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BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) and metabolic syndrome (MetS) are implicated in the aetiology of non-communicable diseases. Our study aimed to evaluate associations between NAFLD and MetS with overall and cause-specific mortality. METHODS: We used dietary, lifestyle, anthropometric and metabolic biomarker data from a random subsample of 15,784 EPIC cohort participants. NAFLD was assessed using the fatty liver index (FLI) and MetS using the revised definition. Indices for metabolic dysfunction-associated fatty liver disease (MAFLD) were calculated. The individual associations of these indices with overall and cause-specific mortality were assessed using multivariable Cox proportional hazards models to estimate hazard ratios (HRs) and 95% confidence intervals (95%CIs). As a subobjective, risk associations with adaptations of new classifications of metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic and alcohol-related liver disease (MetALD) were also assessed. RESULTS: Among the 15,784 sub-cohort participants, a total of 1997 deaths occurred (835 due to cancer, 520 to CVD, 642 to other causes) over a median 15.6 (IQR, 12.3-17.1) years of follow-up. Compared to an FLI < 30, FLI ≥ 60 was associated with increased risks of overall mortality (HR = 1.44, 95%CI = 1.27-1.63), and deaths from cancer (HR = 1.32, 95%CI = 1.09-1.60), CVD (HR = 2.06, 95% CI = 1.61-2.63) or other causes (HR = 1.21, 95%CI = 0.97-1.51). Mortality risk associations were also elevated for individuals with MAFLD compared to those without. Individuals with MetS were at increased risk of all mortality endpoints, except cancer-specific mortality. MASLD and MetALD were associated with higher risk of overall mortality. CONCLUSIONS: Our findings based on a prospective cohort suggest that individuals with hepatic steatosis or metabolic dysfunction have a higher overall and cause-specific mortality risk.
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Síndrome Metabólica , Hepatopatia Gordurosa não Alcoólica , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Estudos Prospectivos , Síndrome Metabólica/mortalidade , Hepatopatia Gordurosa não Alcoólica/mortalidade , Adulto , Idoso , Fatores de Risco , Estudos de Coortes , Fígado Gorduroso/mortalidadeRESUMO
Accumulation of lipid-laden macrophages within the arterial neointima is a critical step in atherosclerotic plaque formation. Here, we show that reduced levels of the cellular plasticity factor ZEB1 in macrophages increase atherosclerotic plaque formation and the chance of cardiovascular events. Compared to control counterparts (Zeb1WT/ApoeKO), male mice with Zeb1 ablation in their myeloid cells (Zeb1∆M/ApoeKO) have larger atherosclerotic plaques and higher lipid accumulation in their macrophages due to delayed lipid traffic and deficient cholesterol efflux. Zeb1∆M/ApoeKO mice display more pronounced systemic metabolic alterations than Zeb1WT/ApoeKO mice, with higher serum levels of low-density lipoproteins and inflammatory cytokines and larger ectopic fat deposits. Higher lipid accumulation in Zeb1∆M macrophages is reverted by the exogenous expression of Zeb1 through macrophage-targeted nanoparticles. In vivo administration of these nanoparticles reduces atherosclerotic plaque formation in Zeb1∆M/ApoeKO mice. Finally, low ZEB1 expression in human endarterectomies is associated with plaque rupture and cardiovascular events. These results set ZEB1 in macrophages as a potential target in the treatment of atherosclerosis.
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Aterosclerose , Placa Aterosclerótica , Animais , Humanos , Masculino , Camundongos , Apolipoproteínas E/genética , Aterosclerose/genética , Aterosclerose/metabolismo , Regulação para Baixo , Lipoproteínas LDL/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Placa Aterosclerótica/metabolismo , Homeobox 1 de Ligação a E-box em Dedo de Zinco/genética , Homeobox 1 de Ligação a E-box em Dedo de Zinco/metabolismoRESUMO
BACKGROUND: Whether cancer risk associated with a higher body mass index (BMI), a surrogate measure of adiposity, differs among adults with and without cardiovascular diseases (CVD) and/or type 2 diabetes (T2D) is unclear. The primary aim of this study was to evaluate separate and joint associations of BMI and CVD/T2D with the risk of cancer. METHODS: This is an individual participant data meta-analysis of two prospective cohort studies, the UK Biobank (UKB) and the European Prospective Investigation into Cancer and nutrition (EPIC), with a total of 577,343 adults, free of cancer, T2D, and CVD at recruitment. We used Cox proportional hazard regressions to estimate multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for associations between BMI and incidence of obesity-related cancer and in turn overall cancer with a multiplicative interaction between BMI and the two cardiometabolic diseases (CMD). HRs and 95% CIs for separate and joint associations for categories of overweight/obesity and CMD status were estimated, and additive interaction was quantified through relative excess risk due to interaction (RERI). RESULTS: In the meta-analysis of both cohorts, BMI (per ~ 5 kg/m2) was positively associated with the risk of obesity-related cancer among participants without a CMD (HR: 1.11, 95%CI: 1.07,1.16), among participants with T2D (HR: 1.11, 95% CI: 1.05,1.18), among participants with CVD (HR: 1.17, 95% CI: 1.11,1.24), and suggestively positive among those with both T2D and CVD (HR: 1.09, 95% CI: 0.94,1.25). An additive interaction between obesity (BMI ≥ 30 kg/m2) and CVD with the risk of overall cancer translated into a meta-analytical RERI of 0.28 (95% CI: 0.09-0.47). CONCLUSIONS: Irrespective of CMD status, higher BMI increased the risk of obesity-related cancer among European adults. The additive interaction between obesity and CVD suggests that obesity prevention would translate into a greater cancer risk reduction among population groups with CVD than among the general population.
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Doenças Cardiovasculares , Diabetes Mellitus Tipo 2 , Neoplasias , Humanos , Adulto , Índice de Massa Corporal , Fatores de Risco , Estudos Prospectivos , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/epidemiologia , Bancos de Espécimes Biológicos , Obesidade/complicações , Obesidade/epidemiologia , Neoplasias/epidemiologia , Neoplasias/complicações , Doenças Cardiovasculares/etiologia , Reino Unido/epidemiologiaRESUMO
Olive oil (OO) is the main source of added fat in the Mediterranean diet (MD). It is a mix of bioactive compounds, including monounsaturated fatty acids, phytosterols, simple phenols, secoiridoids, flavonoids, and terpenoids. There is a growing body of evidence that MD and OO improve obesity-related factors. In addition, obesity has been associated with an increased risk for several cancers: endometrial, oesophageal adenocarcinoma, renal, pancreatic, hepatocellular, gastric cardia, meningioma, multiple myeloma, colorectal, postmenopausal breast, ovarian, gallbladder, and thyroid cancer. However, the epidemiological evidence linking MD and OO with these obesity-related cancers, and their potential mechanisms of action, especially those involving the gut microbiota, are not clearly described or understood. The goals of this review are 1) to update the current epidemiological knowledge on the associations between MD and OO consumption and obesity-related cancers, 2) to identify the gut microbiota mechanisms involved in obesity-related cancers, and 3) to report the effects of MD and OO on these mechanisms.
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Dieta Mediterrânea , Microbioma Gastrointestinal , Neoplasias , Humanos , Azeite de Oliva/uso terapêutico , Obesidade/complicações , Neoplasias/epidemiologia , Neoplasias/etiologia , Neoplasias/prevenção & controleRESUMO
This study analyzed the correlations between the acute and habitual intake of dietary tyrosols, their main food sources, and 24 h urine excretions of tyrosol (Tyr) and hydroxytyrosol (OHTyr) in participants from the European Prospective Investigation into Cancer and Nutrition study (EPIC). Participants (n = 419) were healthy men and women aged from 34 to 73 years from 8 EPIC centers belonging to France, Italy, and Germany. Acute and habitual dietary data were collected using a standardized 24 h dietary recall software and validated country-specific dietary questionnaires, respectively. The intake of 13 dietary tyrosols was estimated using the Phenol-Explorer database. Excretions of Tyr and OHTyr in a single 24 h urine sample were analyzed using tandem mass spectrometry. Urinary excretions of Tyr, OHTyr, and their sum (Tyr + OHTyr) correlated more strongly with their corresponding acute (rhopartial~0.63) rather than habitual intakes (rhopartial~0.47). In addition, individual and combined urinary excretions of Tyr and OHTyr were weakly to moderately correlated with the acute and habitual intake of other individual tyrosol precursors (rhopartial = 0.10-0.44) and especially with major food sources, such as wine (rhopartial = 0.41-0.58), olive oil (rhopartial = 0.25-0.44), and beer (rhopartial = 0.14-0.23). Urinary Tyr + OHTyr excretions were similarly correlated with the acute intake of total tyrosols but differently correlated with food sources among countries. Based on these results, we conclude that 24 h urinary excretions of Tyr + OHTyr could be proposed as biomarkers of total tyrosol intake, preferably for acute intakes.
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Phenol-rich foods consumption such as virgin olive oil (VOO) has been shown to have beneficial effects on cardiovascular diseases. The broader biochemical impact of VOO and phenol-enriched OOs remains, however, unclear. A randomized, double-blind, cross-over, controlled trial was performed with thirty-three hypercholesterolemic individuals who ingested for 3-weeks (25 mL/day): (1) an OO enriched with its own olive oil phenolic compounds (PCs) (500 ppm; FOO); (2) an OO enriched with its own olive oil PCs (250 ppm) plus thyme PCs (250 ppm; FOOT); and (3) a VOO with low phenolic content (80 ppm). Serum lipid and glycemic profiles, serum 1H-NMR spectroscopy-based metabolomics, endothelial function, blood pressure, and cardiovascular risk were measured. We combined OPLS-DA with machine learning modelling to identify metabolites discrimination of the treatment groups. Both phenol-enriched OO interventions decreased the levels of glutamine, creatinine, creatine, dimethylamine, and histidine in comparison to VOO one. In addition, FOOT decreased the plasma levels of glycine and DMSO2 compared to VOO, while FOO decreased the circulating alanine concentrations but increased the plasma levels of acetone and 3-HB compared to VOO. Based on these findings, phenol-enriched OOs were shown to result in a favorable shift in the circulating metabolic phenotype, inducing a reduction in metabolites associated with cardiometabolic diseases.
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Background: The Mediterranean diet (MD) has been proposed as a healthy diet with a potential to lower the incidence of several types of cancer, but there is no data regarding thyroid cancer (TC). We investigated the association between MD adherence, and its components, and the differentiated TC risk within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Methods: Over 450,000 men and women from nine European countries were followed up for a mean of 14.1 years, during which 712 differentiated TC cases were identified. Adherence to MD was estimated using the relative MD (rMED) score, an 18-point scale including alcohol, and the adapted rMED (arMED) score, a 16-point scale excluding alcohol. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox regression models adjusted for potential confounding factors. Results: Adherence to the arMED score was not associated with the risk of differentiated TC (HRhigh vs. low adherence = 0.94, 95% CI: 0.70-1.25; p-trend 0.27), while a suggestive, but non-statistically significant inverse relationship was observed with rMED (HRhigh vs. low adherence = 0.88, 95% CI: 0.68-1.14; p-trend 0.17). Low meat (HRlow vs. high meat intake = 0.81, 95% CI: 0.67-0.99; p-trend = 0.04) and moderate alcohol (HRmoderate vs. non-moderate intake = 0.88, 95% CI: 0.75-1.03) intake were related with lower differentiated TC risk. Conclusions: Our study shows that a high adherence to MD is not strongly related to differentiated TC risk, although further research is required to confirm the impact of MD and, especially, meat intake in TC risk.
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Dieta , Metabolismo dos Lipídeos , Neoplasias , Animais , Dieta/efeitos adversos , Dieta/métodos , Humanos , Lipídeos , Fatores de RiscoRESUMO
SCOPE: The lipidomic analysis of high-density lipoprotein (HDL) could be useful to identify new biomarkers of HDL function. METHODS AND RESULTS: A randomized, controlled, double-blind, crossover trial (33 hypercholesterolaemic subjects) is performed with a control virgin olive oil (VOO), VOO enriched with its own phenolic compounds (FVOO), or VOO enriched with additional phenolic compounds from thyme (FVOOT) for 3 weeks. HDL lipidomic analyses are performed using the Lipidyzer platform. VOO and FVOO intake increase monounsaturated-fatty acids (FAs) and decrease saturated and polyunsaturated FAs in triacylglyceride (TAG) species, among others species. In contrast, FVOOT intake does not induce these FAs changes. The decrease in TAG52:3(FA16:0) after VOO intake and the decrease in TAG52:5(FA18:2) after FVOO intake are inversely associated with changes in HDL resistance to oxidation. After FVOO intake, the decrease in TAG54:6(FA18:2) in HDL is inversely associated with changes in HDL cholesterol efflux capacity. CONCLUSION: VOO and FVOO consumption has an impact on the HDL lipidome, in particular TAG species. Although TAGs are minor components of HDL mass, the observed changes in TAG modulated HDL functionality towards a cardioprotective mode. The assessment of the HDL lipidome is a valuable approach to identify and characterize new biomarkers of HDL function.
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HDL-Colesterol/sangue , Hipercolesterolemia/sangue , Lipidômica/métodos , Azeite de Oliva/farmacologia , Fenóis/farmacologia , Estudos Cross-Over , Método Duplo-Cego , Humanos , Triglicerídeos/sangueRESUMO
Virgin olive oil is a characteristic component and the main source of fat of the Mediterranean diet. It is a mix of high-value health compounds, including monounsaturated fatty acids (mainly oleic acid), simple phenols (such as hydroxytyrosol and tyrosol), secoiridoids (such as oleuropein, oleocanthal), flavonoids, and terpenoids (such as squalene). Olive oil consumption has been shown to improve different aspects of human health and has been associated with a lower risk of cancer. However, the underlying cellular mechanisms involved in such effects are still poorly defined, but seem to be related to a promotion of apoptosis, modulation of epigenetic patterns, blockade of cell cycle, and angiogenesis regulation. The aim of this review is to update the current associations of cancer risk with the Mediterranean diet, olive oil consumption and its main components. In addition, the identification of key olive oil components involved in anticarcinogenic mechanisms and pathways according to experimental models is also addressed.
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Dieta Mediterrânea , Neoplasias/epidemiologia , Neoplasias/fisiopatologia , Azeite de Oliva , Animais , Humanos , IncidênciaRESUMO
The intake of olive oil (OO) enriched with phenolic compounds (PCs) promotes ex vivo HDL-mediated macrophage cholesterol efflux in humans. We aimed to determine the effects of PC-enriched virgin OO on reverse cholesterol transport (RevCT) from macrophages to feces in vivo. Female C57BL/6 mice were given intragastric doses of refined OO (ROO) and a functional unrefined virgin OO enriched with its own PC (FVOO) for 14 days. Our experiments included two independent groups of mice that received intragastric doses of the phenolic extract (PE) used to prepare the FVOO and the vehicle solution (saline), as control, for 14 days. FVOO intake led to a significant increase in serum HDL cholesterol and its ability to induce macrophage cholesterol efflux in vitro when compared with ROO group. This was concomitant with the enhanced macrophage-derived [3H]cholesterol transport to feces in vivo. PE intake per se also increased HDL cholesterol levels and significantly promoted in vivo macrophage-to-feces RevCT rate when compared with saline group. PE upregulated the expression of the main macrophage transporter involved in macrophage cholesterol efflux, the ATP binding cassettea1. Our data provide direct evidence of the crucial role of OO PCs in the induction of macrophage-specific RevCT in vivo.
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There is extensive information of the beneficial effects of virgin olive oil (VOO), especially on cardiovascular diseases. Some VOO healthy properties have been attributed to their phenolic-compounds (PCs). The aim of this review is to present updated data on the effects of olive oil (OO) PCs on the gut microbiota, lipid metabolism, immune system, and obesity, as well as on the crosstalk among them. We summarize experiments and clinical trials which assessed the specific effects of the olive oil phenolic-compounds (OOPCs) without the synergy with OO-fats. Several studies have demonstrated that OOPC consumption increases Bacteroidetes and/or reduces the Firmicutes/Bacteroidetes ratio, which have both been related to atheroprotection. OOPCs also increase certain beneficial bacteria and gut-bacteria diversity which can be therapeutic for lipid-immune disorders and obesity. Furthermore, some of the mechanisms implicated in the crosstalk between OOPCs and these disorders include antimicrobial-activity, cholesterol microbial metabolism, and metabolites produced by bacteria. Specifically, OOPCs modulate short-chain fatty-acids produced by gut-microbiota, which can affect cholesterol metabolism and the immune system, and may play a role in weight gain through promoting satiety. Since data in humans are scarce, there is a necessity for more clinical trials designed to assess the specific role of the OOPCs in this crosstalk.
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Microbioma Gastrointestinal/efeitos dos fármacos , Sistema Imunitário/efeitos dos fármacos , Metabolismo dos Lipídeos/efeitos dos fármacos , Obesidade/tratamento farmacológico , Azeite de Oliva/farmacologia , Fenóis/farmacologia , Doenças Cardiovasculares/prevenção & controle , Colesterol , Humanos , Lipídeos , Azeite de Oliva/químicaRESUMO
SCOPE: We investigate the postprandial modulation of cardiovascular-related microRNAs elicited by extra virgin olive oil (EVOOs) containing different levels of their own polyphenols. METHODS AND RESULTS: It is randomized, postprandial, parallel, double-blind study. Twelve healthy participants consumed 30 mL of EVOO containing low (L-EVOO; 250 mg total phenols kg-1 of oil), medium (M-EVOO; 500 mg total phenols kg-1 of oil), and high (H-EVOO; 750 mg total phenols kg-1 of oil) enriched EVOOs. Postprandial plasma microRNAs levels are analyzed by real-time quantitative PCR. The results show that L-EVOO intake is associated with decreased let-7e-5p and miR-328a-3p levels and increased miR-17-5p and miR-20a-5p, concentrations. M-EVOO decreases plasma let-7e-5p and increases miR-17-5p, miR-20a-5p, and miR-192-5p levels. Finally, H-EVOO decreases let-7e-5p, miR-10a-5p, miR-21-5p, and miR-26b-5p levels. CONCLUSION: During the postprandial state, the levels of let-7e-5p decrease with EVOO regardless of polyphenol content suggesting a general response to the fatty acid composition of EVOO or/and the presence of at least 250 mg polyphenol kg-1 olive oil. Moreover, the miR-17-92 cluster increases by low and medium polyphenol content suggesting a role in fatty acid metabolism and nutrient sensing. Thus, postprandial modulation of circulating microRNAs levels could be a potential mechanism for the cardiovascular benefits associated with EVOO intake.
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Doenças Cardiovasculares/genética , Ácidos Nucleicos Livres/sangue , MicroRNAs/sangue , Azeite de Oliva/farmacologia , Fenóis/farmacologia , Adulto , Glicemia/análise , Simulação por Computador , Método Duplo-Cego , Endotélio Vascular/fisiologia , Feminino , Alimentos Fortificados , Humanos , Lipídeos/sangue , Masculino , Pessoa de Meia-Idade , Azeite de Oliva/química , Fenóis/química , Período Pós-PrandialRESUMO
The atherogenicity of low-density lipoprotein (LDL) and triglyceride-rich lipoproteins (TRLs) may be more significant than LDL cholesterol levels. Clinical trials which have led to increased high-density lipoprotein (HDL) cholesterol have not always seen reductions in cardiovascular disease (CVD). Furthermore, genetic variants predisposing individuals to high HDL cholesterol are not associated with a lower risk of suffering a coronary event, and therefore HDL functionality is considered to be the most relevant aspect. Virgin olive oil (VOO) is thought to play a protective role against CVD. This review describes the effects of VOO and phenol-enriched VOOs on lipoprotein atherogenicity and HDL atheroprotective properties. The studies have demonstrated a decrease in LDL atherogenicity and an increase in the HDL-mediated macrophage cholesterol efflux capacity, HDL antioxidant activity, and HDL anti-inflammatory characteristics after various VOO interventions. Moreover, the expression of cholesterol efflux-related genes was enhanced after exposure to phenol-enriched VOOs in both post-prandial and sustained trials. Improvements in HDL antioxidant properties were also observed after VOO and phenol-enriched VOO interventions. Furthermore, some studies have demonstrated improved characteristics of TRL atherogenicity under postprandial conditions after VOO intake. Large-scale, long-term randomized clinical trials, and Mendelian analyses which assess the lipoprotein state and properties, are required to confirm these results.
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Aterosclerose/tratamento farmacológico , Lipoproteínas/efeitos adversos , Azeite de Oliva/uso terapêutico , Fenóis/química , Animais , Antioxidantes/uso terapêutico , Ensaios Clínicos como Assunto , HumanosRESUMO
Dietary phytosterols, which comprise plant sterols and stanols, reduce plasma Low-Density Lipoprotein-Cholesterol (LDL-C) levels when given 2 g/day. Since this dose has not been reported to cause health-related side effects in long-term human studies, food products containing these plant compounds are used as potential therapeutic dietary options to reduce LDL-C and cardiovascular disease risk. Several mechanisms have been proposed to explain the cholesterol-lowering action of phytosterols. They may compete with dietary and biliary cholesterol for micellar solubilization in the intestinal lumen, impairing intestinal cholesterol absorption. Recent evidence indicates that phytosterols may also regulate other pathways. Impaired intestinal cholesterol absorption is usually associated with reduced cholesterol transport to the liver, which may reduce the incorporation of cholesterol into Very-Low- Density Lipoprotein (VLDL) particles, thereby lowering the rate of VLDL assembly and secretion. Impaired liver VLDL production may reduce the rate of LDL production. On the other hand, significant evidence supports a role for plant sterols in the Transintestinal Cholesterol Excretion (TICE) pathway, although the exact mechanisms by which they promote the flow of cholesterol from the blood to enterocytes and the intestinal lumen remains unknown. Dietary phytosterols may also alter the conversion of bile acids into secondary bile acids, and may lower the bile acid hydrophobic/hydrophilic ratio, thereby reducing intestinal cholesterol absorption. This article reviews the progress to date in research on the molecular mechanisms underlying the cholesterol-lowering effects of phytosterols.
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LDL-Colesterol/antagonistas & inibidores , Fitosteróis/farmacologia , Animais , Ácidos e Sais Biliares/antagonistas & inibidores , Ácidos e Sais Biliares/química , Ácidos e Sais Biliares/metabolismo , LDL-Colesterol/química , LDL-Colesterol/metabolismo , Suplementos Nutricionais , Humanos , Estrutura Molecular , Fitosteróis/administração & dosagem , Fitosteróis/químicaRESUMO
The consumption of antioxidant-rich foods such as virgin olive oil (VOO) promotes high-density lipoprotein (HDL) anti-atherogenic capacities. Intake of functional VOOs (enriched with olive/thyme phenolic compounds (PCs)) also improves HDL functions, but the gene expression changes behind these benefits are not fully understood. Our aim was to determine whether these functional VOOs could enhance the expression of cholesterol efflux-related genes. In a randomized, double-blind, crossover, controlled trial, 22 hypercholesterolemic subjects ingested for three weeks 25 mL/day of: (1) a functional VOO enriched with olive oil PCs (500 mg/kg); (2) a functional VOO enriched with olive oil (250 mg/kg) and thyme PCs (250 mg/kg; FVOOT), and; (3) a natural VOO (olive oil PCs: 80 mg/kg, control intervention). We assessed whether these interventions improved the expression of cholesterol efflux-related genes in peripheral blood mononuclear cells by quantitative reverse-transcription polymerase chain reactions. The FVOOT intervention upregulated the expression of CYP27A1 (P = 0.041 and P = 0.053, versus baseline and the control intervention, respectively), CAV1 (P = 0.070, versus the control intervention), and LXRß, RXRα, and PPARß/δ (P = 0.005, P = 0.005, and P = 0.038, respectively, relative to the baseline). The consumption of a functional VOO enriched with olive oil and thyme PCs enhanced the expression of key cholesterol efflux regulators, such as CYP27A1 and nuclear receptor-related genes.
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Colesterol/sangue , Alimentos Fortificados , Hipercolesterolemia/dietoterapia , Metabolismo dos Lipídeos/genética , Azeite de Oliva/administração & dosagem , Fenóis/administração & dosagem , Extratos Vegetais/administração & dosagem , Thymus (Planta) , Biomarcadores/sangue , Estudos Cross-Over , Método Duplo-Cego , Feminino , Regulação da Expressão Gênica , Humanos , Hipercolesterolemia/sangue , Hipercolesterolemia/diagnóstico , Hipercolesterolemia/genética , Masculino , Pessoa de Meia-Idade , Fatores de Tempo , Resultado do TratamentoRESUMO
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 l-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.
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Colesterol/metabolismo , Microbioma Gastrointestinal , Fígado/metabolismo , Síndrome Metabólica/metabolismo , Metilaminas/metabolismo , Animais , Gluconeogênese/genética , Humanos , Lipogênese/genética , Síndrome Metabólica/genéticaRESUMO
SCOPE: The main findings of the "Virgin Olive Oil and HDL Functionality" (VOHF) study and other related studies on the effect of phenol-enriched virgin olive oil (VOO) supplementation on cardiovascular disease are integrated in the present work. METHODS AND RESULTS: VOHF assessed whether VOOs, enriched with their own phenolic compounds (FVOO) or with those from thyme (FVOOT), improve quantity and functionality of HDL. In this randomized, double-blind, crossover, and controlled trial, 33 hypercholesterolemic subjects received a control VOO (80 mg kg-1 ), FVOO (500 mg kg-1 ), and FVOOT (500 mg kg-1 ; 1:1) for 3 weeks. Both functional VOOs promoted cardioprotective changes, modulating HDL proteome, increasing fat-soluble antioxidants, improving HDL subclasses distribution, reducing the lipoprotein insulin resistance index, increasing endogenous antioxidant enzymes, protecting DNA from oxidation, ameliorating endothelial function, and increasing fecal microbial metabolic activity. Additional cardioprotective benefits were observed according to phenol source and content in the phenol-enriched VOOs. These insights support the beneficial effects of OO and PC from different sources. CONCLUSION: Novel therapeutic strategies should increase HDL-cholesterol levels and enhance HDL functionality. The tailoring of phenol-enriched VOOs is an interesting and useful strategy for enhancing the functional quality of HDL, and thus, it can be used as a complementary tool for the management of hypercholesterolemic individuals.
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Doenças Cardiovasculares/prevenção & controle , HDL-Colesterol/fisiologia , Hipercolesterolemia/tratamento farmacológico , Azeite de Oliva/farmacologia , HDL-Colesterol/sangue , Estudos Cross-Over , Método Duplo-Cego , Humanos , Resistência à Insulina , Azeite de Oliva/administração & dosagem , Azeite de Oliva/análise , Fenóis/farmacologia , ProteomaRESUMO
BACKGROUND: Environmental enteric dysfunction (EED) is widespread throughout the tropics and in children is associated with stunting and other adverse health outcomes. One of the hallmarks of EED is villus damage. In children with severe acute malnutrition (SAM) the severity of enteropathy is greater and short term mortality is high, but the metabolic consequences of enteropathy are unknown. Here, we characterize the urinary metabolic alterations associated with villus health, classic enteropathy biomarkers and anthropometric measurements in severely malnourished children in Zambia. METHODS/PRINCIPAL FINDINGS: We analysed 20 hospitalised children with acute malnutrition aged 6 to 23 months in Zambia. Small intestinal biopsies were assessed histologically (n = 15), anthropometric and gut function measurements were collected and the metabolic phenotypes were characterized by 1H nuclear magnetic resonance (NMR) spectroscopy. Endoscopy could not be performed on community controls children. Growth parameters were inversely correlated with enteropathy biomarkers (p = 0.011) and parameters of villus health were inversely correlated with translocation and permeability biomarkers (p = 0.000 and p = 0.015). Shorter villus height was associated with reduced abundance of metabolites related to gut microbial metabolism, energy and muscle metabolism (p = 0.034). Villus blunting was also related to increased sucrose excretion (p = 0.013). CONCLUSIONS/SIGNIFICANCE: Intestinal villus blunting is associated with several metabolic perturbations in hospitalized children with severe undernutrition. Such alterations include altered muscle metabolism, reinforcing the link between EED and growth faltering, and a disruption in the biochemical exchange between the gut microbiota and host. These findings extend our understanding on the downstream consequences of villus blunting and provide novel non-invasive biomarkers of enteropathy dysfunction. The major limitations of this study are the lack of comparative control group and gut microbiota characterization.