A-I (apoA-I) concentration (p < 0.05), and paraoxonase 1 (PON1) (p < 0.001), lecithin–cholesterol acyltransferase (LCAT) (p < 0.05), and cholesterol ester transfer protein (CETP) activities (p < 0.05). These longitudinal changes were absent in PG. Development of late-onset preeclampsia is preceded by the appearance of lower HDL cholesterol and NCSHDL in the second trimester. We propose that reduced capacity for intestinal HDL synthesis, decreased LCAT activity, and impaired capacity for HDL-mediated cholesterol efflux could be the contributing mechanisms resulting in lower HDL cholesterol. [ABSTRACT FROM AUTHOR]

Dysregulation of lipid metabolism has been implicated in age-related macular degeneration (AMD), the leading cause of blindness among the elderly. Lecithin cholesterol acyltransferase (LCAT) is an important enzyme responsible for lipid metabolism, which could be regulated by DNA methylation during the development of various age-related diseases. This study aimed to assess the association between LCAT DNA methylation and the risk of AMD, and to examine whether plasma vitamin and carotenoid concentrations modified this association. A total of 126 cases of AMD and 174 controls were included in the present analysis. LCAT DNA methylation was detected by quantitative real-time methylation-1specific PCR (qMSP). Circulating vitamins and carotenoids were measured using reversed-phase high-performance liquid chromatography (RP-HPLC). DNA methylation of LCAT was significantly higher in patients with AMD than those in the control subjects. After multivariable adjustment, participants in the highest tertile of LCAT DNA methylation had a 5.37-fold higher risk (95% CI: 2.56, 11.28) of AMD compared with those in the lowest tertile. Each standard deviation (SD) increment of LCAT DNA methylation was associated with a 2.23-fold (95% CI: 1.58, 3.13) increased risk of AMD. There was a J-shaped association between LCAT DNA methylation and AMD risk (Pnon-linearity = 0.03). Higher concentrations of plasma retinol and β-cryptoxanthin were significantly associated with decreased levels of LCAT DNA methylation, with the multivariate-adjusted β coefficient being −0.05 (95% CI: −0.08, −0.01) and −0.25 (95% CI: −0.42, −0.08), respectively. In joint analyses of LCAT DNA methylation and plasma vitamin and carotenoid concentrations, the inverse association between increased LCAT DNA methylation and AMD risk was more pronounced among participants who had a lower concentration of plasma retinol and β-cryptoxanthin. These findings highlight the importance of comprehensively assessing LCAT DNA methylation and increasing vitamin and carotenoid status for the prevention of AMD. [ABSTRACT FROM AUTHOR]

Abstract Background and Aim The role of lecithin: cholesterol acyltransferase (LCAT) and oxidized low‐density lipoprotein (ox‐LDL) in endometrial cancer (EC) or EC with concurrent type 2 diabetes is still unclear. This study investigated the LCAT activity, ox‐LDL, and lipid profile in EC patients with or without type 2 diabetes and compared them with healthy individuals and patients with type 2 diabetes alone. Methods In this cross‐sectional, case–control study, 93 female participants were recruited. The participants were divided into four groups, including EC with type 2 diabetes (n = 19), EC without type 2 diabetes (n = 17), type 2 diabetes (n = 31), and healthy controls (n = 26). Sociodemographic information, the LCAT activity, triglyceride (TG), total cholesterol, high‐density lipoprotein cholesterol (HDL‐C), low‐density lipoprotein cholesterol (LDL‐C), and ox‐LDL levels were collected. One‐way analysis of variance and analysis of covariance, Student's t‐test, Mann–Whitney U‐test, and χ2‐test were used to compare demographic features and laboratory results among studied groups. Regression analyses were also performed to evaluate the interaction effect between EC and type 2 diabetes on serum LCAT activity. Results The LCAT activity was significantly lower, and ox‐LDL levels were significantly higher in all patient groups compared to the healthy controls (p

Pregravid obesity is one of the major risk factors for pregnancy complications such as gestational diabetes mellitus (GDM) and an increased risk of cardiovascular events in children of affected mothers. However, the biological mechanisms that underpin these adverse outcomes are not well understood. High-density lipoproteins (HDLs) are antiatherogenic by promoting the efflux of cholesterol from macrophages and by suppression of inflammation. Functional impairment of HDLs in obese and GDM-complicated pregnancies may have long-term effects on maternal and offspring health. In the present study, we assessed metrics of HDL function in sera of pregnant women with overweight/obesity of the DALI lifestyle trial (prepregnancy BMI ≥ 29 kg/m2) and women with normal weight (prepregnancy BMI < 25 kg/m2), as well as HDL functionalities in cord blood at delivery. We observed that pregravid obesity was associated with impaired serum antioxidative capacity and lecithin–cholesterol acyltransferase activity in both mothers and offspring, whereas maternal HDL cholesterol efflux capacity was increased. Interestingly, functionalities of maternal and fetal HDL correlated robustly. GDM did not significantly further alter the parameters of HDL function and metabolism in women with obesity, so obesity itself appears to have a major impact on HDL functionality in mothers and their offspring. [ABSTRACT FROM AUTHOR]

Background: The dysregulation of CD5L has been reported in hepatocellular carcinoma (HCC). However, its functions in HCC were controversial. In this study, we aimed to identify CD5L-associated pathways and markers and explore their values in HCC diagnosis, prognosis and treatment. Methods: HCC datasets with gene expression profiles and clinical data in TCGA and ICGC were downloaded. The immune/stroma cell infiltrations were estimated with xCell. CD5L-associated pathways and CD5L-associated genes (CD5L-AGs) were identified with gene expression comparisons and gene set enrichment analysis (GSEA). Cox regression, Kaplan–Meier survival analysis, and least absolute shrinkage and selection operator (LASSO) regression analysis were performed. The correlations of the key genes with immune/stroma infiltrations, immunoregulators, and anti-cancer drug sensitivities in HCC were investigated. At protein level, the key genes dysregulations, their correlations and prognostic values were validated in clinical proteomic tumor analysis consortium (CPTAC) database. Serum CD5L and LCAT activity in 50 HCC and 30 normal samples were evaluated and compared. The correlations of serum LCAT activity with alpha-fetoprotein (AFP), albumin (ALB) and high-density lipoprotein (HDL) in HCC were also investigated. Results: Through systemic analyses, 14 CD5L-associated biological pathways, 256 CD5L-AGs and 28 CD5L-associated prognostic and diagnostic genes (CD5L-APDGs) were identified. A risk model consisting of LCAT and CDC20 was constructed for HCC overall survival (OS), which could discriminate HCC OS status effectively in both the training and the validation sets. CD5L, LCAT and CDC20 were shown to be significantly correlated with immune/stroma cell infiltrations, immunoregulators and 31 anti-cancer drug sensitivities in HCC. At protein level, the dysregulations of CD5L, LCAT and CDC20 were confirmed. LCAT and CDC20 were shown to be significantly correlated with proliferation marker MKI67. In serum, no significance of CD5L was shown. However, the lower activity of LCAT in HCC serum was obvious, as well as its significant positive correlations ALB and HDL concentrations. Conclusions: CD5L, LCAT and CDC20 were dysregulated in HCC both at mRNA and protein levels. The LCAT-CDC20 signature might be new predicator for HCC OS. The associations of the three genes with HCC microenvironment and anti-cancer drug sensitivities would provide new clues for HCC immunotherapy and chemotherapy. [ABSTRACT FROM AUTHOR]

Background: Familial lecithin: cholesterol acyltransferase (LCAT) deficiency (FLD) is a severe inherited disease without effective treatment. Patients with FLD develop severe low HDL, corneal opacity, hemolytic anemia, and renal injury. Objective: We developed genetically modified adipocytes (GMAC) secreting LCAT (LCAT-GMAC) for ex vivo gene therapy. GMACs were prepared from the patient’s adipocytes to express LCAT by retroviral gene transduction to secrete functional enzymes. This study aimed to evaluate the safety and efficacy of LCAT-GMAC implantation in an FLD patient. Methods: Proliferative preadipocytes were obtained from a patient using a ceiling culture and retrovirally transduced with LCAT. After obtaining enough cells by expansion culture of the transduced cells, the resulting LCAT-GMACs were implanted into a patient with FLD. To evaluate the safety and efficacy, we analyzed the outcome of the autologous implantation for 24 weeks of observation and subsequent 240 weeks of the follow-up periods. Results: This first-in-human autologous implantation of LCAT-GMACs was shown to be safe by evaluating adverse events. The LCAT-GMAC implantation increased serum LCAT activity by approximately 50% of the baseline and sustained over three years. Consistent with increased LCAT activity, intermediate-density lipoprotein (IDL) and free cholesterol levels of the small and very small HDL fractions decreased. We found the hemoglobin/haptoglobin complex in the hemolyzed pre-implantation sera of the patient. After one week of the implantation, the hemoglobin/haptoglobin complex almost disappeared. Immediately after the implantation, the patient's proteinuria decreased temporarily to mild levels and gradually increased to the baseline. At 48 weeks after implantation, the patient's proteinuria deteriorated with the development of mild hypertension. By the treatment with antihypertensives, the patient's blood pressure normalized. With the normalization of blood pressure, the proteinuria rapidly decreased to mild proteinuria levels. Conclusions: LCAT-GMAC implantation in a patient with FLD is shown to be safe and appears to be effective, in part, for treating anemia and proteinuria in FLD.

Background: To date, no study has investigated the effects of probiotic yogurt as a functional food in patients with chronic heart failure (CHF). Therefore, the aim of this study was to compare the impact of probiotic yogurt versus ordinary yogurt on inflammatory, endothelial, lipid and renal indices in CHF patients. In this randomized, triple‐blind clinical trial, 90 patients with CHF were randomly allocated into two groups to take either probiotic or ordinary yogurt for 10 weeks. Serum levels of soluble tumor necrosis factor‐like weak inducer of apoptosis (sTWEAK), soluble cluster of differentiation 163 (sCD163), asymmetric dimethylarginine (ADMA), and lecithin cholesterol acyltransferase (LCAT) were measured by using ELISA kits, and blood urea nitrogen (BUN) was measured by calorimetry method at baseline and at the end of trial. The P‐value <0.05 was defined as statistically significant. Results: Seventy‐eight patients completed the study. At the end of the intervention, the levels of sTWEAK in both groups increased significantly, and this increase was greater in the probiotic yogurt group [691.84 (335.60, 866.95)] compared to control group [581.96 (444.99, 929.40)], and the difference between the groups was statistically significant after adjusting for confounders (P‐value: 0.257, adjusted P‐value: 0.038). However, no significant differences were found between the groups in the cases of other study indices. Conclusion: Probiotic yogurt may be useful for improving the inflammatory status in patients with CHF through increasing sTWEAK levels, however, further studies are needed in this area. © 2022 Society of Chemical Industry. [ABSTRACT FROM AUTHOR]

Plasma membrane cholesterol is required for proper trafficking and localization of receptors that facilitate severe acute respiratory syndrome coronavirus 2 infection. High-density lipoproteins (HDL) mobilize plasma membrane cholesterol, and HDL-cholesterol levels are associated with the severity of COVID-19 disease and mortality. However, HDL-cholesterol levels poorly reflect the function of this complex family of particles, and a detailed assessment of COVID-19-associated changes in HDL functionality and its prognostic value is lacking. In the present study, we assessed HDL cholesterol efflux capacity, HDL anti-inflammatory and antioxidant properties, and changes in HDL composition and metabolism in COVID-19 (n = 48) and non-COVID pneumonia patients (n = 32). COVID-19 infection markedly reduced the activity of lecithin-cholesteryl-acyltransferase and functional parameters of HDL, such as the cholesterol efflux capacity, arylesterase activity of paraoxonase 1, and anti-oxidative capacity of apoB-depleted serum when compared to non-COVID pneumonia at baseline, paralleled by markedly reduced levels of HDL-cholesterol. Of particular interest, low HDL cholesterol efflux capacity was associated with increased mortality risk in COVID-19 patients, independent of HDL-C levels. Our results highlight profound effects of COVID-19 infection on HDL function, metabolism, and composition. Low HDL cholesterol efflux capacity indicates a fatal course of COVID-19, independent of HDL-cholesterol levels. [ABSTRACT FROM AUTHOR]

Numerous risk factors have been associated with breast cancer (BC), exposure to metalloestrogen, like lead, being such. Since lead involvement in BC is still equivocal, we focused on lead levels in three compartments of BC patients, blood, healthy, and malignant tissues. Also, as the cholesterol role in cancer development was recognized at the beginning of the twentieth century and led to involvement in lipid profile impairment, we further extend our research on lipid profile and enzymes responsible for maintaining lipid balance in BC patients. Fifty-five women diagnosed with BC were enrolled in the study. Forty-one healthy women represented the control group. Lead levels in blood, healthy surrounding and malignant tissue, and lipid profile parameters in serum, were determined. Higher lead levels were obtained in surrounding healthy tissue samples compared to cancerous tissue samples, while blood lead levels of BC women did not differ significantly from the control group. The altered lipid profile scheme in women diagnosed with breast cancer contained significantly higher triglycerides levels (P < 0.001). Moreover, logistic regression analysis revealed triglycerides as a significant predictor of BC (OR = 2.6; P < 0.01). Although statistical significance was missing for lower paraoxonase-1 (PON-1) activities observed in BC women, multivariate logistic regression singled out PON-1 activities as significant BC predictors. The result of the present study further indicated oxidative status imbalance and tissue levels bioelements perturbation. Obtained results in the present study propose possible lead involvement in BC onset accompanied with bioelements redistribution and oxidative stress occurrence. [ABSTRACT FROM AUTHOR]

Diabetes is a group of metabolic diseases characterized by hyperglycemia resulting from defects in insulin secretion, insulin action, or both. The chronic hyperglycemia of diabetes is associated with long-term damage, dysfunction, and failure of various organs. Accordingly, in the current study we have investigated the effect of clove on lipid metabolism, and on oxidative stress-induced inflammation response in diabetic rats. Diabetes was induced intraperitonially by a single injection of streptozotocin (STZ). The treated group received daily orally clove extract, for 4 weeks. Daily treatment by clove lowered significantly blood glucose, HbA1c levels and ameliorates the lipid profiles and showed increased PON1 activity. The study of lipid peroxidation showed that, the treatment with clove decreased TBARS levels in LDL fraction and in pancreas. Furthermore, in pancreas TNF-alpha and IL-1β levels were decreased in treated group. These results were confirmed by the histopathological assessments which clove treatment showed marked improvement of the destructive effect on pancreas islet cells induced by STZ. The present findings clearly demonstrated that clove could prevent many diabetic complications by reducing inflammation and oxidative damage. Thus, the effectiveness of clove in treating diabetes potentially may possibly due to presence of bioactive compounds. [ABSTRACT FROM AUTHOR]

• A patient with low HDL-cholesterol and corneal opacity was identified. • The patient showed no apparent atherosclerosis or CAD. • LCAT activity is relatively maintained and may be related to the patient's phenotype. • Novel frameshift mutation was identified in the APOA1 gene. • Aberrant structure of apoA-I might explain the retained LCAT activity. The proband was a 53-year-old Japanese woman. Despite having no atherosclerotic vascular lesions on a physiological examination, markedly decreased levels of high-density lipoprotein (HDL) were always noted at her annual medical checkup. She also had corneal opacities but neither xanthoma nor tonsillar hypertrophy. A biochemical examination showed decreased levels of both apolipoprotein A-I (apoA-I) (<5 mg/dL) and lecithin–cholesterol acyltransferase (LCAT) activity. Her brother and son also had low concentrations of HDL-cholesterol, suggesting the presence of a genetic abnormality. Therefore, a sequence analysis of the genes for ABCA1, LCAT and apoA-I proteins was performed in the proband. The analysis of the APOA1 gene revealed a novel homozygous two-nucleotide deletion in exon 4 (c.614_615delTC), which causes a frameshift after residue 205 of the apoA-I protein (p.Leu205fs). Since no mutation has been found in the ABCA1 or LCAT gene, functional abnormalities of the carboxyl-terminal region of the apoA-I protein in lipid binding might have caused the low HDL-cholesterol levels and decreased LCAT activity, possibly associated with corneal opacities but not premature CAD, in the patient. [ABSTRACT FROM AUTHOR]

1‐O‐Acylceramides (1‐OACs) have a fatty acid esterified to the 1‐hydroxyl of the sphingosine head group of the ceramide, and recently we identified these lipids as natural components of human and mouse epidermis. Here we show epidermal 1‐OACs arise shortly before birth during the establishment of the water permeability barrier in mice. Fractionation of human epidermis indicates 1‐OACs concentrate in the stratum corneum. During in vitro maturation into reconstructed human epidermis, human keratinocytes dramatically increase 1‐OAC levels indicating they are one source of epidermal 1‐OACs. In search of potential enzymes responsible for 1‐OAC synthesis in vivo, we analyzed mutant mice with deficiencies of ceramide synthases (Cers2, Cers3, or Cers4), diacylglycerol acyltransferases (Dgat1 or Dgat2), elongase of very long fatty acids 3 (Elovl3), lecithin cholesterol acyltransferase (Lcat), stearoyl‐CoA desaturase 1 (Scd1), or acidic ceramidase (Asah1). Overall levels of 1‐OACs did not decrease in any mouse model. In Cers3 and Dgat2‐deficient epidermis they even increased in correlation with deficient skin barrier function. Dagt2 deficiency reshapes 1‐OAC synthesis with an increase in 1‐OACs with N‐linked non‐hydroxylated fatty acids and a 60% decrease compared to control in levels of 1‐OACs with N‐linked hydroxylated palmitate. As none of the single enzyme deficiencies we examined resulted in a lack of 1‐OACs, we conclude that either there is functional redundancy in forming 1‐OAC and more than one enzyme is involved, and/or an unknown acyltransferase of the epidermis performs the final step of 1‐OAC synthesis, the implications of which are discussed. [ABSTRACT FROM AUTHOR]

Anorexia nervosa (AN) is a severe eating disorder affecting primarily female adolescents and younger adults. The energy deprivation associated with AN has been shown to alter lipoprotein metabolism, which may affect cardiovascular risk. However, the mechanisms leading to alterations in the composition, structure, and function of lipoproteins in AN patients are not well-understood yet. Here, we investigated the lipid abnormalities associated with AN, particularly changes in the distribution, composition, metabolism, and function of lipoprotein subclasses. In this exploratory study, we analyzed serum samples of 18 women diagnosed with AN (BMI < 17.5 kg/m2) and 24 normal-weight women (BMI from 18.5–24.9 kg/m2). Using the Quantimetrix Lipoprint® system, we determined low-density lipoprotein (LDL) subclass distribution, including quantitative measurements of very low-density lipoprotein (VLDL), intermediate density lipoprotein (IDL) and high-density lipoprotein (HDL) subclass distribution. We quantified the most abundant apolipoproteins of HDL and assessed lecithin-cholesterol acyltransferase (LCAT) and cholesteryl-ester transfer protein (CETP) activities. In addition, anti-oxidative capacity of apoB-depleted serum and functional metrics of HDL, including cholesterol efflux capacity and paraoxonase activity were assessed. The atherogenic lipoprotein subclasses VLDL and small LDL particles were increased in AN. Levels of VLDL correlated significantly with CETP activity (rs = 0.432, p = 0.005). AN was accompanied by changes in the content of HDL-associated apolipoproteins involved in triglyceride catabolism, such as apolipoprotein C-II (+24%) and apoA-II (−27%), whereas HDL-associated cholesterol, phospholipids, and triglycerides were not altered. Moreover, AN did not affect HDL subclass distribution, cholesterol efflux capacity, and paraoxonase activity. We observed a shift to more atherogenic lipoprotein subclasses in AN patients, whereas HDL functionality and subclass distribution were not altered. This finding underpins potential detrimental effects of AN on lipid metabolism and the cardiovascular system by increasing atherosclerotic risk factors. [ABSTRACT FROM AUTHOR]

Pregravid obesity is one of the major risk factors for pregnancy complications such as gestational diabetes mellitus (GDM) and an increased risk of cardiovascular events in children of affected mothers. However, the biological mechanisms that underpin these adverse outcomes are not well understood. High-density lipoproteins (HDLs) are antiatherogenic by promoting the efflux of cholesterol from macrophages and by suppression of inflammation. Functional impairment of HDLs in obese and GDM-complicated pregnancies may have long-term effects on maternal and offspring health. In the present study, we assessed metrics of HDL function in sera of pregnant women with overweight/obesity of the DALI lifestyle trial (prepregnancy BMI ≥ 29 kg/m2) and women with normal weight (prepregnancy BMI < 25 kg/m2), as well as HDL functionalities in cord blood at delivery. We observed that pregravid obesity was associated with impaired serum antioxidative capacity and lecithin–cholesterol acyltransferase activity in both mothers and offspring, whereas maternal HDL cholesterol efflux capacity was increased. Interestingly, functionalities of maternal and fetal HDL correlated robustly. GDM did not significantly further alter the parameters of HDL function and metabolism in women with obesity, so obesity itself appears to have a major impact on HDL functionality in mothers and their offspring.

Background: Lysine treatment decreased diabetic complications associated with type 2 diabetes in the rat models of diabetes and in vitro. Aims/hypothesis: Herein, in a single-evaluator–blinded, randomized clinical trial, we investigated the effect of L-Lysine (Lys) intervention in type 2 diabetic patients. Methods: Two groups of type 2 diabetic patients (15 females and 10 males in each group) who were under treatment with glibenclamide and metformin underwent a short term (3 months), trial. The test group was orally administered with 3 g/day of Lys. Clinical and biochemical parameters of all patients were measured prior to and after the experimental period and were statistically analyzed. Results: Among the serum parameters, FBS, insulin, HOMA-IR, HSP 70, LCAT, PON1, AOPP, and FRAP improved significantly in the test group. A significant decrease in HbA1c and urine glucose accompanying with positive correlations between HbA1c and FBS, fructosamine and both FBS and HbA1c, HOMA with both insulin and FBS, and FBS with urine glucose indicates that Lys prevents diabetes complications. There were no significant changes in the liver and kidney function tests indicating no toxicity of Lys for patients. Conclusions/interpretation: In conclusion, Lys inhibited protein glycation, improved glycemic control, and increased antioxidant markers in type 2 diabetic patients; thus, it could be suggested for combinatorial therapy of diabetes with oral hypoglycemic agents to protect against vascular risk factors and other diabetic complications. [ABSTRACT FROM AUTHOR]

Reconstituted high density lipoprotein (rHDL) has been regarded as a promising brain-targeting vehicle for anti-glioma drugs under the mediation of apolipoprotein A-I (apoA-I). However, some stability issues relating to drug leakage and consequent reduced targeting efficiency in the course of discoidal rHDL (d-rHDL) circulating in blood hinder its broad application. The objective of the study was to develop a novel stabilized d-rHDL by replacing cholesterol and apoA-I with mono-cholesterol glutarate (MCG) modified apoA-I (termed as mA) and to evaluate its allosteric behavior and glioma targeting. MCG was synthesized through esterifying the hydroxyl of cholesterol with glutaric anhydride and characterized by FI-IR and 1H NMR. d-rHDL assembled with mA (termed as m-d-rHDL) presented similar properties such as minute particle size and disk-like appearance resembling nascent HDL. Morphological transformation observation and in vitro release plots convinced that the modification of cholesterol could effectively inhibit the remolding of d-rHDL. The uptake of m-d-rHDL by LCAT-pretreated bEND.3 cells was significantly higher than that of d-rHDL, thereby serving as another proof for the capability of m-d-rHDL in enhancing targeting property. Besides, apoA-I anchoring into m-d-rHDL played a critical role in the endocytosis process into bEND.3 cells and C6 cells, which implied the possibility of traversing blood brain barrier and accumulating in the brain and glioma. These results suggested that the modification toward cholesterol to improve the stability of d-rHDL is advantageous, and that this obtained m-d-rHDL revealed great potential for realization of suppressing the remolding of d-rHDL in the brain-targeted treatment of glioma for drug delivery.

Background: The whole plant of Coccinia indica is very effective in different types of diseases with fewer side effects. The leaves, roots of this plant were claimed to be useful in the treatment of diabetes mellitus based on folk medicine. The purpose of this study was to examine the antihyperglycemic effect of water extract of C. indica in alloxan diabetes rats. Aims and Objectives: The aim of this study is to find whether the conditions, hyperglyclemia and hyerlipidemia, are correlated and whether the application of the aqueous extract leads to abating these two conditions. Materials-Methods: The aqueous leaves extracts of C. indica (200 mg/kg) were administered orally for 14 days, in alloxan induced diabetic rats on Glucose, Lipid profile, Lipoproteins and Lipid metabolizing enzymes activity. Result: The aqueous leaves extract of C. indica induced significant improvement in glucose, serum Lipids, lipoproteins and lipid metabolizing enzyme activity (HMG CoA reductase, LCAT). Conclusion: The present study indicates that the extract of Coccinia indica exhibits lipid lowering, maintaining lipoproteins concentration and also improves the activities of lipid metabolizing enzyme in hyperglycemic rats leading to an increase in peripheral glucose consumption.

Plasma membrane cholesterol is required for proper trafficking and localization of receptors that facilitate severe acute respiratory syndrome coronavirus 2 infection. High-density lipoproteins (HDL) mobilize plasma membrane cholesterol, and HDL-cholesterol levels are associated with the severity of COVID-19 disease and mortality. However, HDL-cholesterol levels poorly reflect the function of this complex family of particles, and a detailed assessment of COVID-19-associated changes in HDL functionality and its prognostic value is lacking. In the present study, we assessed HDL cholesterol efflux capacity, HDL anti-inflammatory and antioxidant properties, and changes in HDL composition and metabolism in COVID-19 (n = 48) and non-COVID pneumonia patients (n = 32). COVID-19 infection markedly reduced the activity of lecithin-cholesteryl-acyltransferase and functional parameters of HDL, such as the cholesterol efflux capacity, arylesterase activity of paraoxonase 1, and anti-oxidative capacity of apoB-depleted serum when compared to non-COVID pneumonia at baseline, paralleled by markedly reduced levels of HDL-cholesterol. Of particular interest, low HDL cholesterol efflux capacity was associated with increased mortality risk in COVID-19 patients, independent of HDL-C levels. Our results highlight profound effects of COVID-19 infection on HDL function, metabolism, and composition. Low HDL cholesterol efflux capacity indicates a fatal course of COVID-19, independent of HDL-cholesterol levels.

Background: The most common glomerular disorder in children is nephrotic syndrome, associated with high morbidity despite notable advances in its treatment. Many of the nephrotic syndrome complications, including the increased risk of atherosclerosis and thromboembolism, can be linked to dysregulated lipid metabolism and dyslipidemia. Paraoxonase enzyme is responsible for the most of antioxidant properties of HDL, thus preventing the formation of atherogenic ox-LDL molecules, and Lecithin Cholesterol acyltransferase is intimately involved in HDL maturation and is a key component of the reverse cholesterol transport pathway, which removes excess cholesterol molecules from the peripheral tissues to the liver for excretion. Objective: The present study aimed to investigate the serum activities of paraoxonase-1(PON-1) and lecithin cholesterol acyltransferase (LCAT) in children with nephrotic syndrome in an active phase (as newly diagnosed or old cases with acute relapse) also, to study any correlation exists between paraoxonase-1 activity and lipid profile. Methods: This study consists of Group 1 with 40 cases of nephrotic syndrome in the age group of (2-14 years) and Group 2 with 40 age and sex-matched healthy controls. Lipid profile and paraoxonase activity, Lecithin Cholesterol acyltransferase activities were measured in both groups' serum samples. Results: Statistical analysis by student's t-test showed that the mean levels of Total Cholesterol, Triglycerides, LDL were significantly increased in Group 1 when compared to Group 2 (p

High-density lipoproteins (HDL) play a critical role in cholesterol homeostasis. Apolipoprotein E (APOE), particularly the E4 allele, is a significant risk factor for Alzheimer’s disease but is also a key HDL-associated protein involved in lipid transport in both the periphery and central nervous systems. The objective was to determine the influence of the APOE genotype on HDL function and size in the context of Alzheimer’s disease. HDL from 194 participants (non-demented controls, mild cognitive impairment, and Alzheimer’s disease dementia) were isolated from the plasma. The HDL cholesterol efflux capacity (CEC), lecithin-cholesterol acyltransferase (LCAT) activity, and particle diameter were measured. Neuropsychological test scores, clinical dementia rating, and magnetic resonance imaging scores were used to determine if cognition is associated with HDL function and size. HDL CEC and LCAT activity were reduced in APOE3E4 carriers compared to APOE3E3 carriers, regardless of diagnosis. In APOE3E3 carriers, CEC and LCAT activity were lower in patients. In APOE3E4 patients, the average particle size was lower. HDL LCAT activity and particle size were positively correlated with the neuropsychological scores and negatively correlated with the clinical dementia rating. We provide evidence for the first time of APOE genotype-specific alterations in HDL particles in Alzheimer’s disease and an association between HDL function, size, and cognitive function.

Purpose: Lipid metabolism has been poorly explored in subclinical hyperthyroidism. The aim was to examine the effects of exogenous subclinical hyperthyroidism in women under levothyroxine treatment upon plasma lipids and aspects of HDL metabolism.Methodology: Ten women were studied in euthyroidism and again in exogenous subclinical hyperthyroidism. Thyroid function tests and plasma lipids were studied.Results: HDL-cholesterol (increased 21.6%, p = 0.0004), unesterified cholesterol (increased 12.3%, p = 0.04) and Lp(a) (increased 33,3%, P = 0.02) plasma concentrations were higher in subclinical hyperthyroidism compared to euthyroidism, but total cholesterol, LDL, non-HDL cholesterol, triglycerides, apo A-I, apo B were unchanged. PON1 activity (decreased 75%, p = 0.0006) was lower in subclinical hyperthyroidism. There were no changes in HDL particle size, CETP and LCAT concentrations. The in vitro assay that estimates the lipid transfers to HDL showed that esterified cholesterol (increased 7.1%, p = 0.03), unesterified cholesterol (increased 7.8%, p = 0.02) and triglycerides (increased 6.8%, p = 0.006) transfers were higher in subclinical hyperthyroidism. There were no changes in phospholipid transfers to HDL in subclinical hyperthyroidism.Conclusions: Several alterations in the plasma lipid metabolism were observed in the subclinical hyperthyroidism state that highlight the importance of this aspect in the follow-up of those patients. The increase in HDL-C and in the transfer of unesterified and esterified cholesterol to HDL, an important anti-atherogenic HDL function are consistently protective for cardiovascular health. The increase in Lp(a) and the decrease in PON-1 activity that are important risk factors were documented here in subclinical hyperthyroidism and these results should be confirmed in larger studies due to great data variation but should not be neglected in the follow-up of those patients.

Anorexia nervosa (AN) is a severe eating disorder affecting primarily female adolescents and younger adults. The energy deprivation associated with AN has been shown to alter lipoprotein metabolism, which may affect cardiovascular risk. However, the mechanisms leading to alterations in the composition, structure, and function of lipoproteins in AN patients are not well-understood yet. Here, we investigated the lipid abnormalities associated with AN, particularly changes in the distribution, composition, metabolism, and function of lipoprotein subclasses. In this exploratory study, we analyzed serum samples of 18 women diagnosed with AN (BMI < 17.5 kg/m2) and 24 normal-weight women (BMI from 18.5–24.9 kg/m2). Using the Quantimetrix Lipoprint® system, we determined low-density lipoprotein (LDL) subclass distribution, including quantitative measurements of very low-density lipoprotein (VLDL), intermediate density lipoprotein (IDL) and high-density lipoprotein (HDL) subclass distribution. We quantified the most abundant apolipoproteins of HDL and assessed lecithin-cholesterol acyltransferase (LCAT) and cholesteryl-ester transfer protein (CETP) activities. In addition, anti-oxidative capacity of apoB-depleted serum and functional metrics of HDL, including cholesterol efflux capacity and paraoxonase activity were assessed. The atherogenic lipoprotein subclasses VLDL and small LDL particles were increased in AN. Levels of VLDL correlated significantly with CETP activity (rs = 0.432, p = 0.005). AN was accompanied by changes in the content of HDL-associated apolipoproteins involved in triglyceride catabolism, such as apolipoprotein C-II (+24%) and apoA-II (−27%), whereas HDL-associated cholesterol, phospholipids, and triglycerides were not altered. Moreover, AN did not affect HDL subclass distribution, cholesterol efflux capacity, and paraoxonase activity. We observed a shift to more atherogenic lipoprotein subclasses in AN patients, whereas HDL functionality and subclass distribution were not altered. This finding underpins potential detrimental effects of AN on lipid metabolism and the cardiovascular system by increasing atherosclerotic risk factors.

Abstract Background Lecithin-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. Methods The 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. Results The 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). Conclusions The 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 registration UMIN (https://upload.umin.ac.jp/cgi-bin/ctr/ctr_reg_list.cgi) Study ID: UMIN000033228 retrospectively registered 2 July 2018.

Reconstituted high density lipoprotein (rHDL) has been regarded as a promising brain-targeting vehicle for anti-glioma drugs under the mediation of apolipoprotein A-I (apoA-I). However, some stability issues relating to drug leakage and consequent reduced targeting efficiency in the course of discoidal rHDL (d-rHDL) circulating in blood hinder its broad application. The objective of the study was to develop a novel stabilized d-rHDL by replacing cholesterol and apoA-I with mono-cholesterol glutarate (MCG) modified apoA-I (termed as mA) and to evaluate its allosteric behavior and glioma targeting. MCG was synthesized through esterifying the hydroxyl of cholesterol with glutaric anhydride and characterized by FI-IR and 1H NMR. d-rHDL assembled with mA (termed as m-d-rHDL) presented similar properties such as minute particle size and disk-like appearance resembling nascent HDL. Morphological transformation observation and in vitro release plots convinced that the modification of cholesterol could effectively inhibit the remolding of d-rHDL. The uptake of m-d-rHDL by LCAT-pretreated bEND.3 cells was significantly higher than that of d-rHDL, thereby serving as another proof for the capability of m-d-rHDL in enhancing targeting property. Besides, apoA-I anchoring into m-d-rHDL played a critical role in the endocytosis process into bEND.3 cells and C6 cells, which implied the possibility of traversing blood brain barrier and accumulating in the brain and glioma. These results suggested that the modification toward cholesterol to improve the stability of d-rHDL is advantageous, and that this obtained m-d-rHDL revealed great potential for realization of suppressing the remolding of d-rHDL in the brain-targeted treatment of glioma for drug delivery. [ABSTRACT FROM AUTHOR]

Purpose: Lipid metabolism has been poorly explored in subclinical hyperthyroidism. The aim was to examine the effects of exogenous subclinical hyperthyroidism in women under levothyroxine treatment upon plasma lipids and aspects of HDL metabolism. Methodology: Ten women were studied in euthyroidism and again in exogenous subclinical hyperthyroidism. Thyroid function tests and plasma lipids were studied. Results: HDL-cholesterol (increased 21.6%, p = 0.0004), unesterified cholesterol (increased 12.3%, p = 0.04) and Lp(a) (increased 33,3%, P = 0.02) plasma concentrations were higher in subclinical hyperthyroidism compared to euthyroidism, but total cholesterol, LDL, non-HDL cholesterol, triglycerides, apo A-I, apo B were unchanged. PON1 activity (decreased 75%, p = 0.0006) was lower in subclinical hyperthyroidism. There were no changes in HDL particle size, CETP and LCAT concentrations. The in vitro assay that estimates the lipid transfers to HDL showed that esterified cholesterol (increased 7.1%, p = 0.03), unesterified cholesterol (increased 7.8%, p = 0.02) and triglycerides (increased 6.8%, p = 0.006) transfers were higher in subclinical hyperthyroidism. There were no changes in phospholipid transfers to HDL in subclinical hyperthyroidism. Conclusions: Several alterations in the plasma lipid metabolism were observed in the subclinical hyperthyroidism state that highlight the importance of this aspect in the follow-up of those patients. The increase in HDL-C and in the transfer of unesterified and esterified cholesterol to HDL, an important anti-atherogenic HDL function are consistently protective for cardiovascular health. The increase in Lp(a) and the decrease in PON-1 activity that are important risk factors were documented here in subclinical hyperthyroidism and these results should be confirmed in larger studies due to great data variation but should not be neglected in the follow-up of those patients. [ABSTRACT FROM AUTHOR]

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 ferric reducing 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 = 808 nm), Red (λ = 638 nm), Green (λ = 532 nm), and Blue (λ = 450 nm)-to compare the wavelength's effect on different enzymes' activity. Laser power was fixed at 0.01 mW 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 24 h 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. [ABSTRACT FROM AUTHOR]