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Industrial food processing and its possible adverse effects on health are widely debated in scientific literature and media. There is not much known about consumers' attitudes towards the processing of foods. Therefore, a questionnaire (n = 463) was distributed and interviews (n = 11) were conducted with Dutch consumers to evaluate the attitudes and associations towards industrial food processing and to assess opinions about communications on food processing and health. The results showed that 51% of the respondents had a neutral, 23% had a positive, and 26% had a negative attitude towards food processing. Respondents with a background in food by profession or education (n = 159) had more frequently a positive attitude towards food processing (P = 0.008). Respondents and interviewees pointed out both positive and negative associations with industrial processing: additives, artificial, not fresh, low nutritional value, unnatural, but also palatability, food safety, shelf life, and convenience. The questionnaire showed that 70% of the respondents thought food processing had a (slightly) negative health effect. Most interviewees indicated that when doing groceries, food processing per se is not relevant in food choices, although some critically inspected the ingredients. Furthermore, interviewees indicated that communication about food and health is scattered and complex. They would like to gain easy and straightforward information from a central source. From the questionnaire respondents, 60% indicated that they would like to have more information about food processing. In conclusion, most Dutch consumers in this study have a neutral and nuanced attitude towards industrial food processing. A connection with food via profession or education showed a more positive attitude, which may indicate the importance of knowledge and the need for clear communication about nutrition, ingredients, and food processing.
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Several risk factors are associated with gallstone disease after bariatric surgery, but the underlying pathophysiological mechanisms of gallstone formation are unclear. We hypothesize that gallstone formation after bariatric surgery is induced by different pathways compared with gallstone formation in the general population, since postoperative formation occurs rapidly in patients who did not develop gallstones in preceding years. To identify both pathophysiological and potentially protective mechanisms against postoperative gallstone formation, we compared the preoperative fasting metabolome, fecal microbiome, and liver and adipose tissue transcriptome obtained before or during bariatric surgery of obese patients with and without postoperative gallstones. In total, 88 patients were selected from the BARIA longitudinal cohort study. Within this group, 32 patients had postoperative gallstones within 2 years. Gut microbiota metagenomic analyses showed group differences in abundance of 41 bacterial species, particularly abundance of Lactobacillaceae and Enterobacteriaceae in patients without gallstones. Subcutaneous adipose tissue transcriptomic analyses revealed four genes that were suppressed in gallstone patients compared with patients without gallstones. These baseline gene expression and gut microbiota composition differences might relate to protective mechanisms against gallstone formation after bariatric surgery. Moreover, baseline fasting blood samples of patients with postoperative gallstones showed increased levels of several bile acids. Overall, we revealed different genes and bacteria associated with gallstones than those previously reported in the general population, supporting the hypothesis that gallstone formation after bariatric surgery follows a different trajectory. Further research is necessary to confirm the involvement of the bile acids, adipose tissue activity, and microbial species observed here.
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Cirugía Bariátrica , Cálculos Biliares , Microbioma Gastrointestinal , Humanos , Cálculos Biliares/etiología , Cálculos Biliares/cirugía , Microbioma Gastrointestinal/genética , Ácidos y Sales Biliares , Estudios Longitudinales , Cirugía Bariátrica/efectos adversos , Tejido Adiposo , BacteriasRESUMEN
INTRODUCTION: Prevalence of obesity and associated diseases, including type 2 diabetes mellitus, dyslipidaemia and non-alcoholic fatty liver disease (NAFLD), are increasing. Underlying mechanisms, especially in humans, are unclear. Bariatric surgery provides the unique opportunity to obtain biopsies and portal vein blood-samples. METHODS: The BARIA Study aims to assess how microbiota and their metabolites affect transcription in key tissues and clinical outcome in obese subjects and how baseline anthropometric and metabolic characteristics determine weight loss and glucose homeostasis after bariatric surgery. We phenotype patients undergoing bariatric surgery (predominantly laparoscopic Roux-en-Y gastric bypass), before weight loss, with biometrics, dietary and psychological questionnaires, mixed meal test (MMT) and collect fecal-samples and intra-operative biopsies from liver, adipose tissues and jejunum. We aim to include 1500 patients. A subset (approximately 25%) will undergo intra-operative portal vein blood-sampling. Fecal-samples are analyzed with shotgun metagenomics and targeted metabolomics, fasted and postprandial plasma-samples are subjected to metabolomics, and RNA is extracted from the tissues for RNAseq-analyses. Data will be integrated using state-of-the-art neuronal networks and metabolic modeling. Patient follow-up will be ten years. RESULTS: Preoperative MMT of 170 patients were analysed and clear differences were observed in glucose homeostasis between individuals. Repeated MMT in 10 patients showed satisfactory intra-individual reproducibility, with differences in plasma glucose, insulin and triglycerides within 20% of the mean difference. CONCLUSION: The BARIA study can add more understanding in how gut-microbiota affect metabolism, especially with regard to obesity, glucose metabolism and NAFLD. Identification of key factors may provide diagnostic and therapeutic leads to control the obesity-associated disease epidemic.
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Cirugía Bariátrica , Microbioma Gastrointestinal , Obesidad Mórbida/metabolismo , Obesidad Mórbida/cirugía , Proyectos de Investigación , Biología de Sistemas , Adulto , Biomarcadores/metabolismo , Hígado Graso/metabolismo , Femenino , Glucosa/metabolismo , Humanos , Insulina/metabolismo , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Países Bajos , Fenotipo , Triglicéridos/metabolismoRESUMEN
INTRODUCTION: The gut microbiome may contribute to the development of obesity. So far, the extent of microbiome variation in people with obesity has not been determined in large cohorts and for a wide range of body mass index (BMI). Here, we aimed to investigate whether the faecal microbial metagenome can explain the variance in several clinical phenotypes associated with morbid obesity. METHODS: Caucasian subjects were recruited at our hospital. Blood pressure and anthropometric measurements were taken. Dietary intake was determined using questionnaires. Shotgun metagenomic sequencing was performed on faecal samples from 177 subjects. RESULTS: Subjects without obesity (n = 82, BMI 24.7 ± 2.9 kg m-2 ) and subjects with obesity (n = 95, BMI 38.6 ± 5.1 kg m-2 ) could be clearly distinguished based on microbial composition and microbial metabolic pathways. A total number of 52 bacterial species differed significantly in people with and without obesity. Independent of dietary intake, we found that microbial pathways involved in biosynthesis of amino acids were enriched in subjects with obesity, whereas pathways involved in the degradation of amino acids were depleted. Machine learning models showed that more than half of the variance in body fat composition followed by BMI could be explained by the gut microbiome, composition and microbial metabolic pathways, compared with 6% of variation explained in triglycerides and 9% in HDL. CONCLUSION: Based on the faecal microbiota composition, we were able to separate subjects with and without obesity. In addition, we found strong associations between gut microbial amino acid metabolism and specific microbial species in relation to clinical features of obesity.
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Microbioma Gastrointestinal , Obesidad Mórbida/microbiología , Delgadez/microbiología , Adulto , Aminoácidos/metabolismo , Índice de Masa Corporal , Heces/microbiología , Humanos , Aprendizaje Automático , Redes y Vías Metabólicas , Metagenómica , Persona de Mediana Edad , Obesidad Mórbida/metabolismo , Delgadez/metabolismoRESUMEN
Sporadically, patients with a proven defect in either mFAO or OXPHOS are described presenting with a metabolic profile and clinical phenotype expressing concurrent defects in both pathways. Biochemical linkages between both processes are tight. Therefore, it is striking that concurrent dysfunction of both systems occurs so infrequent. In this review, the linkages between OXPHOS and mFAO and the hypothesized processes responsible for concurrent problems in both systems are reviewed, both from the point of view of primary biochemical connections and secondary cellular responses, i.e. signaling pathways constituting nutrient-sensing networks. We propose that affected signaling pathways may play an important role in the phenomenon of concurrent defects. Recent data indicate that interference in the affected signaling pathways may resolve the pathological phenotype even though the primary enzyme deficiency persists. This offers new (unexpected) prospects for treatment of these inborn errors of metabolism. This article is part of a Special Issue entitled: From Genome to Function.
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There is unequivocal evidence that high-density lipoprotein (HDL) cholesterol levels in plasma are inversely associated with the risk of cardiovascular disease (CVD). Studies of families with inherited HDL disorders and genetic association studies in general (and patient) population samples have identified a large number of factors that control HDL cholesterol levels. However, they have not resolved why HDL cholesterol and CVD are inversely related. A growing body of evidence from nongenetic studies shows that HDL in patients at increased risk of CVD has lost its protective properties and that increasing the cholesterol content of HDL does not result in the desired effects. Hopefully, these insights can help improve strategies to successfully intervene in HDL metabolism. It is clear that there is a need to revisit the HDL hypothesis in an unbiased manner. True insights into the molecular mechanisms that regulate plasma HDL cholesterol and triglycerides or control HDL function could provide the handholds that are needed to develop treatment for, e.g., type 2 diabetes and the metabolic syndrome. Especially genome-wide association studies have provided many candidate genes for such studies. In this review we have tried to cover the main molecular studies that have been produced over the past few years. It is clear that we are only at the very start of understanding how the newly identified factors may control HDL metabolism. In addition, the most recent findings underscore the intricate relations between HDL, triglyceride, and glucose metabolism indicating that these parameters need to be studied simultaneously.
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Enfermedades Cardiovasculares/sangre , HDL-Colesterol/sangre , Animales , Biomarcadores/sangre , Enfermedades Cardiovasculares/etiología , Enfermedades Cardiovasculares/genética , HDL-Colesterol/química , HDL-Colesterol/genética , Predisposición Genética a la Enfermedad , Humanos , Fenotipo , Factores Protectores , Conformación Proteica , Medición de Riesgo , Factores de Riesgo , Relación Estructura-ActividadRESUMEN
Background: 3ß-hydroxy-Δ5-C27-steroid-oxidoreductase (3ß-HSD) deficiency is a bile acid synthesis disorder that leads to the absence of normal primary bile acids and the accumulation of abnormal bile acids. This results in cholestatic jaundice, fat-soluble vitamin deficiency, acholic or fatty stools and failure to thrive. Bile acid supplementation is used to treat 3ß-HSD-deficiency and its symptoms. Methods: This report details the case of a 28-year-old woman diagnosed with 3ß-HSD-deficiency, who was treated with glycine-conjugated deoxycholic acid (gDCA). Results: gDCA treatment successfully restored normal bile acid levels, improved body weight by reducing fat malabsorption, and was well-tolerated with no observed liver problems or side effects. Conclusions: As a potent FXR ligand, gDCA might exert its action through FXR activation leading to bile acid synthesis regulation.
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Obesity and type 2 diabetes mellitus (T2DM) are attributed to a combination of genetic susceptibility and lifestyle factors. Their increasing prevalence necessitates further studies on modifiable causative factors and novel treatment options. The gut microbiota has emerged as an important contributor to the obesity--and T2DM--epidemic proposed to act by increasing energy harvest from the diet. Although obesity is associated with substantial changes in the composition and metabolic function of the gut microbiota, the pathophysiological processes remain only partly understood. In this review we will describe the development of the adult human microbiome and discuss how the composition of the gut microbiota changes in response to modulating factors. The influence of short-chain fatty acids, bile acids, prebiotics, probiotics, antibiotics and microbial transplantation is discussed from studies using animal and human models. Ultimately, we aim to translate these findings into therapeutic pathways for obesity and T2DM in humans.
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Ácidos y Sales Biliares/metabolismo , Diabetes Mellitus Tipo 2/microbiología , Ácidos Grasos Volátiles/metabolismo , Tracto Gastrointestinal/microbiología , Metagenoma , Obesidad/microbiología , Animales , Antibacterianos/uso terapéutico , Cirugía Bariátrica , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/fisiopatología , Dieta , Tracto Gastrointestinal/metabolismo , Tracto Gastrointestinal/fisiopatología , Humanos , Ratones , Obesidad/metabolismo , Obesidad/fisiopatología , Prebióticos , Probióticos/uso terapéuticoRESUMEN
We evaluated oxyphytosterol (OPS) concentrations in plasma and various tissues of two genetically modified mouse models with either increased cholesterol (apoE KO mice) or increased cholesterol and plant sterol (PS) concentrations (apoExABCG8 dKO mice). Sixteen female apoE KO and 16 dKO mice followed the same standard, low OPS-chow diet. Animals were euthanized at 36 weeks to measure PS and OPS concentrations in plasma, brain, liver and aortic tissue. Cholesterol and oxysterol (OS) concentrations were analyzed as reference for sterol oxidation in general. Plasma campesterol (24.1 ± 4.3 vs. 11.8 ± 3.0 mg/dL) and sitosterol (67.4 ± 12.7 vs. 4.9 ± 1.1 mg/dL) concentrations were severely elevated in the dKO compared to the apoE KO mice (p < 0.001). Also, in aortic and brain tissue, PS levels were significantly elevated in dKO. However, plasma, aortic and brain OPS concentrations were comparable or even lower in the dKO mice. In contrast, in liver tissue, both PS and OPS concentrations were severely elevated in the dKO compared to apoE KO mice (sum OPS: 7.4 ± 1.6 vs. 4.1 ± 0.8 ng/mg, p < 0.001). OS concentrations followed cholesterol concentrations in plasma and all tissues suggesting ubiquitous oxidation. Despite severely elevated PS concentrations, OPS concentrations were only elevated in liver tissue, suggesting that OPS are primarily formed in the liver and plasma concentrations originate from hepatic spill-over into the circulation.
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Hígado/metabolismo , Oxiesteroles/sangre , Fitosteroles/sangre , Transportador de Casete de Unión a ATP, Subfamilia G, Miembro 8/genética , Animales , Apolipoproteínas E/genética , Colesterol/análogos & derivados , Colesterol/sangre , Colesterol/metabolismo , Femenino , Metabolismo de los Lípidos/genética , Lipoproteínas/genética , Ratones , Ratones Noqueados , Oxidación-Reducción , Oxiesteroles/metabolismo , Fitosteroles/metabolismo , Sitoesteroles/sangre , Sitoesteroles/metabolismoRESUMEN
AIMS: We aimed to describe differences in the prevalence of intermediate hyperglycaemia (IH) between six ethnic groups. Moreover, to investigate differences in the association of the classifications of IH with the incidence of T2DM between ethnic groups. METHODS: We included 3759 Dutch, 2826 African Surinamese, 1646 Ghanaian, 2571 Turkish, 2691 Moroccan and 1970 South Asian Surinamese origin participants of the HELIUS study. IH was measured by fasting plasma glucose (FPG) and HbA1c. We calculated age-, BMI and physical-activity-adjusted prevalence of IH by sex, and calculated age and sex-adjusted hazard ratios (HR)for the association between IH and T2DM in each ethnic group. RESULTS: The prevalence of IH was higher among ethnic minority groups (68.6-41.7%) than the Dutch majority (34.9%). The prevalence of IH categories varied across subgroups. Combined increased FPG and HbA1c was most prevalent in South-Asian Surinamese men (27.6%, 95 %CI: 24.5-30.9%), and in Dutch women (4.2%, 95 %CI: 3.4-5.1%). The HRs for T2DM for each IH-classification did not differ significantly between ethnic groups. HRs were highest for the combined classification, e.g., HR = 8.1, 95 %CI: 2.5-26.6 in the Dutch. CONCLUSION: We found a higher prevalence of IH in ethnic minority versus majority groups, but did not find evidence for a differential association of IH with incident T2DM.
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Diabetes Mellitus Tipo 2 , Hiperglucemia , Diabetes Mellitus Tipo 2/etiología , Etnicidad , Femenino , Ghana , Hemoglobina Glucada , Humanos , Hiperglucemia/complicaciones , Hiperglucemia/epidemiología , Incidencia , Masculino , Grupos Minoritarios , Países Bajos/epidemiología , PrevalenciaRESUMEN
PURPOSE: Cachexia is a multifactorial syndrome, associated with poor survival in patients with cancer, and is influenced by the gut microbiota. We investigated the effects of fecal microbiota transplantation (FMT) on cachexia and treatment response in patients with advanced gastroesophageal cancer. EXPERIMENTAL DESIGN: In a double-blind randomized placebo-controlled trial performed in the Amsterdam University Medical Center, we assigned 24 cachectic patients with metastatic HER2-negative gastroesophageal cancer to either allogenic FMT (healthy obese donor) or autologous FMT, prior to palliative chemotherapy (capecitabine and oxaliplatin). Primary objective was to assess the effect of allogenic FMT on satiety. Secondary outcomes were other features of cachexia, along with disease control rate (DCR), overall survival (OS), progression-free survival (PFS), and toxicity. Finally, exploratory analyses were performed on the effect of FMT on gut microbiota composition (metagenomic sequencing) and metabolites (untargeted metabolomics). RESULTS: Allogenic FMT did not improve any of the cachexia outcomes. Patients in the allogenic group (n = 12) had a higher DCR at 12 weeks (P = 0.035) compared with the autologous group (n = 12), longer median OS of 365 versus 227 days [HR = 0.38; 95% confidence interval (CI), 0.14-1.05; P = 0.057] and PFS of 204 versus 93 days (HR = 0.50; 95% CI, 0.21-1.20; P = 0.092). Patients in the allogenic group showed a significant shift in fecal microbiota composition after FMT (P = 0.010) indicating proper engraftment of the donor microbiota. CONCLUSIONS: FMT from a healthy obese donor prior to first-line chemotherapy did not affect cachexia, but may have improved response and survival in patients with metastatic gastroesophageal cancer. These results provide a rational for larger FMT trials.
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Caquexia/etiología , Caquexia/terapia , Neoplasias Esofágicas/complicaciones , Trasplante de Microbiota Fecal , Microbioma Gastrointestinal , Neoplasias Gástricas/complicaciones , Adulto , Anciano , Caquexia/microbiología , Método Doble Ciego , Neoplasias Esofágicas/microbiología , Neoplasias Esofágicas/patología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Obesidad/microbiología , Sobrepeso/microbiología , Neoplasias Gástricas/microbiología , Neoplasias Gástricas/patologíaRESUMEN
Subjects with increased cholesterol absorption might benefit more from statin therapy combined with a cholesterol absorption inhibitor. We assessed whether baseline cholesterol absorption markers were associated with response to ezetimibe/simvastatin therapy, in terms of LDL-cholesterol (LDL-C) lowering and cholesterol absorption inhibition, in patients with familial hypercholesterolemia (FH). In a posthoc analysis of the two-year ENHANCE trial, we assessed baseline cholesterol-adjusted campesterol (campesterol/TC) and sitosterol/TC ratios in 591 FH patients. Associations with LDL-C changes and changes in cholesterol absorption markers were evaluated by multiple regression analysis. No association was observed between baseline markers of cholesterol absorption and the extent of LDL-C response to ezetimibe/simvastatin therapy (beta = 0.020, P = 0.587 for campesterol/TC and beta<0.001, P = 0.992 for sitosterol/TC). Ezetimibe/simvastatin treatment reduced campesterol levels by 68% and sitosterol levels by 62%; reductions were most pronounced in subjects with the highest cholesterol absorption markers at baseline, the so-called high absorbers (P < 0.001). Baseline cholesterol absorption status does not determine LDL-C lowering response to ezetimibe/simvastatin therapy in FH, despite more pronounced cholesterol absorption inhibition in high absorbers. Hence, these data do not support the use of baseline absorption markers as a tool to determine optimal cholesterol lowering strategy in FH patients. However, due to the exploratory nature of any posthoc analysis, these results warrant further prospective evaluation in different populations.
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Anticolesterolemiantes/uso terapéutico , Azetidinas/uso terapéutico , Colesterol/sangre , Colesterol/metabolismo , Hiperlipoproteinemia Tipo II/tratamiento farmacológico , Absorción Intestinal/efectos de los fármacos , Simvastatina/uso terapéutico , Adulto , Anciano , Anticolesterolemiantes/clasificación , Biomarcadores/sangre , Colesterol/análogos & derivados , LDL-Colesterol/sangre , Método Doble Ciego , Quimioterapia Combinada , Ezetimiba , Femenino , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Masculino , Persona de Mediana Edad , Fitosteroles/sangre , Sitoesteroles/sangre , Estadística como AsuntoRESUMEN
Evidence is accumulating that short chain fatty acids (SCFA) play an important role in the maintenance of gut and metabolic health. The SCFA acetate, propionate and butyrate are produced from the microbial fermentation of indigestible carbohydrates and appear to be key mediators of the beneficial effects elicited by the gut microbiome. Microbial SCFA production is essential for gut integrity by regulating the luminal pH, mucus production, providing fuel for epithelial cells and effects on mucosal immune function. SCFA also directly modulate host metabolic health through a range of tissue-specific mechanisms related to appetite regulation, energy expenditure, glucose homeostasis and immunomodulation. Therefore, an increased microbial SCFA production can be considered as a health benefit, but data are mainly based on animal studies, whereas well-controlled human studies are limited. In this review an expert group by ILSI Europe's Prebiotics Task Force discussed the current scientific knowledge on SCFA to consider the relationship between SCFA and gut and metabolic health with a particular focus on human evidence. Overall, the available mechanistic data and limited human data on the metabolic consequences of elevated gut-derived SCFA production strongly suggest that increasing SCFA production could be a valuable strategy in the preventing gastro-intestinal dysfunction, obesity and type 2 diabetes mellitus. Nevertheless, there is an urgent need for well controlled longer term human SCFA intervention studies, including measurement of SCFA fluxes and kinetics, the heterogeneity in response based on metabolic phenotype, the type of dietary fibre and fermentation site in fibre intervention studies and the control for factors that could shape the microbiome like diet, physical activity and use of medication.
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Ácidos Grasos Volátiles/metabolismo , Enfermedades Gastrointestinales/prevención & control , Microbioma Gastrointestinal , Tracto Gastrointestinal/inmunología , Tracto Gastrointestinal/microbiología , Animales , Metabolismo de los Hidratos de Carbono , Diabetes Mellitus Tipo 2/prevención & control , Interacciones Microbiota-Huesped , Humanos , Obesidad/prevención & control , PrebióticosRESUMEN
A recent population-based study showed that cholesteryl ester transfer protein (CETP) gene variations, which relate to lower plasma CETP, may predict increased cardiovascular risk, in spite of higher HDL cholesterol. Among other functions, CETP activity contributes to cellular cholesterol efflux, an early step in the anti-atherogenic reverse cholesterol transport (RCT) process. We hypothesized that cellular cholesterol efflux stimulating capacity of plasma could be associated with CETP gene variation. In this study, we tested the extent to which the ability of plasma to promote cholesterol efflux from cultured human fibroblasts is associated with CETP gene variation. In 223 men, the -629C-->A CETP promoter polymorphism, plasma lipids, CETP mass, cholesteryl ester transfer (CET), lecithin:cholesterol acyltransferase (LCAT) activity and the ability of plasma to promote cholesterol efflux from human skin fibroblasts, obtained from a single normolipidemic donor, were determined. In -629CC homozygotes (n=52), cholesterol efflux, plasma CETP mass, CET and LCAT activity were higher, whereas HDL cholesterol was lower compared to -629 AA homozygotes (n=62) and -629CA+AA carriers (n=171) (P<0.05 to P<0.001). Univariate correlation analysis showed that cellular cholesterol efflux was related to CETP genotype (P=0.04), plasma CET (P<0.05), LCAT activity (P<0.001) and apo A-I (P<0.05). Multiple linear regression analysis confirmed the independent association of cellular cholesterol efflux to plasma with CETP genotype. In conclusion, an association of cellular cholesterol efflux with the -629C-->A CETP polymorphism, possibly also involving LCAT activity, could provide a mechanism explaining why CETP gene variation, which relates to lower plasma CETP, does not confer diminished cardiovascular risk.
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Proteínas de Transferencia de Ésteres de Colesterol/metabolismo , Colesterol/metabolismo , Fibroblastos/metabolismo , Fosfatidilcolina-Esterol O-Aciltransferasa/metabolismo , Plasma , Polimorfismo Genético/genética , Regiones Promotoras Genéticas/genética , Adenina/metabolismo , Células Cultivadas , Proteínas de Transferencia de Ésteres de Colesterol/genética , Citosina/metabolismo , Fibroblastos/enzimología , Humanos , MasculinoRESUMEN
OBJECTIVE: Studies in mice suggest that plasma apoM is lowered in hyperinsulinaemic diabetes and that apoM stimulates formation of pre-beta-HDL. Pre-beta-HDL is an acceptor of cellular cholesterol and may be critical for reverse cholesterol transport. Herein, we examined whether patients with type 2 diabetes have reduced plasma apoM and whether apoM is associated with pre-beta-HDL formation and cellular cholesterol efflux. DESIGN: In 78 patients with type 2 diabetes and 89 control subjects, we measured plasma apoM with ELISA, pre-beta-HDL and pre-beta-HDL formation, phospholipid transfer protein (PLTP) activity and the ability of plasma to promote cholesterol efflux from cultured fibroblasts. RESULTS: ApoM was approximately 9% lower in patients with type 2 diabetes compared to controls (0.025 +/- 0.006 vs. 0.027 +/- 0.007 g L(-1), P = 0.01). The difference in apoM was largely attributable to diabetes-associated obesity. ApoM was positively related to both HDL (r = 0.16; P = 0.04) and LDL cholesterol (r = 0.28; P = 0.0003). Pre-beta-HDL and pre-beta-HDL formation were not different between diabetic and control subjects. ApoM predicted pre-beta-HDL (r = 0.16; P = 0.04) and pre-beta-HDL formation (r = 0.19; P = 0.02), even independently of positive relationships with apoA-I, HDL-cholesterol and PLTP activity. Cellular cholesterol efflux to plasma was positively related to pre-beta-HDL and PLTP activity but not significantly to apoM. CONCLUSIONS: Plasma apoM is modestly reduced in type 2 diabetes. Pre-beta-HDL and pre-beta-HDL formation are positively associated with apoM, supporting the hypothesis that apoM plays a role in HDL remodelling in humans. Lower apoM may provide a mechanism to explain why pre-beta-HDL formation is not increased in type 2 diabetes despite elevated PLTP activity.
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Apolipoproteínas/sangre , Diabetes Mellitus Tipo 2/sangre , Lipoproteínas de Alta Densidad Pre-beta/biosíntesis , Anciano , Apolipoproteína A-I/sangre , Apolipoproteínas M , Biomarcadores/sangre , Estudios de Casos y Controles , Células Cultivadas , Colesterol/sangre , Colesterol/metabolismo , HDL-Colesterol/sangre , Diabetes Mellitus Tipo 2/metabolismo , Femenino , Fibroblastos/metabolismo , Lipoproteínas de Alta Densidad Pre-beta/sangre , Humanos , Modelos Lineales , Lipocalinas , Masculino , Síndrome Metabólico/sangre , Persona de Mediana Edad , Proteínas de Transferencia de Fosfolípidos/sangre , Estadísticas no ParamétricasRESUMEN
Dietary plant sterols and stanols as present in our diet and in functional foods are well-known for their inhibitory effects on intestinal cholesterol absorption, which translates into lower low-density lipoprotein cholesterol concentrations. However, emerging evidence suggests that plant sterols and stanols have numerous additional health effects, which are largely unnoticed in the current scientific literature. Therefore, in this review we pose the intriguing question "What would have occurred if plant sterols and stanols had been discovered and embraced by disciplines such as immunology, hepatology, pulmonology or gastroenterology before being positioned as cholesterol-lowering molecules?" What would then have been the main benefits and fields of application of plant sterols and stanols today? We here discuss potential effects ranging from its presence and function intrauterine and in breast milk towards a potential role in the development of non-alcoholic steatohepatitis (NASH), cardiovascular disease (CVD), inflammatory bowel diseases (IBD) and allergic asthma. Interestingly, effects clearly depend on the route of entrance as observed in intestinal-failure associated liver disease (IFALD) during parenteral nutrition regimens. It is only until recently that effects beyond lowering of cholesterol concentrations are being explored systematically. Thus, there is a clear need to understand the full health effects of plant sterols and stanols.
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Asma/tratamiento farmacológico , Enfermedades Cardiovasculares/tratamiento farmacológico , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Fitosteroles/farmacología , Sitoesteroles/farmacología , Asma/metabolismo , Enfermedades Cardiovasculares/metabolismo , Colesterol/metabolismo , LDL-Colesterol/antagonistas & inhibidores , LDL-Colesterol/metabolismo , Humanos , Enfermedades Inflamatorias del Intestino/metabolismo , Absorción Intestinal/efectos de los fármacos , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Fitosteroles/administración & dosificación , Sitoesteroles/administración & dosificaciónRESUMEN
Genetic parameters for somatic cell score (SCS) in the Italian Holstein-Friesian population were estimated addressing the pattern of genetic correlation with protein yield in different parities (first, second, and third) and on different days in milk within each parity. Three approaches for parameter estimation were applied using random samples of herds from the national database of the Italian Holstein Association. Genetic correlations for lactation measures (305-d protein yield and lactation SCS) were positive in the first parity (0.31) and close to zero in the second (0.01) and third (0.09) parities. These results indicated that larger values of SCS were genetically associated with increased production. The second and third sets of estimates were based on random regression test-day models, modeling the shape of lactation curve with the Wilmink function and fourth-order Legendre polynomials, respectively. Genetic correlations from both random regression models showed a specific pattern associated with days in milk within and across parities. Estimates varied from positive to negative in the first and second parity, and from null to negative in the third parity. Patterns were similar for both random regression models. The average overall correlation between SCS and protein yield was zero or slightly positive in the first lactation and ranged from zero to negative in later lactations. Correlation estimates differed by parity and stage of lactation. They also demonstrated the dubiousness of applying a single genetic correlation measure between SCS and protein in setting selection strategies. Differences in magnitude and the sign of genetic correlations between SCS and yields across and within parities should be accounted for in selection schemes.
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Bovinos/genética , Proteínas de la Leche/análisis , Leche/química , Leche/citología , Modelos Genéticos , Animales , Femenino , Lactancia/genéticaRESUMEN
Metaphase spindles assemble to a steady state in length by mechanisms that involve microtubule dynamics and motor proteins, but they are incompletely understood. We found that Xenopus extract spindles recapitulate the length of egg meiosis II spindles, by using mechanisms intrinsic to the spindle. To probe these mechanisms, we perturbed microtubule polymerization dynamics and opposed motor proteins and measured effects on spindle morphology and dynamics. Microtubules were stabilized by hexylene glycol and inhibition of the catastrophe factor mitotic centromere-associated kinesin (MCAK) (a kinesin 13, previously called XKCM) and destabilized by depolymerizing drugs. The opposed motors Eg5 and dynein were inhibited separately and together. Our results are consistent with important roles for polymerization dynamics in regulating spindle length, and for opposed motors in regulating the relative stability of bipolar versus monopolar organization. The response to microtubule destabilization suggests that an unidentified tensile element acts in parallel with these conventional factors, generating spindle shortening force.
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Extractos Celulares/química , Meiosis , Microtúbulos/efectos de los fármacos , Huso Acromático/metabolismo , Adenilil Imidodifosfato/farmacología , Animales , Western Blotting , Dineínas/antagonistas & inhibidores , Femenino , Glicoles/farmacología , Cinesinas/antagonistas & inhibidores , Cinética , Microscopía de Polarización , Microscopía por Video , Modelos Biológicos , Oocitos/química , Xenopus , Proteínas de Xenopus/antagonistas & inhibidoresRESUMEN
BACKGROUND: Gut microbiota-derived short-chain fatty acids (SCFAs) have been associated with beneficial metabolic effects. However, the direct effect of oral butyrate on metabolic parameters in humans has never been studied. In this first in men pilot study, we thus treated both lean and metabolic syndrome male subjects with oral sodium butyrate and investigated the effect on metabolism. METHODS: Healthy lean males (n = 9) and metabolic syndrome males (n = 10) were treated with oral 4 g of sodium butyrate daily for 4 weeks. Before and after treatment, insulin sensitivity was determined by a two-step hyperinsulinemic euglycemic clamp using [6,6-2H2]-glucose. Brown adipose tissue (BAT) uptake of glucose was visualized using 18F-FDG PET-CT. Fecal SCFA and bile acid concentrations as well as microbiota composition were determined before and after treatment. RESULTS: Oral butyrate had no effect on plasma and fecal butyrate levels after treatment, but did alter other SCFAs in both plasma and feces. Moreover, only in healthy lean subjects a significant improvement was observed in both peripheral (median Rd: from 71 to 82 µmol/kg min, p < 0.05) and hepatic insulin sensitivity (EGP suppression from 75 to 82% p < 0.05). Although BAT activity was significantly higher at baseline in lean (SUVmax: 12.4 ± 1.8) compared with metabolic syndrome subjects (SUVmax: 0.3 ± 0.8, p < 0.01), no significant effect following butyrate treatment on BAT was observed in either group (SUVmax lean to 13.3 ± 2.4 versus metabolic syndrome subjects to 1.2 ± 4.1). CONCLUSIONS: Oral butyrate treatment beneficially affects glucose metabolism in lean but not metabolic syndrome subjects, presumably due to an altered SCFA handling in insulin-resistant subjects. Although preliminary, these first in men findings argue against oral butyrate supplementation as treatment for glucose regulation in human subjects with type 2 diabetes mellitus.
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Tejido Adiposo Pardo/efectos de los fármacos , Tejido Adiposo Pardo/metabolismo , Butiratos/administración & dosificación , Glucosa/metabolismo , Resistencia a la Insulina/fisiología , Síndrome Metabólico/metabolismo , Delgadez/metabolismo , Administración Oral , Adulto , Ácidos y Sales Biliares/metabolismo , Metabolismo Energético , Ácidos Grasos Volátiles/sangre , Ácidos Grasos Volátiles/metabolismo , Heces/química , Fluorodesoxiglucosa F18 , Microbioma Gastrointestinal , Humanos , Hígado/metabolismo , Masculino , Síndrome Metabólico/tratamiento farmacológico , Proyectos Piloto , Tomografía Computarizada por Tomografía de Emisión de Positrones , Radiofármacos , Adulto JovenRESUMEN
The ABC transporter ABCA1 regulates HDL levels and is considered to control the first step of reverse cholesterol transport from the periphery to the liver. To test this concept, we studied the effect of ABCA1 deficiency on hepatic metabolism and hepatobiliary flux of cholesterol in mice. Hepatic lipid contents and biliary secretion rates were determined in Abca1(-/-), Abca1(+/-), and Abca1(+/+) mice with a DBA background that were fed either standard chow or a high-fat, high-cholesterol diet. Hepatic cholesterol and phospholipid contents in Abca1(-/-) mice were indistinguishable from those in Abca1(+/-) and Abca1(+/+) mice on both diets. In spite of the absence of HDL, biliary secretion rates of cholesterol, bile salts, and phospholipid were unimpaired in Abca1(-/-) mice. Neither the hepatic expression levels of genes controlling key steps in cholesterol metabolism nor the contribution of de novo synthesis to biliary cholesterol and bile salts were affected by Abca genotype. Finally, fecal excretion of neutral and acidic sterols was similar in all groups. We conclude that plasma HDL levels and ABCA1 activity do not control net cholesterol transport from the periphery via the liver into the bile, indicating that the importance of HDL in reverse cholesterol transport requires re-evaluation.