Functional metabolomics reveals arsenic-induced inhibition of linoleic acid metabolism in mice kidney in drinking water.

Arsenic (As) is a heavy metal known for its detrimental effects on the kidneys, but the precise mechanisms underlying its toxicity remain unclear. In this study, we employed an integrated approach combining traditional toxicology methods with functional metabolomics to explore the nephrotoxicity induced by As in mice. Our findings demonstrated that after 28 days of exposure to sodium arsenite, blood urea nitrogen, serum creatinine levels were significantly increased, and pathological examination of the kidneys revealed dilation of renal tubules and glomerular injury. Additionally, uric acid, total cholesterol, and low-density lipoprotein cholesterol levels were significant increased while triglyceride level was decreased, resulting in renal insufficiency and lipid disorders. Subsequently, the kidney metabolomics analysis revealed that As exposure disrupted 24 differential metabolites, including 14 up-regulated and 10 down-regulated differential metabolites. Ten metabolic pathways including linoleic acid and glycerophospholipid metabolism were significantly enriched. Then, 80 metabolic targets and 168 predicted targets were identified using metabolite network pharmacology analysis. Of particular importance, potential toxicity targets, such as glycine amidinotransferase, mitochondrial (GATM), and nitric oxide synthase, and endothelial (NOS3), were prioritized through the "metabolite-target-pathway" network. Receiver operating characteristics curve and molecular docking analyses suggested that 1-palmitoyl-2-myristoyl-sn-glycero-3-PC, linoleic acid, and L-hydroxyarginine might be functional metabolites associated with GATM and NOS3. Moreover, targeted verification result showed that the level of linoleic acid in As group was 0.4951 µg/mL, which was significantly decreased compared with the control group. And in vivo and in vitro protein expression experiments confirmed that As exposure inhibited the expression of GATM and NOS3. In conclusion, these results suggest that As-induced renal injury may be associated with the inhibition of linoleic acid metabolism through the down-regulation of GATM and NOS3, resulting in decreased levels of linoleic acid, 1-palmitoyl-2-myristoyl-sn-glycero-3-PC, and L-hydroxyarginine metabolites.

17 variants interaction of Wnt/ß-catenin pathway associated with development of osteonecrosis of femoral head in Chinese Han population.

The genes of Wnt/ß-catenin pathway may have potential roles in fat accumulation of Non-traumatic osteonecrosis of the femoral head (ONFH), but the effects of their variants in the pathway on ONFH development have been remained unclear. To explore the potential roles of the variants in the development of ONFH, we completed the investigation of the paired interactions as well as their related biological functions of 17 variants of GSK3ß, LRP5, and FRP4 genes etc. in the pathway. The genotyping of the 17 variants were finished by MASS ARRAY PLATFORM in a 560 ONFH case-control system. The association of variants interactions with ONFH risk and clinical traits was evaluated by logistic regression analysis etc. and bioinformatics technology. The results showed that the genotype, allele frequency, and genetic models of Gsk3ß rs334558 (G/A), SFRP4 rs1052981 (A/G), and LRP5 rs312778 (T/C) were significantly associated with the increased and decreased ONFH risk and clinical traits, respectively (P < 0.001-0.0002). Particularly, the paired interactions of six variants as well as eight variants also showed statistically increased and decreased ONFH risk, bilateral hip lesions risk and stage IV risk of ONFH, respectively (P < 0.044-0.004). Our results not only at the first time simultaneously showed exact serum lipid disorder and abnormal platelet function of ONFH in the same study system with the 17 variants polymorphisms of Wnt/ß-catenin pathway but also shed light on the variants closely intervening the lipid disorder and abnormal coagulation of ONFH.

The brominated flame retardant tetrabromobisphenol A-bis(2,3-dibromo-2-methylpropyl ether) as well as hexabromocyclododecane lead to lipid disorders in mice.

The brominated flame retardant tetrabromobisphenol A-bis(2,3-dibromo-2-methylpropyl ether) (TBBPA-DBMPE) is a recommended substitute for hexabromocyclododecane (HBCD), a banned persistent organic pollutant, yet its potential toxicities remains largely unexplored. Here, we investigated the effects of a long-term exposure to TBBPA-DBMPE at nominal doses of 50 and 1000 µg/kg/d on lipid homeostasis in CD-1 mice, in comparison with 50 µg/kg/d HBCD as a positive control. Male pups received chemical treatments through maternal administration via drinking water from postnatal day 0-21, followed by direct administration through drinking water after weaning. On the 23rd week after treatment, the oral lipid tolerance test revealed that low-dose TBBPA-DBMPE as well as HBCD affected lipid tolerance, although the fasting serum triglyceride (TG) levels were not altered. When chemical treatment was extended to the 32nd week, TBBPA-DBMPE-treated animals displayed adipocyte hypertrophy in both white adipose tissue (eWAT) and brown adipose tissue (BAT) and hepatic steatosis, which was largely consistent with the effects of HBCD. These findings indicate that like HBCD, TBBPA-DBMPE led to increased lipid load in mice. Interestingly, we also observed intestinal histological changes, coupled with increased expression of lipid absorption-related genes in both HBCD and TBBPA-DBMPE treatments, suggesting increased lipid absorption. This was supported by in vitro findings that both HBCD and TBBPA-DBMPE promoted lipid accumulation in IEC-6 cells under the stress of oleic acid for 6 h, implying that altered lipid absorption by the intestine may partly contributed to increased lipid load in mice. Overall, the effects of 50 µg/kg/d TBBPA-DBMPE in terms of some parameters were comparable with 50 µg/kg/d HBCD, suggesting that TBBPA-DBMPE may not be an ideal substitute of HBCD.

Evaluation of the Needs and Experiences of Patients with Hypertriglyceridemia: Social Media Listening Infosurveillance Study.

BACKGROUND: Hypertriglyceridemia is a risk factor for cardiovascular diseases. Internet usage in China is increasing, giving rise to large-scale data sources, especially to access, disseminate, and discuss medical information. Social media listening (SML) is a new approach to analyze and monitor online discussions related to various health-related topics in diverse diseases, which can generate insights into users' experiences and expectations. However, to date, no studies have evaluated the utility of SML to understand patients' cognizance and expectations pertaining to the management of hypertriglyceridemia. OBJECTIVE: The aim of this study was to utilize SML to explore the disease cognition level of patients with hypertriglyceridemia, choice of intervention measures, and the status quo of online consultations and question-and-answer (Q&A) search platforms. METHODS: An infosurveillance study was conducted wherein a disease-specific comprehensive search was performed between 2004 and 2020 in Q&A search and online consultation platforms. Predefined single and combined keywords related to hypertriglyceridemia were used in the search, including disease, symptoms, diagnosis, and treatment indicators; lifestyle interventions; and therapeutic agents. The search output was aggregated using an aggregator tool and evaluated. RESULTS: Disease-specific consultation data (n=69,845) and corresponding response data (n=111,763) were analyzed from 20 data sources (6 Q&A search platforms and 14 online consultation platforms). Doctors from inland areas had relatively high voice volumes and appear to exert a substantial influence on these platforms. Patients with hypertriglyceridemia engaging on the internet have an average level of cognition about the disease and its intervention measures. However, a strong demand for the concept of the disease and "how to treat it" was observed. More emphasis on the persistence of the disease and the safety of medications was observed. Young patients have a lower willingness for drug interventions, whereas patients with severe hypertriglyceridemia have a clearer intention to use drug intervention and few patients have a strong willingness for the use of traditional Chinese medicine. CONCLUSIONS: Findings from this disease-specific SML study revealed that patients with hypertriglyceridemia in China actively seek information from both online Q&A search and consultation platforms. However, the integrity of internet doctors' suggestions on lifestyle interventions and the accuracy of drug intervention recommendations still need to be improved. Further, a combined prospective qualitative study with SML is required for added rigor and confirmation of the relevance of the findings.

Bilateral primary orbital xanthogranulomas: A case report and comparison of xanthomatous conditions.

This report describes an unusual and diagnostically challenging case of subcutaneous soft tissue xanthogranulomas of bilateral orbits of a 58-year-old female patient seen in a private oculoplastics practice. Accurate and timely diagnosis is crucial in xanthogranulomatous diseases so that any systemic manifestations can be identified and addressed in a multidisciplinary fashion. Periorbital xanthogranuloma is a frequent early manifestation of adult xanthogranulomatous disease, and its association with life-threatening systemic disease requires accurate diagnosis and prompt work-up. This case describes an otherwise asymptomatic patient who presented with bilateral orbital masses causing visually significant ptosis, initially diagnosed as soft tissue xanthomas, and later identified as xanthogranulomas. It is important for physicians of all fields, from primary care to surgical subspecialty, to be aware that xanthogranulomatous disease may first present as periorbital lesions and/or orbital masses, and that further work-up for vision and life-threatening systemic disease is warranted.

Lipid disorders in children: diagnosis and treatment.

Cardiovascular disease is a leading cause of death in western countries and pediatric lipid disorders create a lifelong continuous risk that starts from childhood. Increased knowledge and awareness on these disorders could prove to be life saving for many patients.

Volanesorsen to treat severe hypertriglyceridaemia: A pooled analysis of randomized controlled trials.

BACKGROUND: Patients with severe hypertriglyceridaemia (sHTG) are often refractory to lipid-lowering therapy. Apolipoprotein (Apo) CIII inhibition could be promising to treat subjects with sHTG. The antisense oligonucleotide against APOC3 mRNA volanesorsen was recently introduced to treat sHTG. We performed a systematic review and meta-analysis of RCTs on the efficacy and safety of volanesorsen as compared to placebo treatment in patients with severe HTG. METHODS: Studies were systematically searched in the PubMed, Web of Science and Scopus databases according to PRISMA guidelines. The last search was performed on 7 February 2022. RESULTS: Four studies showed significant reduction in TG after 3 months of treatment with volanesorsen as compared with placebo (MD: -73.9%; 95%CI: -93.5%, -54.2; p < .001 I2  = 89.05%; p < .001); VLDL-C level (MD: -71.0%; 95%CI: -76.6%, -65.4%; p < .001 I2  = 94.1%; p < .001); Apo-B48 level (MD: -69.03%; 95%CI: -98.59.4%, -39.47%; p < .001, I2  = 93.51%; p < .001) and Apo-CIII level (MD: -80.0%; 95%CI: -97.5%, -62.5; p < .001 I2  = 94.1%; p < .001) with an increase in HDL-C level (MD: +45.92%, 95%CI: +37.24%, +54.60%; p < .001 I2  = 94.34%; p < .001) and in LDL-C level (MD: +68.6%, 95%CI: +7.0%, +130.1%; p < .001 I2  = 96.18%; p < .001) without a significant elevation of Apo-B100 level (MD: +4.58%, 95%CI: -5.64%, +14.79%; p = .380 I2  = 95.09%; p < .001) in 139 volanesorsen patients as compared to 100 placebo-treated controls. Most of adverse events were mild and related to local injection site reactions. CONCLUSIONS: In patients with severe HTG, volanesorsen is associated with a significant reduction in TG, VLDL-C, Apo-B48 and non-HDL-C and increment of HDL-C as compared to placebo. Documented efficacy is accompanied by an acceptable safety profile.

Toxicity of triphenyl phosphate toward the marine rotifer Brachionus plicatilis: Changes in key life-history traits, rotifer-algae population dynamics and the metabolomic response.

Triphenyl phosphate (TPhP) is used as a flame retardant that gradually leaks from products into the marine environment and thus may threaten low-trophic-level marine organisms, such as zooplankton. To assess the effect of TPhP on these taxa, we treated the marine rotifer Brachionus plicatilis as a target and examined the changes in key life history parameters and the metabolome after exposure to TPhP at 0.02, 1 and 5 mg/L. Additionally, the rotifer-Phaeocystis population dynamics (a simulation of the prey-predator relationship) were studied under TPhP stress. Our results showed that TPhP at 1 and 5 mg/L reduced the average lifespan and the total offspring number and prolonged the prereproductive time, suggesting damage to survival and fecundity. In the 0.02 mg/L group, no obvious damage occurred in the overall condition of rotifers, but the volume of parental rotifers after the first brood decreased. This implied that rotifers sacrificed somatic growth to reproduction in the initial period of TPhP exposure at the low concentration. All the tested TPhP concentrations altered the rotifer-Phaeocystis population dynamic changes, especially that 1 mg/L TPhP reduced the ability of rotifers to remove this harmful alga, as evidenced by the decrease in the maximum population density of rotifers and the extended time to P. globosa extinction. At the molecular level, metabolomics identified 84 and 206 differentially expressed metabolites, most of which were enriched in glycerophospholipid metabolism, steroid biosynthesis and sphingolipid metabolism. Nile red staining showed a decrease in neutral lipids in rotifers, further indicating a disorder of lipid metabolism induced by TPhP. Moreover, the balance between ROS production and the defense system was disrupted by TPhP, which contributed to its toxicity. This finding will promote the understanding of the ecological risk and mode of action of TPhP in aquatic environments.

Critical roles of FTO-mediated mRNA m6A demethylation in regulating adipogenesis and lipid metabolism: Implications in lipid metabolic disorders.

The goal this review is to clarify the effects of the fat mass and obesity-associated protein (FTO) in lipid metabolism regulation and related underlying mechanisms through the FTO-mediated demethylation of m6A modification. FTO catalyzes the demethylation of m6A to alter the processing, maturation and translation of the mRNAs of lipid-related genes. FTO overexpression in the liver promotes lipogenesis and lipid droplet (LD) enlargement and suppresses CPT-1-mediated fatty acid oxidation via the SREBP1c pathway, promoting excessive lipid storage and nonalcoholic fatty liver diseases (NAFLD). FTO enhances preadipocyte differentiation through the C/EBPß pathway, and facilitates adipogenesis and fat deposition by altering the alternative splicing of RUNX1T1, the expression of PPARγ and ANGPTL4, and the phosphorylation of PLIN1, whereas it inhibits lipolysis by inhibiting IRX3 expression and the leptin pathway, causing the occurrence and development of obesity. Suppression of the PPARß/δ and AMPK pathways by FTO-mediated m6A demethylation damages lipid utilization in skeletal muscles, leading to the occurrence of diabetic hyperlipidemia. m6A demethylation by FTO inhibits macrophage lipid influx by downregulating PPARγ protein expression and accelerates cholesterol efflux by phosphorylating AMPK, thereby impeding foam cell formation and atherosclerosis development. In summary, FTO-mediated m6A demethylation modulates the expression of lipid-related genes to regulate lipid metabolism and lipid disorder diseases.

Consensus clinical recommendations for the management of plasma lipid disorders in the Middle East: 2021 update.

BACKGROUND AND AIMS: Disorders of plasma lipids remain key risk factors for the development of atherosclerotic cardiovascular disease (ASCVD) in the Middle East and are estimated to increase more dramatically in the next decade than in any other global region except Africa. This statement is an update to the 2016 consensus clinical recommendations for the management of plasma lipid disorders in the Middle East, following the evaluation of newer cholesterol-lowering agents in randomised controlled cardiovascular outcome trials, as well as the publication of revised international guidelines. METHODS: A multidisciplinary panel of regional experts was convened to update the consensus clinical recommendations for the management of plasma lipids in the Middle East. The recommendations constructed in 2016 were reviewed against emerging research since publication. RESULTS: Newly developed Middle East ASCVD risk categories were established using the multiple risk group categories from the recently updated international guidelines and the epidemiological evidence from the Gulf Region. These consensus recommendations support a more intensive reduction of LDL-C across cardiovascular risk categories. Alongside low-density lipoprotein cholesterol, we recommend non-high-density lipoprotein cholesterol as a primary treatment target. Lifestyle modifications remain the first-line treatment recommendation for all patients. The first-line pharmacological treatment in patients with dyslipidaemia is statin therapy, with a number of second-line agents available. The selection of a second lipid-lowering agent for combination therapy with statin should be based on the lipid-lowering target of the patient. Guidance is also provided on the management of underlying conditions and special populations; of particular pertinence in the region are familial hypercholesterolaemia, diabetes and metabolic dyslipidaemia. New therapies have emerged from research that found positive outcomes in reducing low-density lipoprotein cholesterol levels. The initial results of these newly researched drugs strongly indicate their inclusion as future therapies in dyslipidaemia management in the Middle East. CONCLUSIONS: These updated consensus clinical recommendations provide practicing clinicians with comprehensive, region-specific guidance to improve the detection and management of plasma lipid disorders in patients in the Middle East.

Polygenic risk score for hypercholesterolemia in a Brazilian familial hypercholesterolemia cohort.

Background and aims: Familial hypercholesterolemia (FH) is a genetic disorder characterized by high levels of LDL-C leading to premature cardiovascular disease (CAD). Only about 40% of individuals with a clinical diagnosis of FH have a causative genetic variant identified, and a proportion of genetically negative cases may have a polygenic cause rather than a still unidentified monogenic cause. This work aims to evaluate and validate the role of a polygenic risk score (PRS) associated with hypercholesterolemia in a Brazilian FH cohort and its clinical implications. Methods: We analyzed a previously derived PRS of 12 and 6 SNPs (Single Nucleotide Polymorphism) in 684 FH individuals (491 mutation-negative [FH/M-], 193 mutation-positive [FH/M+]) and in 1605 controls. Coronary artery calcium (CAC) score was also evaluated. Results: The PRS was independently associated with LDL-C in control individuals (p < 0.001). Within this group, in individuals in the highest quartile of the 12 SNPs PRS, the odds ratio for CAC score >100 was 1.7 (95% CI: 1.01-2.88, p = 0.04) after adjustment for age and sex. Subjects in the FH/M- group had the highest mean score in both 12 and 6 SNPs PRS (38.25 and 27.82, respectively) when compared to the other two groups (p = 2.2 × 10-16). Both scores were also higher in the FH/M+ group (36.48 and 26.26, respectively) when compared to the control group (p < 0.001 for the two scores) but inferior to the FH/M- group. Within FH individuals, the presence of a higher PRS score was not associated with LDL-C levels or with CAD risk. Conclusion: A higher PRS is associated with significantly higher levels of LDL-C and it is independently associated with higher CAC in the Brazilian general population. A polygenic cause can explain a fraction of FH/M- individuals but does not appear to be a modulator of the clinical phenotype among FH individuals, regardless of mutation status.

The G2A Receptor Deficiency Aggravates Atherosclerosis in Rats by Regulating Macrophages and Lipid Metabolism.

The orphan G protein-coupled receptor G2A has been linked to atherosclerosis development. However, available data from mouse models are controversial. Rat G2A receptor bears more similarities with its human homolog. We proposed that the atherosclerosis model established from Ldlr -/- rat, which has been reported to share more similar phenotypes with the human disease, may help to further understand this lipid receptor. G2A deletion was found markedly aggravated in the lipid disorder in the rat model, which has not been reported in mouse studies. Examination of aortas revealed exacerbated atherosclerotic plaques in G2A deficient rats, together with increased oxidative stress and macrophage accumulation. In addition, consistently promoted migration and apoptosis were noticed in G2A deficient macrophages, even in macrophages from G2A single knockout rats. Further analysis found significantly declined phosphorylation of PI3 kinase (PI3K) and AKT, together with reduced downstream genes Bcl2 and Bcl-xl, suggesting possible involvement of PI3K/AKT pathway in G2A regulation to macrophage apoptosis. These data indicate that G2A modulates atherosclerosis by regulating lipid metabolism and macrophage migration and apoptosis. Our study provides a new understanding of the role of G2A in atherosclerosis, supporting it as a potential therapeutic target.

Exercise improves lipid metabolism disorders induced by high-fat diet in a SESN2/JNK-independent manner.

SESN2 and JNK are emerging powerful stress-inducible proteins in regulating lipid metabolism. The aim of this study was to determine the underlying mechanism of SESN2/JNK signaling in exercise to improve lipid disorder induced by high-fat diet (HFD). Our data showed that HFD and SESN2 knockout resulted in abnormalities including elevated body weight, increased fat mass, serum total cholesterol, lipid biosynthesis related proteins, and a concomitant increase of pJNK-Thr183/Tyr185. The above changes were reversed by exercise training. SESN2 silencing or JNK inhibition in palmitate-treated C2C12 further confirmed that SESN2 and JNK play a vital role in lipid biosynthesis. Rescue experiment further demonstrated that SESN2 reduced lipid biosynthesis through inhibition of JNK. SESN2/JNK signaling axis regulates lipid biosynthesis in both animal and cell models with abnormalities of lipid metabolism induced by HFD or palmitate treatment. This study provided evidence that exercise ameliorated lipid metabolic disorder induced by HFD feeding or by SESN2 knockout. SESN2 may improve lipid metabolism through inhibition JNK expression in skeletal muscle cells, providing a molecular mechanism that may represent an attractive target for the treatment of lipid disorder. Novelty: Exercise improved lipid disorder induced by HFD feeding and SESN2 knockout. SESN2 and JNK play a vital role in lipid biosynthesis in vivo and in vitro. SESN2 suppressed JNK to improve lipid metabolism in skeletal muscle cells.

Thermodynamics and structure of model bio-membrane of liver lipids in presence of imidazolium-based ionic liquids.

Ionic liquids (ILs) are the attractions of researchers today due to their vast area of potential applications. For biomedical uses, it becomes essential to understand their interactions with cellular membrane. Here, the membrane is mimicked with lipid bilayer and monolayer composed of liver lipids extract. Three archetypal imidazolium based ILs, 1-decyl-3-methylimidazolium tetrafluoroborate ([DMIM][BF4] or [C10MIM][BF4]), 1-octyl-3-methylimidazolium tetrafluoroborate, ([OMIM][BF4] or [C8MIM][BF4]) and 1-ethyl-3-methylimidazolium tetrafluoroborate ([EMIM][BF4] or [C2MIM][BF4]) having different alkyl chain lengths are used in the present study. The isothermal titration calorimetry (ITC) measurements showed that [DMIM][BF4] interacts strongest with the liver lipid membrane compared to other two ILs which have relatively shorter alkyl chain length. The low values of stoichiometry ratio of ILs indicates that ILs penetrate within the core of the lipid bilayer. The interaction of ILs with the liver lipid membrane is found to be mainly driven by entropy which could be due to the change in the structure of the lipid membrane at local or global scales. Dynamic light scattering (DLS) measurements indicate that there are no changes in the size of vesicles due to addition of [DMIM][BF4] indicating stability of the vesicles. On the other hand, x-ray reflectivity (XRR) measurements showed a concentration dependent change in the monolayer structure. At low concentration of the IL, the monolayer thickness decreases, exhibiting an increase in the electron density of the layer. However, at higher concentrations, the monolayer thickness increases proving a concentration dependent effects of the IL on the arrangement of the molecules.

Using Machine Learning to Evaluate the Role of Microinflammation in Cardiovascular Events in Patients With Chronic Kidney Disease.

Background: Lipid metabolism disorder, as one major complication in patients with chronic kidney disease (CKD), is tied to an increased risk for cardiovascular disease (CVD). Traditional lipid-lowering statins have been found to have limited benefit for the final CVD outcome of CKD patients. Therefore, the purpose of this study was to investigate the effect of microinflammation on CVD in statin-treated CKD patients. Methods: We retrospectively analysed statin-treated CKD patients from January 2013 to September 2020. Machine learning algorithms were employed to develop models of low-density lipoprotein (LDL) levels and CVD indices. A fivefold cross-validation method was employed against the problem of overfitting. The accuracy and area under the receiver operating characteristic (ROC) curve (AUC) were acquired for evaluation. The Gini impurity index of the predictors for the random forest (RF) model was ranked to perform an analysis of importance. Results: The RF algorithm performed best for both the LDL and CVD models, with accuracies of 82.27% and 74.15%, respectively, and is therefore the most suitable method for clinical data processing. The Gini impurity ranking of the LDL model revealed that hypersensitive C-reactive protein (hs-CRP) was highly relevant, whereas statin use and sex had the least important effects on the outcomes of both the LDL and CVD models. hs-CRP was the strongest predictor of CVD events. Conclusion: Microinflammation is closely associated with potential CVD events in CKD patients, suggesting that therapeutic strategies against microinflammation should be implemented to prevent CVD events in CKD patients treated by statin.

Astragalus Flavone Ameliorates Atherosclerosis and Hepatic Steatosis Via Inhibiting Lipid-Disorder and Inflammation in apoE-/- Mice.

Atherosclerosis is a major pathogenic driver of cardiovascular diseases. Foam cell formation plays a key role in atherogenesis, which is affected by lipid disorder and inflammation. Therefore, inhibition of foam cell formation is a therapeutic approach for atherosclerosis treatment. Total flavone of Astragalus membranaceus (TFA) is extracted from A. membranaceus that has protective effect on cardiovascular disease. However, the effect of TFA on atherosclerosis and the underlying mechanism remains unknown. In this study, we determined whether TFA could inhibit atherosclerosis and uncovered the underlying mechanism. In vivo, ApoE deficient mice were treated with TFA and high-fat diet for 16 weeks. Subsequently, atherosclerotic lesions, hepatic steatosis and associated genes expression in vitro and in vivo were determined. We found that TFA reduced atherosclerotic lesion size and enhanced plaque stability, which might be attributed to improved lipid disorder, reduced inflammation and decreased monocyte adhesion. Mechanistically, TFA inhibited hepatic steatosis via regulating the genes responsible for lipid metabolism, by which ameliorating the lipid disorder. Moreover, in macrophage, TFA reduced the expression of scavenger receptors such as CD36 and SRA; and promoted the expression of ATP-binding cassette transporter A1 and G1 (ABCA1/G1). More importantly, TFA reduced miR-33 expression and dampened NFκB activity, by which de-repressing ABCA1/G1 activity and inhibiting the inflammation. Collectively, TFA can attenuate atherosclerosis via dual suppression of miR-33 and NFκB pathway, and partially through inhibition of scavenger receptors in macrophage. In addition, TFA ameliorates the hepatic steatosis and lipid disorder, which in turn contributes to the amelioration of atherosclerosis, suggesting that TFA might be a novel therapeutic approach for inhibition of atherosclerosis and hepatic steatosis.

Familial hypercholesterolemia: The skin speaks.

Familial hypercholesterolaemia (FH) is an autosomal dominant inherited disorder of lipoprotein metabolism caused by defects in the low-density lipoprotein receptor (LDLR) gene. It is characterized by high low-density lipoprotein (LDL) cholesterol levels, premature cardiovascular disease (CVD), and tendon xanthomas. We present the case of a 26-year-old gentleman who presented with multiple nodular eruptions over the extensor aspects of upper and lower limbs and was diagnosed as FH on the basis of positive family history, typical lipid profile abnormalities, and biopsy of the nodule consistent with tendon xanthomas. The diagnosis and management of this case is deftly feasible at the primary care level.

Determination of globotriaosylceramide analogs in the organs of a mouse model of Fabry disease.

Fabry disease is a heritable lipid disorder caused by the low activity of α-galactosidase A and characterized by the systemic accumulation of globotriaosylceramide (Gb3). Recent studies have reported a structural heterogeneity of Gb3 in Fabry disease, including Gb3 isoforms with different fatty acids and Gb3 analogs with modifications on the sphingosine moiety. However, Gb3 assays are often performed only on the selected Gb3 isoforms. To precisely determine the total Gb3 concentration, here we established two methods for determining both Gb3 isoforms and analogs. One was the deacylation method, involving Gb3 treatment with sphingolipid ceramide N-deacylase, followed by an assay of the deacylated products, globotriaosylsphingosine (lyso-Gb3) and its analogs, by ultra-performance LC coupled to tandem MS (UPLC-MS/MS). The other method was a direct assay established in the present study for 37 Gb3 isoforms and analogs/isoforms by UPLC-MS/MS. Gb3s from the organs of symptomatic animals of a Fabry disease mouse model were mainly Gb3 isoforms and two Gb3 analogs, such as Gb3(+18) containing the lyso-Gb3(+18) moiety and Gb3(-2) containing the lyso-Gb3(-2) moiety. The total concentrations and Gb3 analog distributions determined by the two methods were comparable. Gb3(+18) levels were high in the kidneys (24% of total Gb3) and the liver (13%), and we observed Gb3(-2) in the heart (10%) and the kidneys (5%). These results indicate organ-specific expression of Gb3 analogs, insights that may lead to a deeper understanding of the pathophysiology of Fabry disease.

Investigating high blood pressure, type-2 diabetes, dislipidemia, and body mass index to determine the health status of people over 30 years.

INTRODUCTION: Over the past decades, the pattern of diseases in human societies had changed from infectious diseases to noncommunicable diseases (NCDs), and according to the report by the World Health Organization, the highest burden of disease is attributed to NCDs. The study was conducted to determine the status of hypertension, type-2 diabetes, lipid disorders, and body mass index (BMI) among the patients aged over 30 years admitted to health centers of Karaj, Iran. MATERIALS AND METHODS: In this cross-sectional study, the population included 2947 men and women aged 30 years and above admitted to six health-care centers in Karaj. The questionnaire includes demographic characteristics and had the questions on hypertension, diabetes and their risk factors, like lipid disorders and BMI was administered. The data were analyzed in SPSS, version 23, software using descriptive (frequency, percentage, mean, and standard deviation) and analytical (Chi-square and analysis of variance) tests (P < 0.01). RESULTS: About 10% of the participants had diabetes and 15% of the participants had hypertension. About 32% of the participants had dyslipidemia and 87% of the participants were overweight or obese and over 35% were obese. Furthermore, with the increase in BMI, the prevalence of lipid disorder, hypertension, and type-2 diabetes increased in the studied population (P < 0.01). CONCLUSION: According to the results, a high percentage of people had hypertension, type-2 diabetes, hyperlipidemia, and BMI in the population. Gender segregation showed that lipid disorders, overweight, and obesity in women were more than in men and percentage of people with hypertension among male were significantly higher than in females. In the case of type-2 diabetes, the results showed no statistically significant differences between men and women. The results may be helpful in developing educational strategies and prevention and control of these diseases.

The Role of Genetics in Cardiovascular Risk Reduction: Findings From a Single Lipid Clinic and Review of the Literature.

BACKGROUND: Genetic information is not routinely obtained in the management of most lipid disorders or in primary or secondary prevention of cardiovascular disease (CVD). We sought to determine the prevalence of pathogenic variants associated with lipoprotein metabolism or coronary artery disease (CAD) in a single lipid clinic and discuss the future use of genetic information in CVD prevention. METHODS: Genetic testing was offered to patients with hypertriglyceridemia (defined as pre-treatment fasting triglycerides ≥150 mg/dL), elevated LDL-C (defined as pre-treatment ≥190 mg/dL), low HDL-C (defined as ≤40 mg/dL), elevated lipoprotein (a) (defined as ≥50 mg/dL or 100 nmol/L) or premature CAD (defined as an acute coronary syndrome or revascularization before age 40 years in men and 50 years in women) using next-generation DNA sequencing of 327 exons and selected variants in 129 genes known or suspected to be associated with lipoprotein metabolism or CAD. RESULTS: 82 of 84 patients (97.6%) were found to have a variant associated with abnormal lipid metabolism or CAD. The most common pathogenic or likely pathogenic variants included those of the LDL receptor (15 patients) and lipoprotein lipase (9 patients). Other common variants included those of apolipoprotein A5 (14 patients) and variants associated with elevated lipoprotein (a) (25 patients). CONCLUSIONS: The majority of patients presenting to a single lipid clinic were found to have at least one variant associated with abnormal lipoprotein metabolism or CAD. Incorporating genetic information, including the use of genetic risk scores, is anticipated in the future care of lipid disorders and CVD prevention.