Macrophage Cholesterol Efflux Downregulation Is Not Associated with Abdominal Aortic Aneurysm (AAA) Progression

Recent studies have raised the possibility of a role for lipoproteins, including high-density lipoprotein cholesterol (HDLc), in abdominal aortic aneurysm (AAA). The study was conducted in plasmas from 39 large size AAA patients (aortic diameter > 50 mm), 81 small/medium size AAA patients (aortic diameter between 30 and 50 mm) and 38 control subjects (aortic diameter 5 mm per year) in patients with small/medium size AAA. Moreover, no correlation was found between MCE capacity and the aneurysm growth rate. A multivariate Cox regression analysis revealed a significant association between lower MCE capacity with the need for surgery in all AAA patients. Nevertheless, the significance was lost when only small/medium size AAA patients were included. Our results suggest that MCE, a major HDL functional activity, is not involved in AAA progression

Divergent Effects of Glycemic Control and Bariatric Surgery on Circulating Concentrations of TMAO in Newly Diagnosed T2D Patients and Morbidly Obese

High circulating concentrations of the gut microbiota-derived metabolite trimethylamine N-oxide (TMAO) are significantly associated with the risk of obesity and type 2 diabetes (T2D). We aimed at evaluating the impact of glycemic control and bariatric surgery on circulating concentrations of TMAO and its microbiota-dependent intermediate, γ-butyrobetaine (γBB), in newly diagnosed T2D patients and morbidly obese subjects following a within-subject design. Based on HbA1c concentrations, T2D patients achieved glycemic control. However, the plasma TMAO and γBB concentrations were significantly increased, without changes in estimated glomerular filtration rate. Bariatric surgery was very effective in reducing weight in obese subjects. Nevertheless, the surgery reduced plasma γBB concentrations without affecting TMAO concentrations and the estimated glomerular filtration rate. Considering these results, an additional experiment was carried out in male C57BL/6J mice fed a Western-type diet for twelve weeks. Neither diet-induced obesity nor insulin resistance were associated with circulating TMAO and γBB concentrations in these genetically defined mice strains. Our findings do not support that glycemic control or bariatric surgery improve the circulating concentrations of TMAO in newly diagnosed T2D and morbidly obese patients

TMAO and Gut Microbial-Derived Metabolites TML and γBB Are Not Associated with Thrombotic Risk in Patients with Venous Thromboembolism

Background: The present work evaluates the association between circulating concentrations of Trimethylamine-N-oxide (TMAO), gamma butyrobetaine (γBB), and trimetyllisine (TML) in controls and patients with venous thromboembolism (VTE) with coagulation parameters. Methods: The study involved 54 VTE patients and 57 controls. Platelet function, platelet hyperreactivity, platelet adhesiveness, thrombosis-associated parameters, and thrombin generation parameters were studied. Plasma TMAO, γBB, and TML determination was performed using an ultra-high-performance liquid chromatography system coupled with mass spectrometry. Results: No differences were found for TMAO, γBB, or TML concentrations between controls and VTE patients. In thrombin generation tests, TMAO, γBB, and TML showed a positive correlation with lag time and time to peak. TMAO, γBB, and TML negatively correlated with peak height. No significant differences were observed regarding TMAO, γBB, and TML concentrations between the two blood withdrawals, nor when the control and VTE patients were analyzed separately. No correlation was observed between these gut metabolites and platelet function parameters. Conclusions: No differences were found regarding TMAO, γBB, and TML concentrations between the control and VTE groups. Some correlations were found; however, they were mild or went in the opposite direction of what would be expected if TMAO and its derivatives were related to VTE risk

Therapeutic potential of emerging NAD+-increasing strategies for cardiovascular diseases

Altres ajuts: Fundació La Marató de TV3 (303/C/2016)(201602.30.31)Cardiovascular diseases are the leading cause of death worldwide. Aging and/or metabolic stress directly impact the cardiovascular system. Over the last few years, the contributions of altered nicotinamide adenine dinucleotide (NAD+) metabolism to aging and other pathological conditions closely related to cardiovascular diseases have been intensively investigated. NAD+ bioavailability decreases with age and cardiometabolic conditions in several mammalian tissues. Compelling data suggest that declining tissue NAD+ is commonly related to mitochondrial dysfunction and might be considered as a therapeutic target. Thus, NAD+ replenishment by either genetic or natural dietary NAD+-increasing strategies has been recently demonstrated to be effective for improving the pathophysiology of cardiac and vascular health in different experimental models, as well as human health, to a lesser extent. Here, we review and discuss recent experimental evidence illustrating that increasing NAD+ bioavailability, particularly by the use of natural NAD+ precursors, may offer hope for new therapeutic strategies to prevent and treat cardiovascular diseases

The capacity of apob-depleted plasma in inducing atp-binding cassette a1/g1-mediated macrophage cholesterol efflux-but not gut microbial-derived metabolites-is independently associated with mortality in patients with st-segment elevation myocardial infarction

Altres ajuts: Fundació per a la Bioquímica Clínica i Patologia MolecularImpaired HDL-mediated macrophage cholesterol efflux and higher circulating concentrations of trimethylamine N-oxide (TMAO) levels are independent risk factors for cardiovascular mortality. The TMAO precursors, γ-butyrobetaine (γBB) and Trimethyllysine (TML), have also been recently associated with cardiovascular death, but their interactions with HDL-mediated cholesterol efflux remain unclear. We aimed to determine the associations between APOB depleted plasma-mediated macrophage cholesterol efflux and plasma TMAO, γBB, and TML concentrations and explore their association with two-year follow-up mortality in patients with acute ST-elevation myocardial infarction (STEMI) and unstable angina (UA). Baseline and ATP-binding cassette transporter ABCA1 and ABCG1 (ABCA1/G1)-mediated macrophage cholesterol efflux to APOB-depleted plasma was decreased in patients with STEMI, and the latter was further impaired in those who died during follow-up. Moreover, the circulating concentrations of TMAO, γBB, and TML were higher in the deceased STEMI patients when compared with the STEMI survivors or UA patients. However, after statistical adjustment, only ABCA1/G1-mediated macrophage cholesterol efflux remained significantly associated with mortality. Furthermore, neither the TMAO, γBB, nor TML levels altered the HDL-mediated macrophage cholesterol efflux in vitro. We conclude that impaired ABCA1/G1-mediated macrophage cholesterol efflux is independently associated with mortality at follow-up in STEMI patients

Increasing breast milk betaine modulates Akkermansia abundance in mammalian neonates and improves long-term metabolic health

Accelerated postnatal growth is a potentially modifiable risk factor for future obesity. To study how specific breast milk components contribute to early growth and obesity risk, we quantified one-carbon metabolism-related metabolites in human breast milk and found an inverse association between milk betaine content and infant growth. This association was replicated in an independent and geographically distinct cohort. To determine the potential role of milk betaine in modulating offspring obesity risk, we performed maternal betaine supplementation experiments in mice. Higher betaine intake during lactation increased milk betaine content in dams and led to lower adiposity and improved glucose homeostasis throughout adulthood in mouse offspring. These effects were accompanied by a transient increase in Akkermansia spp. abundance in the gut during early life and a long-lasting increase in intestinal goblet cell number. The link between breast milk betaine and Akkermansia abundance in the gut was also observed in humans, as infants exposed to higher milk betaine content during breastfeeding showed higher fecal Akkermansia muciniphila abundance. Furthermore, administration of A. muciniphila to mouse pups during the lactation period partially replicated the effects of maternal breast milk betaine, including increased intestinal goblet cell number, lower adiposity, and improved glucose homeostasis during adulthood. These data demonstrate a link between breast milk betaine content and long-term metabolic health of offspring.info:eu-repo/semantics/acceptedVersio

Estudi de l’estat de seleni en sang i en líquid cefaloraquidi de pacients pediàtrics amb malalties neurològiques

[cat] L’objectiu principal d’aquesta tesis doctoral ha estat estudiar l’estat del Se en sang i LCR de pacients amb errors congènits del metabolisme amb tractament dietètic i altres trastorns neuropediàtrics de diferent etiologia. En el primer treball ens plantejàvem l’establiment de valors de referència per a determinats elements traça en sang total. La necessitat venia de la inexistència d’estudis sobre l’estat d’aquests elements en poblacions pediàtriques afectades de diferents errors congènits del metabolisme. En el segon treball ens plantejàvem l’establiment de valors de referència per a seleni en LCR. La necessitat venia de la inexistència d’estudis sobre l’estat d’aquest element en poblacions pediàtriques i de la possible associació entre una alteració de l’estat de Seleni i algunes disfuncions neurològiques. Un cop establerts els valors de referència de Se en LCR, el tercer treball consistia en valorar l’estat de Se en pacients amb malalties neurològiques per intentar detectar alguna deficiència o excés de Se en els líquids d’aquests pacients. A part de valorar l’estat de Se, preteníem valorar també altres paràmetres bioquímiques com HVA, 5-MTHF, 5-HIAA, proteïnes, activitat de GPx i pterines, per tal de veure si les correlacions observades en l’anterior treball es mantenien. Finalment, l’últim treball es centrava en l’estudi d’un grup de pacients amb uns valors de Se en LCR permanentment elevats sense tenir-ne una explicació clara. Aquests pacients (que s’havien identificat en el tercer treball) estaven afectats de la síndrome de Kearns-Sayre (malaltia mitocondrial que es manifesta per deleció del DNA mitocondrial). En aquest nou treball ens plantejàvem l’estudi d’uns paràmetres bioquímics que ens permetessin detectar la disfunció del plexe coroïdal en pacients afectats d’aquesta síndrome. Així doncs i a títol de discussió, una de les nostres principals necessitats pel control regular dels pacients amb malalties metabòliques i tractament dietètic era la monitorització de diferents elements traça en diferents fluids biològics. Tradicionalment s’havia descrit deficiències d’alguns d’aquests elements en pacients que tenen com a base del seu tractament les dietes restrictives. De tots els elements, el Se semblava un candidat ideal, ja que prèviament s’havien descrit deficiències en algunes malalties, com la fenilcetonúria.La importància del Se radica en que és un element essencial per al correcte funcionament de les selenoproteïnes. Per tant, ens semblava d’interès monitoritzar les concentracions de Se tant en sang (com a marcador de dèficit nutricional) com en LCR (com a marcador potencial de mecanismes fisiopatològics en malalties d’àmbit neuropediàtric). Les fites més importants del nostre treball han estat tres: 1. L’estandardització del procediment en sang ha permès establir la tècnica de forma rutinària per al control de trastorns nutricionals al nostre centre. Des d’un punt de vista científic, la conclusió més important és que el dèficit de seleni és comú a les malalties metabòliques amb tractament dietètic i que per tant el seu estudi i suplementació són necessàries per a l’òptim control de les malalties. 2. Respecte a l’estudi del seleni a nivell central, les aportacions han estat més rellevants ja que era un camp poc estudiat. Hem establert per primera vegada valors normals de Se en LCR per a una població pediàtrica i confirmat que el cervell es un òrgan que regula mot bé l’homeòstasi d’aquest element traça, ja que els valors eren independents dels observats en sang. 3. Especialment rellevant creiem que és el perfil que ens va permetre valorar la funció del plexe coroïdal en la síndrome de KSS i el diagnòstic directe d’un cas. Aquest resultats no tan sols tenen un valor per a la pràctica diagnòstica, sinó que obren la porta a la investigació d’altres malalties en les que s’afecta el plexe coroïdal.||PhD STUDENT NAME Mireia Tondo Colomer TESIS TITLE Blood and cerebrospinal fluid selenium status in paediatric patients affected with neurological diseases. SUMMARY Our objective was to study blood and CSF Se status in patients with IEM with dietary treatment and other neurological disorders with different clinical aetiology. In this first study our objective was the establishment of reference values for some trace elements in whole blood. At that time, studies of several trace element status for a paediatric population with different inborn errors of metabolism were scarce. To achieve this aim, we used an Induced Couple Plasma Mass Spectrometer (ICP-MS), which allowed multiple analyses of different trace elements using a small sample volume. Leftover samples form patients who came to our hospital for minor surgery were used as reference population. In this second study our objective was the establishment of cerebrospinal fluid selenium reference values. At that time, no previous studies of Se central nervous system status for a paediatric population existed in the scientific literature. CSF Se concentrations had to be considered in order to find out any possible association between Se status and some neurological functions. Moreover, the implications of Se in the synthesis and function of more than 20 selenoproteins indicated that central nervous system Se status was important. After the establishment of CSF Se reference values for a paediatric population, the next step was to evaluate Se CSF concentrations in paediatric patients with different neurological disorders. Previous studies demonstrated the tight regulation of Se homeostasis in brain as well as the evidence of the role of Se in CNS disorder pathophysiology. In spite of growing evidence of the role of Se in CNS, no studies of Se CNS status in a large cohort of paediatric patients affected with different neurological disorders had been carried out. Finally, our last study derived from the one before which allowed us to identify a group of patients with clearly high CSF Se values. The main common feature was that all patients had a mitochondrial DNA deletion syndrome (Kearns Sayre Syndrome). This group of patients was not included in the previous work and was treated separately.PhD STUDENT NAME Mireia Tondo Colomer TESIS TITLE Blood and cerebrospinal fluid selenium status in paediatric patients affected with neurological diseases. SUMMARY Our objective was to study blood and CSF Se status in patients with IEM with dietary treatment and other neurological disorders with different clinical aetiology. In this first study our objective was the establishment of reference values for some trace elements in whole blood. At that time, studies of several trace element status for a paediatric population with different inborn errors of metabolism were scarce. To achieve this aim, we used an Induced Couple Plasma Mass Spectrometer (ICP-MS), which allowed multiple analyses of different trace elements using a small sample volume. Leftover samples form patients who came to our hospital for minor surgery were used as reference population. In this second study our objective was the establishment of cerebrospinal fluid selenium reference values. At that time, no previous studies of Se central nervous system status for a paediatric population existed in the scientific literature. CSF Se concentrations had to be considered in order to find out any possible association between Se status and some neurological functions. Moreover, the implications of Se in the synthesis and function of more than 20 selenoproteins indicated that central nervous system Se status was important. After the establishment of CSF Se reference values for a paediatric population, the next step was to evaluate Se CSF concentrations in paediatric patients with different neurological disorders. Previous studies demonstrated the tight regulation of Se homeostasis in brain as well as the evidence of the role of Se in CNS disorder pathophysiology. In spite of growing evidence of the role of Se in CNS, no studies of Se CNS status in a large cohort of paediatric patients affected with different neurological disorders had been carried out. Finally, our last study derived from the one before which allowed us to identify a group of patients with clearly high CSF Se values. The main common feature was that all patients had a mitochondrial DNA deletion syndrome (Kearns Sayre Syndrome). This group of patients was not included in the previous work and was treated separately

Gut Microbiota-Derived TMAO: A Causal Factor Promoting Atherosclerotic Cardiovascular Disease?

Trimethylamine-N-oxide (TMAO) is the main diet-induced metabolite produced by the gut microbiota, and it is mainly eliminated through renal excretion. TMAO has been correlated with an increased risk of atherosclerotic cardiovascular disease (ASCVD) and related complications, such as cardiovascular mortality or major adverse cardiovascular events (MACE). Meta-analyses have postulated that high circulating TMAO levels are associated with an increased risk of cardiovascular events and all-cause mortality, but the link between TMAO and CVD remains not fully consistent. The results of prospective studies vary depending on the target population and the outcome studied, and the adjustment for renal function tends to decrease or reverse the significant association between TMAO and the outcome studied, strongly suggesting that the association is substantially mediated by renal function. Importantly, one Mendelian randomization study did not find a significant association between genetically predicted higher TMAO levels and cardiometabolic disease, but another found a positive causal relationship between TMAO levels and systolic blood pressure, which—at least in part—could explain the link with renal function. The mechanisms by which TMAO can increase this risk are not clearly elucidated, but current evidence indicates that TMAO induces cholesterol metabolism alterations, inflammation, endothelial dysfunction, and platelet activation. Overall, there is no fully conclusive evidence that TMAO is a causal factor of ASCVD, and, especially, whether TMAO induces or just is a marker of hypertension and renal dysfunction requires further study

Trimethylamine N -Oxide : A Link among Diet, Gut Microbiota, Gene Regulation of Liver and Intestine Cholesterol Homeostasis and HDL Function

Altres ajuts: grant 12/C/2015 from La Fundació la Marató TV3 (to F.B.-V.).Recent evidence, including massive gene-expression analysis and a wide-variety of other multi-omics approaches, demonstrates an interplay between gut microbiota and the regulation of plasma lipids. Gut microbial metabolism of choline and -carnitine results in the formation of trimethylamine (TMA) and concomitant conversion into trimethylamine- N -oxide (TMAO) by liver flavin monooxygenase 3 (FMO3). The plasma level of TMAO is determined by the genetic variation, diet and composition of gut microbiota. Multiple studies have demonstrated an association between TMAO plasma levels and the risk of atherothrombotic cardiovascular disease (CVD). We aimed to review the molecular pathways by which TMAO production and FMO3 exert their proatherogenic effects. TMAO may promote foam cell formation by upregulating macrophage scavenger receptors, deregulating enterohepatic cholesterol and bile acid metabolism and impairing macrophage reverse cholesterol transport (RCT). Furthermore, FMO3 may promote dyslipidemia by regulating multiple genes involved in hepatic lipogenesis and gluconeogenesis. FMO3 also impairs multiple aspects of cholesterol homeostasis, including transintestinal cholesterol export and macrophage-specific RCT. At least part of these FMO3-mediated effects on lipid metabolism and atherogenesis seem to be independent of the TMA/TMAO formation. Overall, these findings have the potential to open a new era for the therapeutic manipulation of the gut microbiota to improve CVD risk

HDL-like-Mediated Cell Cholesterol Trafficking in the Central Nervous System and Alzheimer's Disease Pathogenesis

Altres ajuts: Ministerio de Universidades FPU20/07440The main aim of this work is to review the mechanisms via which high-density lipoprotein (HDL)-mediated cholesterol trafficking through the central nervous system (CNS) occurs in the context of Alzheimer's disease (AD). Alzheimer's disease is characterized by the accumulation of extracellular amyloid beta (Aβ) and abnormally hyperphosphorylated intracellular tau filaments in neurons. Cholesterol metabolism has been extensively implicated in the pathogenesis of AD through biological, epidemiological, and genetic studies, with the APOE gene being the most reproducible genetic risk factor for the development of AD. This manuscript explores how HDL-mediated cholesterol is transported in the CNS, with a special emphasis on its relationship to Aβ peptide accumulation and apolipoprotein E (ApoE)-mediated cholesterol transport. Indeed, we reviewed all existing works exploring HDL-like-mediated cholesterol efflux and cholesterol uptake in the context of AD pathogenesis. Existing data seem to point in the direction of decreased cholesterol efflux and the impaired entry of cholesterol into neurons among patients with AD, which could be related to impaired Aβ clearance and tau protein accumulation. However, most of the reviewed studies have been performed in cells that are not physiologically relevant for CNS pathology, representing a major flaw in this field. The ApoE4 genotype seems to be a disruptive element in HDL-like-mediated cholesterol transport through the brain. Overall, further investigations are needed to clarify the role of cholesterol trafficking in AD pathogenesis