Molecular effects of the consumption of margarine and butter varying in trans fat composition: a parallel human intervention study

BACKGROUND Whereas the dietary intake of industrial trans fatty acids (iTFA) has been specifically associated with inflammation, cardiovascular disease, and type 2 diabetes, understanding the impact of dietary fats on human health remains challenging owing to their complex composition and individual effects of their lipid components on metabolism. The aim of this study is to profile the composition of blood, measured by the fatty acid (FAs) profile and untargeted metabolome of serum and the transcriptome of blood cells, in order to identify molecular signatures that discriminate dietary fat intakes. METHODS In a parallel study, the molecular effects of consuming dairy fat containing ruminant TFA (rTFA) or margarine containing iTFA were investigated. Healthy volunteers (n = 42; 45-69 y) were randomly assigned to diets containing margarine without TFA as major source of fat (wTFA control group with 0.4 g TFA per 100 g margarine), margarine with iTFA (iTFA group with 4.1 g TFA per 100 g margarine), or butter with rTFA (rTFA group with 6.3 g TFA per 100 g butter) for 4 weeks. The amounts of test products were individually selected so that fat intake contributed to 30-33% of energy requirements and TFA in the rTFA and iTFA groups contributed to up to 2% of energy intake. Changes in fasting blood values of lipid profiles (GC with flame-ionization detection), metabolome profiles (LC-MS, GC-MS), and gene expression (microarray) were measured. RESULTS Eighteen FAs, as well as 242 additional features measured by LC-MS (185) and GC-MS (54) showed significantly different responses to the diets (P$_{FDR-adjusted}$ < 0.05), mainly distinguishing butter from the margarine diets while gene expression was not differentially affected. The most abundant TFA in the butter, i.e. TFA containing (E)-octadec-11-enoic acid (C18:1 t11; trans vaccenic acid), and margarines, i.e. TFA containing (E)-octadec-9-enoic acid (C18:1 t9; elaidic acid) were reflected in the significantly different serum levels of TFAs measured after the dietary interventions. CONCLUSIONS The untargeted serum metabolome differentiates margarine from butter intake although the identification of the discriminating features remains a bottleneck. The targeted serum FA profile provides detailed information on specific molecules differentiating not only butter from margarine intake but also diets with different content of iTFAs in margarine. TRIAL REGISTRATION ClinicalTrials.gov NCT00933322

Molecular effects of the consumption of margarine and butter varying in trans fat composition: a parallel human intervention study.

BACKGROUND Whereas the dietary intake of industrial trans fatty acids (iTFA) has been specifically associated with inflammation, cardiovascular disease, and type 2 diabetes, understanding the impact of dietary fats on human health remains challenging owing to their complex composition and individual effects of their lipid components on metabolism. The aim of this study is to profile the composition of blood, measured by the fatty acid (FAs) profile and untargeted metabolome of serum and the transcriptome of blood cells, in order to identify molecular signatures that discriminate dietary fat intakes. METHODS In a parallel study, the molecular effects of consuming dairy fat containing ruminant TFA (rTFA) or margarine containing iTFA were investigated. Healthy volunteers (n = 42; 45-69 y) were randomly assigned to diets containing margarine without TFA as major source of fat (wTFA control group with 0.4 g TFA per 100 g margarine), margarine with iTFA (iTFA group with 4.1 g TFA per 100 g margarine), or butter with rTFA (rTFA group with 6.3 g TFA per 100 g butter) for 4 weeks. The amounts of test products were individually selected so that fat intake contributed to 30-33% of energy requirements and TFA in the rTFA and iTFA groups contributed to up to 2% of energy intake. Changes in fasting blood values of lipid profiles (GC with flame-ionization detection), metabolome profiles (LC-MS, GC-MS), and gene expression (microarray) were measured. RESULTS Eighteen FAs, as well as 242 additional features measured by LC-MS (185) and GC-MS (54) showed significantly different responses to the diets (PFDR-adjusted < 0.05), mainly distinguishing butter from the margarine diets while gene expression was not differentially affected. The most abundant TFA in the butter, i.e. TFA containing (E)-octadec-11-enoic acid (C18:1 t11; trans vaccenic acid), and margarines, i.e. TFA containing (E)-octadec-9-enoic acid (C18:1 t9; elaidic acid) were reflected in the significantly different serum levels of TFAs measured after the dietary interventions. CONCLUSIONS The untargeted serum metabolome differentiates margarine from butter intake although the identification of the discriminating features remains a bottleneck. The targeted serum FA profile provides detailed information on specific molecules differentiating not only butter from margarine intake but also diets with different content of iTFAs in margarine. TRIAL REGISTRATION ClinicalTrials.gov NCT00933322

Systematic interaction network filtering identifies CRMP1 as a novel suppressor of huntingtin misfolding and neurotoxicity

Assemblies of huntingtin (HTT) fragments with expanded polyglutamine (polyQ) tracts are a pathological hallmark of Huntington's disease (HD). The molecular mechanisms by which these structures are formed and cause neuronal dysfunction and toxicity are poorly understood. Here, we utilized available gene expression data sets of selected brain regions of HD patients and controls for systematic interaction network filtering in order to predict disease-relevant, brain region-specific HTT interaction partners. Starting from a large protein-protein interaction (PPI) data set, a step-by-step computational filtering strategy facilitated the generation of a focused PPI network that directly or indirectly connects 13 proteins potentially dysregulated in HD with the disease protein HTT. This network enabled the discovery of the neuron-specific protein CRMP1 that targets aggregation-prone, N-terminal HTT fragments and suppresses their spontaneous self-assembly into proteotoxic structures in various models of HD. Experimental validation indicates that our network filtering procedure provides a simple but powerful strategy to identify disease-relevant proteins that influence misfolding and aggregation of polyQ disease proteins.DFG [SFB740, 740/2-11, SFB618, 618/3-09, SFB/TRR43 A7]; BMBF(NGFN-Plus) [01GS08169-73, 01GS08150, 01GS08108]; HDSA Coalition for the Cure; EU (EuroSpin) [Health-F2-2009-241498, HEALTH-F2-2009-242167]; Helmholtz Association (MSBN, HelMA) [HA-215]; FCT [IF/00881/2013]info:eu-repo/semantics/publishedVersio

Inhibition of anti-tumor immunity by melanoma cell-derived Activin-A depends on STING

The transforming growth factor-β (TGF-β) family member activin A (hereafter Activin-A) is overexpressed in many cancer types, often correlating with cancer-associated cachexia and poor prognosis. Activin-A secretion by melanoma cells indirectly impedes CD8+ T cell-mediated anti-tumor immunity and promotes resistance to immunotherapies, even though Activin-A can be proinflammatory in other contexts. To identify underlying mechanisms, we here analyzed the effect of Activin-A on syngeneic grafts of Braf mutant YUMM3.3 mouse melanoma cells and on their microenvironment using single-cell RNA sequencing. We found that the Activin-A-induced immune evasion was accompanied by a proinflammatory interferon signature across multiple cell types, and that the associated increase in tumor growth depended at least in part on pernicious STING activity within the melanoma cells. Besides corroborating a role for proinflammatory signals in facilitating immune evasion, our results suggest that STING holds considerable potential as a therapeutic target to mitigate tumor-promoting Activin-A signaling at least in melanoma

Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus

A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 × 10-20), ER-negative BC (P=1.1 × 10-13), BRCA1-associated BC (P=7.7 × 10-16) and triple negative BC (P-diff=2 × 10-5). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 × 10-3) and ABHD8 (P<2 × 10-3). Chromosome conformation capture identifies interactions between four candidate SNPs and ABHD8, and luciferase assays indicate six risk alleles increased transactivation of the ADHD8 promoter. Targeted deletion of a region containing risk SNP rs56069439 in a putative enhancer induces ANKLE1 downregulation; and mRNA stability assays indicate functional effects for an ANKLE1 3′-UTR SNP. Altogether, these data suggest that multiple SNPs at 19p13 regulate ABHD8 and perhaps ANKLE1 expression, and indicate common mechanisms underlying breast and ovarian cancer risk

An original phylogenetic approach identified mitochondrial haplogroup T1a1 as inversely associated with breast cancer risk in BRCA2 mutation carriers

Introduction: Individuals carrying pathogenic mutations in the BRCA1 and BRCA2 genes have a high lifetime risk of breast cancer. BRCA1 and BRCA2 are involved in DNA double-strand break repair, DNA alterations that can be caused by exposure to reactive oxygen species, a main source of which are mitochondria. Mitochondrial genome variations affect electron transport chain efficiency and reactive oxygen species production. Individuals with different mitochondrial haplogroups differ in their metabolism and sensitivity to oxidative stress. Variability in mitochondrial genetic background can alter reactive oxygen species production, leading to cancer risk. In the present study, we tested the hypothesis that mitochondrial haplogroups modify breast cancer risk in BRCA1/2 mutation carriers. Methods: We genotyped 22,214 (11,421 affected, 10,793 unaffected) mutation carriers belonging to the Consortium of Investigators of Modifiers of BRCA1/2 for 129 mitochondrial polymorphisms using the iCOGS array. Haplogroup inference and association detection were performed using a phylogenetic approach. ALTree was applied to explore the reference mitochondrial evolutionary tree and detect subclades enriched in affected or unaffected individuals. Results: We discovered that subclade T1a1 was depleted in affected BRCA2 mutation carriers compared with the rest of clade T (hazard ratio (HR) = 0.55; 95% confidence interval (CI), 0.34 to 0.88; P = 0.01). Compared with the most frequent haplogroup in the general population (that is, H and T clades), the T1a1 haplogroup has a HR of 0.62 (95% CI, 0.40 to 0.95; P = 0.03). We also identified three potential susceptibility loci, including G13708A/rs28359178, which has demonstrated an inverse association with familial breast cancer risk. Conclusions: This study illustrates how original approaches such as the phylogeny-based method we used can empower classical molecular epidemiological studies aimed at identifying association or risk modification effects.Peer reviewe

Genome-Wide Association Study in BRCA1 Mutation Carriers Identifies Novel Loci Associated with Breast and Ovarian Cancer Risk

BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer), with a further replication in an additional sample of 2,646 BRCA1 carriers. We identified a novel breast cancer risk modifier locus at 1q32 for BRCA1 carriers (rs2290854, P = 2.7×10-8, HR = 1.14, 95% CI: 1.09-1.20). In addition, we identified two novel ovarian cancer risk modifier loci: 17q21.31 (rs17631303, P = 1.4×10-8, HR = 1.27, 95% CI: 1.17-1.38) and 4q32.3 (rs4691139, P = 3.4×10-8, HR = 1.20, 95% CI: 1.17-1.38). The 4q32.3 locus was not associated with ovarian cancer risk in the general population or BRCA2 carriers, suggesting a BRCA1-specific associat

Innovation et développement dans les systèmes agricoles et alimentaires

L’innovation est souvent présentée comme l’un des principaux leviers pour promouvoir un développement plus durable et plus inclusif. Dans les domaines de l’agriculture et de l’alimentation, l’innovation est marquée par des spécificités liées à sa relation à la nature, mais aussi à la grande diversité d’acteurs concernés, depuis les agriculteurs jusqu’aux consommateurs, en passant par les services de recherche et de développement. L’innovation émerge des interactions entre ces acteurs, qui mobilisent des ressources et produisent des connaissances dans des dispositifs collaboratifs, afin de générer des changements. Elle recouvre des domaines aussi variés que les pratiques de production, l’organisation des marchés, ou les pratiques alimentaires. L’innovation est reliée aux grands enjeux de développement : innovation agro-écologique, innovation sociale, innovation territoriale, etc. Cet ouvrage porte un regard sur l’innovation dans les systèmes agricoles et alimentaires. Il met un accent particulier sur l’accompagnement de l’innovation, en interrogeant les méthodes et les organisations, et sur l’évaluation de l’innovation au regard de différents critères. Il s’appuie sur des réflexions portées par différentes disciplines scientifiques, sur des travaux de terrain conduits tant en France que dans de nombreux pays du Sud, et enfin sur les expériences acquises en accompagnant des acteurs qui innovent. Il combine des synthèses sur l’innovation et des études de cas emblématiques pour illustrer les propos. L’ouvrage est destiné aux enseignants, professionnels, étudiants et chercheurs

Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus

A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P = 9.2 x 10(-20)), ER-negative BC (P = 1.1 x 10(-13)), BRCA1-associated BC (P = 7.7 x 10(-16)) and triple negative BC (P-diff = 2 x 10(-5)). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P = 2 x 10(-3)) and ABHD8 (PPeer reviewe