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1.
ESC Heart Fail ; 8(5): 3643-3655, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34342166

RESUMO

There is an urgent need for models that faithfully replicate heart failure with preserved ejection fraction (HFpEF), now recognized as the most common form of heart failure in the world. In vitro approaches have several shortcomings, most notably the immature nature of stem cell-derived human cardiomyocytes [induced pluripotent stem cells (iPSC)] and the relatively short lifespan of primary cardiomyocytes. Three-dimensional 'organoids' incorporating mature iPSCs with other cell types such as endothelial cells and fibroblasts are a significant advance, but lack the complexity of true myocardium. Animal models can replicate many features of human HFpEF, and rodent models are the most common, and recent attempts to incorporate haemodynamic, metabolic, and ageing contributions are encouraging. Differences relating to species, physiology, heart rate, and heart size are major limitations for rodent models. Porcine models mitigate many of these shortcomings and approximate human physiology more closely, but cost and time considerations limit their potential for widespread use. Ex vivo analysis of failing hearts from animal models offer intriguing possibilities regarding cardiac substrate utilisation, but are ultimately subject to the same constrains as the animal models from which the hearts are obtained. Ex vivo approaches using human myocardial biopsies can uncover new insights into pathobiology leveraging myocardial energetics, substrate turnover, molecular changes, and systolic/diastolic function. In collaboration with a skilled cardiothoracic surgeon, left ventricular endomyocardial biopsies can be obtained at the time of valvular surgery in HFpEF patients. Critically, these tissues maintain their disease phenotype, preserving inter-relationship of myocardial cells and extracellular matrix. This review highlights a novel approach, where ultra-thin myocardial tissue slices from human HFpEF hearts can be used to assess changes in myocardial structure and function. We discuss current approaches to modelling HFpEF, describe in detail the novel tissue slice model, expand on exciting opportunities this model provides, and outline ways to improve this model further.

2.
Nat Commun ; 12(1): 4992, 2021 08 17.
Artigo em Inglês | MEDLINE | ID: mdl-34404777

RESUMO

Liquid chromatography-mass spectrometry-based metabolomics studies are increasingly applied to large population cohorts, which run for several weeks or even years in data acquisition. This inevitably introduces unwanted intra- and inter-batch variations over time that can overshadow true biological signals and thus hinder potential biological discoveries. To date, normalisation approaches have struggled to mitigate the variability introduced by technical factors whilst preserving biological variance, especially for protracted acquisitions. Here, we propose a study design framework with an arrangement for embedding biological sample replicates to quantify variance within and between batches and a workflow that uses these replicates to remove unwanted variation in a hierarchical manner (hRUV). We use this design to produce a dataset of more than 1000 human plasma samples run over an extended period of time. We demonstrate significant improvement of hRUV over existing methods in preserving biological signals whilst removing unwanted variation for large scale metabolomics studies. Our tools not only provide a strategy for large scale data normalisation, but also provides guidance on the design strategy for large omics studies.


Assuntos
Metabolômica/métodos , Cromatografia Líquida , Humanos , Espectrometria de Massas/métodos , Modelos Biológicos , Fluxo de Trabalho
3.
Commun Biol ; 4(1): 826, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-34211098

RESUMO

Genome-wide association studies have identified SLC16A13 as a novel susceptibility gene for type 2 diabetes. The SLC16A13 gene encodes SLC16A13/MCT13, a member of the solute carrier 16 family of monocarboxylate transporters. Despite its potential importance to diabetes development, the physiological function of SLC16A13 is unknown. Here, we validate Slc16a13 as a lactate transporter expressed at the plasma membrane and report on the effect of Slc16a13 deletion in a mouse model. We show that Slc16a13 increases mitochondrial respiration in the liver, leading to reduced hepatic lipid accumulation and increased hepatic insulin sensitivity in high-fat diet fed Slc16a13 knockout mice. We propose a mechanism for improved hepatic insulin sensitivity in the context of Slc16a13 deficiency in which reduced intrahepatocellular lactate availability drives increased AMPK activation and increased mitochondrial respiration, while reducing hepatic lipid content. Slc16a13 deficiency thereby attenuates hepatic diacylglycerol-PKCε mediated insulin resistance in obese mice. Together, these data suggest that SLC16A13 is a potential target for the treatment of type 2 diabetes and non-alcoholic fatty liver disease.


Assuntos
Diabetes Mellitus Tipo 2/genética , Predisposição Genética para Doença/genética , Resistência à Insulina/genética , Metabolismo dos Lipídeos/genética , Transportadores de Ácidos Monocarboxílicos/genética , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Diabetes Mellitus Tipo 2/metabolismo , Dieta Hiperlipídica/efeitos adversos , Expressão Gênica , Humanos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mitocôndrias/metabolismo , Transportadores de Ácidos Monocarboxílicos/deficiência , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/metabolismo , Obesidade/etiologia , Obesidade/genética , Obesidade/metabolismo , Consumo de Oxigênio/genética
5.
Nat Metab ; 3(6): 810-828, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34099926

RESUMO

Reduced protein intake, through dilution with carbohydrate, extends lifespan and improves mid-life metabolic health in animal models. However, with transition to industrialised food systems, reduced dietary protein is associated with poor health outcomes in humans. Here we systematically interrogate the impact of carbohydrate quality in diets with varying carbohydrate and protein content. Studying 700 male mice on 33 isocaloric diets, we find that the type of carbohydrate and its digestibility profoundly shape the behavioural and physiological responses to protein dilution, modulate nutrient processing in the liver and alter the gut microbiota. Low (10%)-protein, high (70%)-carbohydrate diets promote the healthiest metabolic outcomes when carbohydrate comprises resistant starch (RS), yet the worst outcomes were with a 50:50 mixture of monosaccharides fructose and glucose. Our findings could explain the disparity between healthy, high-carbohydrate diets and the obesogenic impact of protein dilution by glucose-fructose mixtures associated with highly processed diets.


Assuntos
Dieta , Carboidratos da Dieta/metabolismo , Proteínas na Dieta/metabolismo , Metabolismo Energético , Homeostase , Animais , Glucose/metabolismo , Nível de Saúde , Masculino , Camundongos , Obesidade/etiologia , Obesidade/metabolismo , Amido/metabolismo
6.
BMC Med Educ ; 21(1): 332, 2021 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-34103030

RESUMO

BACKGROUND: Teaching is an important professional skill for physicians and providing feedback is an important part of teaching. Medical students can practice their feedback skills by giving each other peer feedback. Therefore, we developed a peer feedback training in which students observed a peer that modelled the use of good feedback principles. Students then elaborated on the modelled feedback principles through peer discussion. This combination of peer modelling and discussing the modelled feedback principles was expected to enhance emulation of the feedback principles compared to (1) only peer modelling and (2) discussing the feedback principles without previous modelling. METHODS: In a quasi-experimental study design, 141 medical students were assigned randomly to three training conditions: peer modelling plus discussion (MD), non-peer modelled example (NM) or peer modelling without discussion (M). Before and after the training, they commented on papers written by peers. These comments served as a pre- and a post-measure of peer feedback. The comments were coded into different functions and aspects of the peer feedback. Non-parametrical Kruskall-Wallis tests were used to check for pre- and post-measure between-group differences in the functions and aspects. RESULTS: Before the training, there were no significant between-group differences in feedback functions and aspects. After the training, the MD-condition gave significantly more positive peer feedback than the NM-condition. However, no other functions or aspects were significantly different between the three conditions, mainly because the within-group interquartile ranges were large. CONCLUSIONS: The large interquartile ranges suggest that students differed substantially in the effort placed into giving peer feedback. Therefore, additional incentives may be needed to motivate students to give good feedback. Teachers could emphasise the utility value of peer feedback as an important professional skill and the importance of academic altruism and professional accountability in the peer feedback process. Such incentives may convince more students to put more effort into giving peer feedback.


Assuntos
Educação de Graduação em Medicina , Médicos , Estudantes de Medicina , Competência Clínica , Retroalimentação , Humanos , Grupo Associado
7.
Cells ; 10(5)2021 04 22.
Artigo em Inglês | MEDLINE | ID: mdl-33922315

RESUMO

Despite effective prevention programs targeting cardiovascular risk factors, coronary artery disease (CAD) remains the leading cause of death. Novel biomarkers are needed for improved risk stratification and primary prevention. To assess for independent associations between plasma metabolites and specific CAD plaque phenotypes we performed liquid chromatography mass-spectrometry on plasma from 1002 patients in the BioHEART-CT study. Four metabolites were examined as candidate biomarkers. Dimethylguanidino valerate (DMGV) was associated with presence and amount of CAD (OR) 1.41 (95% Confidence Interval [CI] 1.12-1.79, p = 0.004), calcified plaque, and obstructive CAD (p < 0.05 for both). The association with amount of plaque remained after adjustment for traditional risk factors, ß-coefficient 0.17 (95% CI 0.02-0.32, p = 0.026). Glutamate was associated with the presence of non-calcified plaque, OR 1.48 (95% CI 1.09-2.01, p = 0.011). Phenylalanine was associated with amount of CAD, ß-coefficient 0.33 (95% CI 0.04-0.62, p = 0.025), amount of calcified plaque, (ß-coefficient 0.88, 95% CI 0.23-1.53, p = 0.008), and obstructive CAD, OR 1.84 (95% CI 1.01-3.31, p = 0.046). Trimethylamine N-oxide was negatively associated non-calcified plaque OR 0.72 (95% CI 0.53-0.97, p = 0.029) and the association remained when adjusted for traditional risk factors. In targeted metabolomic analyses including 53 known metabolites and controlling for a 5% false discovery rate, DMGV was strongly associated with the presence of calcified plaque, OR 1.59 (95% CI 1.26-2.01, p = 0.006), obstructive CAD, OR 2.33 (95% CI 1.59-3.43, p = 0.0009), and amount of CAD, ß-coefficient 0.3 (95% CI 0.14-0.45, p = 0.014). In multivariate analyses the lipid and nucleotide metabolic pathways were both associated with the presence of CAD, after adjustment for traditional risk factors. We report novel associations between CAD plaque phenotypes and four metabolites previously associated with CAD. We also identified two metabolic pathways strongly associated with CAD, independent of traditional risk factors. These pathways warrant further investigation at both a biomarker and mechanistic level.

8.
J Physiol ; 599(5): 1513-1531, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33492681

RESUMO

KEY POINTS: Acute nicotinamide riboside (NR) supplementation does not alter substrate metabolism at rest, during or in recovery from endurance exercise. NR does not alter NAD+ -sensitive signalling pathways in human skeletal muscle. NR supplementation and acute exercise influence the NAD+ metabolome. ABSTRACT: Oral supplementation of the NAD+ precursor nicotinamide riboside (NR) has been reported to alter metabolism alongside increasing sirtuin (SIRT) signalling and mitochondrial biogenesis in rodent skeletal muscle. However, whether NR supplementation can elicit a similar response in human skeletal muscle is unclear. This study assessed the effect of 7-day NR supplementation on whole-body metabolism and exercise-induced mitochondrial biogenic signalling in skeletal muscle. Eight male participants (age: 23 ± 4 years, V ̇ O 2 peak 46.5 ± 4.4 ml kg-1  min-1 ) received 1 week of NR or cellulose placebo (PLA) supplementation (1000 mg day-1 ). Muscle biopsies were collected from the medial vastus lateralis prior to supplementation and pre-, immediately post- and 3 h post-exercise (1 h of 60% Wmax cycling) performed following the supplementation period. There was no effect of NR supplementation on substrate utilisation at rest or during exercise or on skeletal muscle mitochondrial respiration. Global acetylation, auto-PARylation of poly ADP-ribose polymerase 1 (PARP1), acetylation of Tumour protein 53 (p53)Lys382 and Manganese superoxide dismutase (MnSOD)Lys122 were also unaffected by NR supplementation or exercise. NR supplementation did not increase skeletal muscle NAD+ concentration, but it did increase the concentration of deaminated NAD+ precursors nicotinic acid riboside (NAR) and nicotinic acid mononucleotide (NAM) and methylated nicotinamide breakdown products (Me2PY and Me4PY), demonstrating the skeletal muscle bioavailability of NR supplementation. In summary, 1 week of NR supplementation does not alter whole-body metabolism or skeletal muscle signal transduction pathways implicated in the mitochondrial adaptation to endurance exercise.


Assuntos
Músculo Esquelético , Niacinamida , Suplementos Nutricionais , Exercício Físico , Masculino , NAD , Niacinamida/análogos & derivados , Compostos de Piridínio
9.
Cardiovasc Res ; 117(2): 613-622, 2021 01 21.
Artigo em Inglês | MEDLINE | ID: mdl-32239128

RESUMO

AIMS: To examine the metabolic adaptation to an 80-day exercise intervention in healthy young male adults where lifestyle factors such as diet, sleep, and physical activities are controlled. METHODS AND RESULTS: This study involved cross-sectional analysis before and after an 80-day aerobic and strength exercise intervention in 52 young, adult, male, newly enlisted soldiers in 2015. Plasma metabolomic analyses were performed using liquid chromatography, tandem mass spectrometry. Data analyses were performed between March and August 2019. We analysed changes in metabolomic profiles at the end of an 80-day exercise intervention compared to baseline, and the association of metabolite changes with changes in clinical parameters. Global metabolism was dramatically shifted after the exercise training programme. Fatty acids and ketone body substrates, key fuels used by exercising muscle, were dramatically decreased in plasma in response to increased aerobic fitness. There were highly significant changes across many classes of metabolic substrates including lipids, ketone bodies, arginine metabolites, endocannabinoids, nucleotides, markers of proteolysis, products of fatty acid oxidation, microbiome-derived metabolites, markers of redox stress, and substrates of coagulation. For statistical analyses, a paired t-test was used and Bonferroni-adjusted P-value of <0.0004 was considered to be statistically significant. The metabolite dimethylguanidino valeric acid (DMGV) (recently shown to predict lack of metabolic response to exercise) tracked maladaptive metabolic changes to exercise; those with increases in DMGV levels had increases in several cardiovascular risk factors; changes in DMGV levels were significantly positively correlated with increases in body fat (P = 0.049), total and LDL cholesterol (P = 0.003 and P = 0.007), and systolic blood pressure (P = 0.006). This study was approved by the Departments of Defence and Veterans' Affairs Human Research Ethics Committee and written informed consent was obtained from each subject. CONCLUSION: For the first time, the true magnitude and extent of metabolic adaptation to chronic exercise training are revealed in this carefully designed study, which can be leveraged for novel therapeutic strategies in cardiometabolic disease. Extending the recent report of DMGV's predictive utility in sedentary, overweight individuals, we found that it is also a useful marker of poor metabolic response to exercise in young, healthy, fit males.

10.
Cardiovasc Res ; 117(2): 435-449, 2021 01 21.
Artigo em Inglês | MEDLINE | ID: mdl-32267921

RESUMO

AIMS: The microbiome-derived metabolite trimethylamine-N-oxide (TMAO) has attracted major interest and controversy both as a diagnostic biomarker and therapeutic target in atherothrombosis. METHODS AND RESULTS: Plasma TMAO increased in mice on 'unhealthy' high-choline diets and notably also on 'healthy' high-fibre diets. Interestingly, TMAO was found to be generated by direct oxidation in the gut in addition to oxidation by hepatic flavin-monooxygenases. Unexpectedly, two well-accepted mouse models of atherosclerosis, ApoE-/- and Ldlr-/- mice, which reflect the development of stable atherosclerosis, showed no association of TMAO with the extent of atherosclerosis. This finding was validated in the Framingham Heart Study showing no correlation between plasma TMAO and coronary artery calcium score or carotid intima-media thickness (IMT), as measures of atherosclerosis in human subjects. However, in the tandem-stenosis mouse model, which reflects plaque instability as typically seen in patients, TMAO levels correlated with several characteristics of plaque instability, such as markers of inflammation, platelet activation, and intraplaque haemorrhage. CONCLUSIONS: Dietary-induced changes in the microbiome, of both 'healthy' and 'unhealthy' diets, can cause an increase in the plasma level of TMAO. The gut itself is a site of significant oxidative production of TMAO. Most importantly, our findings reconcile contradictory data on TMAO. There was no direct association of plasma TMAO and the extent of atherosclerosis, both in mice and humans. However, using a mouse model of plaque instability we demonstrated an association of TMAO plasma levels with atherosclerotic plaque instability. The latter confirms TMAO as being a marker of cardiovascular risk.

11.
Am J Physiol Endocrinol Metab ; 319(3): E509-E518, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32663097

RESUMO

Dimethylguanidino valeric acid (DMGV) is a marker of fatty liver disease, incident coronary artery disease, cardiovascular mortality, and incident diabetes. Recently, it was reported that circulating DMGV levels correlated positively with consumption of sugary beverages and negatively with intake of fruits and vegetables in three Swedish community-based cohorts. Here, we validate these results in the Framingham Heart Study Third Generation Cohort. Furthermore, in mice, diets rich in sucrose or fat significantly increased plasma DMGV concentrations. DMGV is the product of metabolism of asymmetric dimethylarginine (ADMA) by the hepatic enzyme AGXT2. ADMA can also be metabolized to citrulline by the cytoplasmic enzyme DDAH1. We report that a high-sucrose diet induced conversion of ADMA exclusively into DMGV (supporting the relationship with sugary beverage intake in humans), while a high-fat diet promoted conversion of ADMA to both DMGV and citrulline. On the contrary, replacing dietary native starch with high-fiber-resistant starch increased ADMA concentrations and induced its conversion to citrulline, without altering DMGV concentrations. In a cohort of obese nondiabetic adults, circulating DMGV concentrations increased and ADMA levels decreased in those with either liver or muscle insulin resistance. This was similar to changes in DMGV and ADMA concentrations found in mice fed a high-sucrose diet. Sucrose is a disaccharide of glucose and fructose. Compared with glucose, incubation of hepatocytes with fructose significantly increased DMGV production. Overall, we provide a comprehensive picture of the dietary determinants of DMGV levels and association with insulin resistance.


Assuntos
Biomarcadores/metabolismo , Guanidinas/metabolismo , Cardiopatias/metabolismo , Doenças Metabólicas/metabolismo , Valeratos/metabolismo , Adulto , Amidoidrolases/metabolismo , Animais , Bebidas Gaseificadas , Citrulina/metabolismo , Dieta , Gorduras na Dieta/farmacologia , Humanos , Resistência à Insulina , Fígado/enzimologia , Estudos Longitudinais , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/metabolismo , Sacarose/farmacologia , Transaminases/metabolismo
12.
Nat Commun ; 11(1): 2843, 2020 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-32487995

RESUMO

Poor access to human left ventricular myocardium is a significant limitation in the study of heart failure (HF). Here, we utilise a carefully procured large human heart biobank of cryopreserved left ventricular myocardium to obtain direct molecular insights into ischaemic cardiomyopathy (ICM) and dilated cardiomyopathy (DCM), the most common causes of HF worldwide. We perform unbiased, deep proteomic and metabolomic analyses of 51 left ventricular (LV) samples from 44 cryopreserved human ICM and DCM hearts, compared to age-, gender-, and BMI-matched, histopathologically normal, donor controls. We report a dramatic reduction in serum amyloid A1 protein in ICM hearts, perturbed thyroid hormone signalling pathways and significant reductions in oxidoreductase co-factor riboflavin-5-monophosphate and glycolytic intermediate fructose-6-phosphate in both; unveil gender-specific changes in HF, including nitric oxide-related arginine metabolism, mitochondrial substrates, and X chromosome-linked protein and metabolite changes; and provide an interactive online application as a publicly-available resource.


Assuntos
Cardiomiopatia Dilatada/metabolismo , Isquemia Miocárdica/metabolismo , Caracteres Sexuais , Transdução de Sinais , Cardiomiopatia Dilatada/patologia , Feminino , Ventrículos do Coração/metabolismo , Ventrículos do Coração/patologia , Humanos , Masculino , Metaboloma , Metabolômica , Pessoa de Meia-Idade , Isquemia Miocárdica/patologia , Miocárdio/metabolismo , Miocárdio/patologia , Análise de Componente Principal , Mapas de Interação de Proteínas , Proteoma/metabolismo , Proteômica , Doadores de Tecidos
13.
Nutrients ; 12(5)2020 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-32455838

RESUMO

The majority of the epidemiological evidence over the past few decades has linked high intake of fats, especially saturated fats, to increased risk of diabetes and cardiovascular disease. However, findings of some recent studies (e.g., the PURE study) have contested this association. High saturated fat diets (HFD) have been widely used in rodent research to study the mechanism of insulin resistance and metabolic syndrome. Two separate but somewhat overlapping models-the diacylglycerol (DAG) model and the ceramide model-have emerged to explain the development of insulin resistance. Studies have shown that lipid deposition in tissues such as muscle and liver inhibit insulin signaling via the toxic molecules DAG and ceramide. DAGs activate protein kinase C that inhibit insulin-PI3K-Akt signaling by phosphorylating serine residues on insulin receptor substrate (IRS). Ceramides are sphingolipids with variable acyl group chain length and activate protein phosphatase 2A that dephosphorylates Akt to block insulin signaling. In adipose tissue, obesity leads to infiltration of macrophages that secrete pro-inflammatory cytokines that inhibit insulin signaling by phosphorylating serine residues of IRS proteins. For cardiovascular disease, studies in humans in the 1950s and 1960s linked high saturated fat intake with atherosclerosis and coronary artery disease. More recently, trials involving Mediterranean diet (e.g., PREDIMED study) have indicated that healthy monounsaturated fats are more effective in preventing cardiovascular mortality and coronary artery disease than are low-fat, low-cholesterol diets. Antioxidant and anti-inflammatory effects of Mediterranean diets are potential mediators of these benefits.


Assuntos
Doenças Cardiovasculares/metabolismo , Dieta Hiperlipídica/efeitos adversos , Tecido Adiposo/metabolismo , Animais , Doenças Cardiovasculares/etiologia , Ceramidas/metabolismo , Citocinas/metabolismo , Diabetes Mellitus/metabolismo , Dieta com Restrição de Gorduras , Diglicerídeos/metabolismo , Ácidos Graxos/metabolismo , Humanos , Insulina/metabolismo , Resistência à Insulina/fisiologia , Síndrome Metabólica , Obesidade , Fosfatidilinositol 3-Quinases/metabolismo
14.
Cell Rep ; 30(10): 3566-3582.e4, 2020 03 10.
Artigo em Inglês | MEDLINE | ID: mdl-32160557

RESUMO

Every-other-day fasting (EODF) is an effective intervention for the treatment of metabolic disease, including improvements in liver health. But how the liver proteome is reprogrammed by EODF is currently unknown. Here, we use EODF in mice and multi-omics analysis to identify regulated pathways. Many changes in the liver proteome are distinct after EODF and absent after a single fasting bout. Key among these is the simultaneous induction by EODF of de novo lipogenesis and fatty acid oxidation enzymes. Together with activation of oxidative stress defenses, this contributes to the improvements in glucose tolerance and lifespan after EODF. Enrichment analysis shows unexpected downregulation of HNF4α targets by EODF, and we confirm HNF4α inhibition. Suppressed HNF4α targets include bile synthetic enzymes and secreted proteins, such as α1-antitrypsin or inflammatory factors, which reflect EODF phenotypes. Interactive online access is provided to a data resource (https://www.larancelab.com/eodf), which provides a global view of fasting-induced mechanisms in mice.


Assuntos
Jejum , Genômica , Fator 4 Nuclear de Hepatócito/metabolismo , alfa 1-Antitripsina/metabolismo , Animais , Colesterol/biossíntese , Regulação para Baixo , Jejum/sangue , Fígado/metabolismo , Masculino , Metabolômica , Camundongos Endogâmicos C57BL , Oxirredução , Estresse Oxidativo , Proteoma/metabolismo , Proteômica , Transcrição Genética
15.
Mol Genet Metab ; 128(4): 476-482, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31679996

RESUMO

A small minority (< 3%) of protein-coding genetic variants are predicted to lead to loss of protein function. However, these predicted loss-of-function (pLOF) variants can provide insight into mode of transcriptional effect. To examine how these changes are propagated to phenotype, we determined associations with downstream metabolites. We performed association analyses of 37 pLOF variants - previously reported to be significantly associated with disease in >400,000 subjects in UK Biobank - with metabolites. We conducted these analyses in three community-based cohorts: the Framingham Heart Study (FHS) Offspring Cohort, FHS Generation 3, and the KORA F4 cohort. We identified 19 new low-frequency or rare (minor allele frequency (MAF) <5%) pLOF variant-metabolite associations, and 12 new common (MAF > 5%) pLOF variant-metabolite associations. Rare pLOF variants in the genes BTN3A2, ENPEP, and GEM that have been associated with blood pressure in UK Biobank, were associated with vasoactive metabolites indoxyl sulfate, asymmetric dimethylarginine (ADMA), and with niacinamide, respectively. A common pLOF variant in gene CCHCR1, associated with asthma in UK Biobank, was associated with histamine and niacinamide in FHS Generation 3, both reported to play a role in this disease. Common variants in olfactory receptor gene OX4C11 that associated with blood pressure in UK Biobank were associated with the nicotine metabolite cotinine, suggesting an interaction between altered olfaction, smoking behaviour, and blood pressure. These findings provide biological validity for pLOF variant-disease associations, and point to the effector roles of common metabolites. Such an approach may provide novel disease markers and therapeutic targets.


Assuntos
Metabolismo Energético , Estudos de Associação Genética , Predisposição Genética para Doença , Mutação com Perda de Função , Fenótipo , Alelos , Biomarcadores , Pressão Sanguínea , Frequência do Gene , Estudos de Associação Genética/métodos , Histamina/metabolismo , Humanos
17.
Heart Asia ; 11(1): e011134, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31031831

RESUMO

Aims: MicroRNAs (miRNAs), small non-coding RNAs, have been implicated as regulators of multiple phases of atherothrombosis, and some reports have suggested altered levels in coronary artery in-stent restenosis (ISR). We recently demonstrated that miR-93-5 p was able to discriminate between patients with stable coronary artery disease (CAD) and those with no CAD, after adjusting for traditional risk factors (RFs). Thus, we wanted to determine if circulating miRNAs could predict coronary ISR. Objective: To determine if circulating miRNAs have diagnostic capability for determining ISR in a cohort of matched patients with and without ISR. Approach and results: To determine if miRNA plasma levels are elevated in coronary ISR, we conducted a study comprising 78 patients (39 with no ISR and 39 with ISR) and measured plasma miRNAs in each. We then determined the predictive ability of differential miRNAs, adjusting for Framingham Heart Study (FHS) RFs, and stent length and diameter, to discriminate between ISR and no ISR. After correction for multiple testing, two miRNAs-miR425-5p and miR-93-5 p-were differential between patients with ISR and patients without ISR. Only miR-93-5 p remained a strong independent predictor of ISR after correction for FHS RFs (OR 6.30, p=0.008) and FHS RFs plus stent length and diameter (OR 4.80, p=0.02) and improved discriminatory power for ISR over FHS RFs alone in receiver operator characteristic curve analysis. Conclusion: This novel finding that miR-93-5 p independently predicts ISR extends our recent observation that miR-93-5 p predicted CAD after adjustment for traditional CAD RFs. These data suggest further potential diagnostic utility.

18.
Nutrients ; 11(3)2019 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-30823446

RESUMO

The prevalence and incidence of metabolic syndrome is reaching pandemic proportions worldwide, thus warranting an intensive search for novel preventive and treatment strategies. Recent studies have identified a number of soluble factors secreted by adipocytes and myocytes (adipo-/myokines), which link sedentary life style, abdominal obesity, and impairments in carbohydrate and lipid metabolism. In this review, we discuss the metabolic roles of the recently discovered myokine ß-aminoisobutyric acid (BAIBA), which is produced by skeletal muscle during physical activity. In addition to physical activity, the circulating levels of BAIBA are controlled by the mitochondrial enzyme alanine: glyoxylate aminotransferase 2 (AGXT2), which is primarily expressed in the liver and kidneys. Recent studies have shown that BAIBA can protect from diet-induced obesity in animal models. It induces transition of white adipose tissue to a "beige" phenotype, which induces fatty acids oxidation and increases insulin sensitivity. While the exact mechanisms of BAIBA-induced metabolic effects are still not well understood, we discuss some of the proposed pathways. The reviewed data provide new insights into the connection between physical activity and energy metabolism and suggest that BAIBA might be a potential novel drug for treatment of the metabolic syndrome and its cardiovascular complications.


Assuntos
Ácidos Aminoisobutíricos/metabolismo , Metabolismo dos Carboidratos/fisiologia , Metabolismo dos Lipídeos/fisiologia , Animais , Metabolismo Energético/fisiologia , Humanos , Músculo Esquelético/fisiologia
19.
FASEB J ; 33(7): 8033-8042, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30925066

RESUMO

Recent research has shown significant health benefits deriving from high-dietary fiber or microbiome-accessible carbohydrate consumption. Compared with native starch (NS), dietary resistant starch (RS) is a high microbiome-accessible carbohydrate that significantly alters the gut microbiome. The aim of this study was to determine the systemic metabolic effects of high microbiome-accessible carbohydrate. Male C57BL/6 mice were divided into 2 groups and fed either NS or RS for 18 wk (n = 20/group). Metabolomic analyses revealed that plasma levels of numerous metabolites were significantly different between the RS-fed and NS-fed mice, many of which are microbiome-derived. Most strikingly, we observed a 22-fold increase in gut microbiome-derived tryptophan metabolite indole-3-propionate (IPA), which was positively correlated with several gut microbiota, including Allobaculum, Bifidobacterium, and Lachnospiraceae, with Allobaculum having the most consistently increased abundance of all the IPA-associated taxa across all RS-fed mice. In addition, major changes were observed for metabolites solely or primarily metabolized in the gut (e.g., trimethylamine-N-oxide), metabolites that have a significant entero-hepatic circulation (i.e., bile acids), lipid metabolites (e.g., cholesterol sulfate), metabolites indicating increased energy turnover (e.g., tricarboxylic acid cycle intermediates and ketone bodies), and increased antioxidants such as reduced glutathione. Our findings reveal potentially novel mediators of high microbiome-accessible carbohydrate-derived health benefits.-Koay,Y. C., Wali. J. A., Luk, A. W. S., Macia, L., Cogger, V. C., Pulpitel, T. J., Wahl, D., Solon-Biet, S. M., Holmes, A., Simpson, S. J., O'Sullivan, J. F. Ingestion of resistant starch by mice markedly increases microbiome-derived metabolites.


Assuntos
Microbioma Gastrointestinal , Amido/farmacologia , Ração Animal , Animais , Bactérias/metabolismo , Ácidos e Sais Biliares/metabolismo , Cromatografia Líquida , Interações Hidrofóbicas e Hidrofílicas , Indóis/sangue , Lipídeos/sangue , Masculino , Metaboloma , Metilaminas/sangue , Camundongos , Camundongos Endogâmicos C57BL , Solubilidade , Amido/farmacocinética , Espectrometria de Massas em Tandem
20.
iScience ; 12: 41-52, 2019 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-30665196

RESUMO

Circulating tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) levels are reduced in patients with cardiovascular disease, and TRAIL gene deletion in mice exacerbates atherosclerosis and inflammation. How TRAIL protects against atherosclerosis and why levels are reduced in disease is unknown. Here, multiple strategies were used to identify the protective source of TRAIL and its mechanism(s) of action. Samples from patients with coronary artery disease and bone-marrow transplantation experiments in mice lacking TRAIL revealed monocytes/macrophages as the main protective source. Accordingly, deletion of TRAIL caused a more inflammatory macrophage with reduced migration, displaying impaired reverse cholesterol efflux and efferocytosis. Furthermore, interleukin (IL)-18, commonly increased in plasma of patients with cardiovascular disease, negatively regulated TRAIL transcription and gene expression, revealing an IL-18-TRAIL axis. These findings demonstrate that TRAIL is protective of atherosclerosis by modulating monocyte/macrophage phenotype and function. Manipulating TRAIL levels in these cells highlights a different therapeutic avenue in the treatment of cardiovascular disease.

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