Biology subjects

Koulman, A.

Publications and source records attributed to Koulman, A..

At least 19 recordsLinked to original sources

bioRxiv2026

Pathological levels of α-synuclein increase basal mitophagy in Parkinson's dopamine neurons

Elevated -synuclein results in mitochondrial dysfunction, however the exact mechanism is poorly understood. -Synuclein localises to multiple subcellular sites including mitochondria, where it binds anionic lipids which regulate mitochondrial dynamics through DRP1. We hypothesised that pathogenic levels of -synuclein lead to dysregulation of mitophagy and lipid-dependent mitochondrial dynamics, causing mitochondrial and neuronal dysfunction. Using induced pluripotent stem cell-dopamine neurons (iPSC-DANs) carrying the -synuclein gene triplication mutation (SNCA-Trp) which causes an early-onset form of Parkinson's disease (PD), we established that elevated -synuclein increased basal mitophagy compared to healthy controls and overall loss of mitochondrial mass. This was associated with accumulation of basal mitophagy receptors BNIP3 and NIX and decreased proteasome activity, and was independent of PINK1-Parkin mitophagy. We identified reduced mitochondrial gene expression by single cell RNAseq, mirroring heightened mitophagy and mitochondrial depletion. We found increased levels of DRP1-dependent mitochondrial fission and perturbed levels of anionic lipids, including cardiolipin and phosphatidic acid, two lipids which directly bind to -synuclein. Pharmacological inhibition of DRP1 reversed the excessive basal mitophagy in SNCA-Trp neurons and restored deficits in cellular ATP and calcium release. Finally, we assessed neuronal function and found that impairment of mitochondrial dysfunction by elevated -synuclein led to reductions in neuronal firing activity. Inhibition of DRP1 rescued the neuronal activity deficit in SNCA-Trp neurons, suggesting that relieving - instead of increasing - mitophagy pressure may be beneficial in -synuclein-driven PD.

cell biology↗

bioRxiv2026

Phenotypic screening in Parkinson's iPSC-dopamine neurons identifies the FASN-SREBP1 axis as a potential therapeutic target

Parkinson's disease (PD) remains highly challenging to model in vitro, particularly when seeking robust functional phenotypes for target discovery. Patient-derived induced pluripotent stem cell dopaminergic neurons (iPSC-DANs) offer a promising platform to address this challenge. Because calcium dyshomeostasis is well-described in PD pathophysiology, it offers a platform for phenotypic screening. We have previously shown that GBA-N370S iPSC-DANs display impaired intracellular calcium release. Here, we used this disease-relevant phenotype to undertake a 4,108-compound phenotypic screen in GBA-N370S (GBA-NS) iPSC-DANs. This screen identified fatty acid synthase (FASN) as the most enriched protein target. The ability of compounds to rescue calcium release correlated with biochemical potency against FASN across multiple chemical series. We confirmed that FASN knockdown increased intracellular calcium release, supporting an on-target effect. Untargeted lipidomics demonstrated broad remodelling of the neuronal lipidome after FASN inhibition, confirming target engagement. FASN inhibition also increased active a-glucocerebrosidase (GCase), reduced extracellular a-synuclein release and ER stress, and altered RASGRF1 expression. Mechanistically, FASN inhibition activated sterol regulatory element-binding protein 1 (SREBP1), and SREBP1 overexpression alone was sufficient to increase intracellular calcium release, identifying a FASN-SREBP1-calcium homeostasis axis in human neurons. Finally, the FASN inhibitor BI 99179 achieved brain exposure and reduced brain fatty acid levels while inducing an SRE-associated transcriptional response in a Parkinson's mouse model, providing evidence of in vivo target engagement. These findings establish patient iPSC-neuron functional screening as a tractable discovery platform to identify targets which can be taken in vivo and nominate the FASN-SREBP1 axis as a candidate therapeutic pathway in PD.

neuroscience↗

bioRxiv2026

CLN6 is a glycerophosphoglycerol epimerase in bis(monoacylglycero)phosphate biosynthesis

Lysosomal catabolism depends on bis(monoacylglycero)phosphate (BMP), a phospholipid with atypical S,S stereochemistry of unknown biosynthetic origin. CLN8 and CLN5 catalyze sequential acylation steps in BMP synthesis, and their loss of function causes Batten disease, a group of inherited neurodegenerative lysosomal storage disorders. Here we identify CLN6, a biochemically uncharacterized endoplasmic reticulum protein whose loss also causes Batten disease, as the calcium-dependent glycerophosphoglycerol epimerase that establishes BMP stereochemistry upstream of CLN8. CLN6 deficiency depletes BMP in cells, mice, and patient lysosomes, and reduces lysosomal hydrolase levels. BMP-precursor supplementation bypasses CLN6, restores BMP and increases hydrolase abundance in CLN6-deficient cells and mice. These findings place three Batten disease proteins in a single biosynthetic pathway and reveal BMP deficiency as a reversible cause of disrupted lysosomal hydrolase homeostasis.

biochemistry↗

bioRxiv2026

Nuclear Pct1 couples phosphatidylcholine synthesis with membrane biogenesis

Phosphatidylcholine (PC) is the major eukaryotic phospholipid and its synthesis must be homeostatically controlled to prevent excess membrane and organelle growth. Here we investigate how PC synthesis by the Kennedy pathway is coordinated with membrane biogenesis. In budding yeast, the rate-limiting enzyme Pct1 is nuclear and reversibly associates with the inner nuclear membrane (INM) in response to lipid packing defects caused by low PC. We show that the enzymes acting after Pct1 to generate PC remain at the endoplasmic reticulum (ER) during pathway activation. Relocating the final PC synthesis step to different endomembrane sites does not alter the kinetics of Pct1 release from the INM, indicating that newly made PC equilibrates with the INM rapidly. In contrast, elevated phosphatidic acid locks Pct1 at the INM, prevents pathway inactivation and drives nuclear/ER membrane proliferation. These results support a model in which nuclear Pct1 senses lipid imbalance while ER-localized enzymes supply PC; disrupting this homeostasis leads to uncontrolled membrane biogenesis.

cell biology↗

bioRxiv2025

Stereospecific GPG acylation by CLN8 drives BMP biosynthesis and its loss leads to Batten disease

Loss-of-function mutations in the endoplasmic reticulum membrane protein CLN8 cause Batten disease, a neurodegenerative lysosomal storage disorder1. Together with the lysosomal enzyme CLN5, CLN8 mediates the biosynthesis of bis(monoacylglycero)phosphate (BMP), a phospholipid essential for lysosomal function and distinguished by its unique S,S stereochemistry2,3. However, the role of CLN8 in BMP synthesis has remained unclear. Here we establish that CLN8 is a glycerophosphoglycerol (GPG) acyltransferase that catalyses the stereospecific acylation of S,S-GPG to produce S,S-lysophosphatidylglycerol (LPG), the CLN5 substrate in BMP synthesis. Using cryo-electron microscopy, we resolve structures of the CLN8 homodimer in apo and substrate-bound states at 2.7 [A] resolution, revealing the active site architecture and a ping-pong acyl transfer mechanism. Batten disease-causing missense mutations impair CLN8 enzymatic activity in vitro and reduce BMP levels in a Cln8R24G knock- in mouse, whereas the Cln8mnd mouse frameshift mutation causes complete loss of BMP in vivo. Exogenous S,S-LPG, but not the R,S stereoisomer, restored BMP synthesis in CLN8- deficient cells and mice, and improved neurological phenotypes in cln8 mutant zebrafish. Together, these findings define the enzymatic function of CLN8, elucidate the biochemical basis of CLN8 Batten disease, and establish a proof-of-concept for treating it through stereospecific BMP precursor supplementation.

biochemistry↗

bioRxiv2025

Functional Lipid Analysis via Index-Based Lipidomics Profile: A New Computational Module in LipidOne

Understanding the functional roles of lipids is essential for interpreting metabolic phenotypes in health, disease, and dietary interventions. Here, we present a major update to LipidOne, a user-friendly web-based platform for lipidomic data interpretation (lipidone.eu), introducing the novel analytical module: Functional Lipid Analysis (FLA). This component enables the assessment of the quantitative features of lipidomic datasets through a biologically structured, index-based approach. The FLA module computes 42 indices representing specific lipid function-- including membrane structure, energy storage, and signaling. These indices are derived from lipid classes, molecular species, and fatty acyl-, alkyl-, and alkenyl-chain composition. Each index is statistically compared across experimental groups and analyzed and visualized through dedicated tools, including bar plots, volcano plots, PCA, PLS-DA, heatmaps, and functional radar charts. Every index is semantically annotated with biologically meaningful phrases, allowing users to move beyond numerical variations and toward mechanistic insights of lipid function. In the FLA module, index variations are further linked to predicted protein mediators, bridging lipid alterations to enzymatic pathways and enabling network-based interpretations. This integrative strategy lays the foundation for a systems biology perspective, connecting lipidomics to proteomics and or transcriptomics yielding functional pathway analysis. We demonstrate the utility of this framework using datasets from two published works. In both cases, FLA confirmed the authors conclusions and yielded additional, biologically coherent functional readouts not originally emphasized. By shifting the focus from individual lipid species to interpretable biochemical indices, LipidOne 2.3 offers a reproducible, scalable, and biologically informed platform for systems-level lipid biology and hypothesis generation.

bioinformatics↗

bioRxiv2025

Biological landscape of acute illness in children in sub-Saharan Africa and South Asia

Childhood illnesses including pneumonia, diarrhoea and malaria are leading causes of hospitalisation and mortality in resource-limited settings. However, we lack understanding of whether systemic responses to such diverse clinical syndromes are shared or specific, how they are impacted by malnutrition and how they differ from well children. We performed multi-omic profiling of plasma proteins, and serum metabolites and lipids in acutely ill hospitalised and well children in sub-Saharan Africa and South Asia. Using network-based clustering and mixed-effects modelling, we identified common and syndrome-specific omics responses to acute illness. We found that malnutrition often modifies host responses to disease. Although the internal structure of individual omics modules was largely preserved between ill and well children, the interactions between these preserved modules were markedly reorganised during acute illness. Compared to well children, biological systems in hospitalised children were more interconnected, exhibiting denser cross-omics interactions. These findings reveal widespread multisystem mobilisation during paediatric acute illness, offer deeper mechanistic insights and highlight candidate pathways for therapeutic intervention in high-burden settings.

systems biology↗

bioRxiv2025

IRP1 deficiency alters mitochondrial metabolism and protects against metabolic syndrome pathologies

Iron regulatory protein 1 (IRP1) is a post-transcriptional regulator of cellular iron metabolism. In mice, loss of IRP1 causes polycythemia through translational de-repression of hypoxia-inducible factor 2 (HIF2) mRNA, which increases renal erythropoietin production. Here we show that Irp1-/- mice develop fasting hypoglycemia and are protected against high-fat diet-induced hyperglycemia and hepatic steatosis. Discovery-based proteomics of Irp1-/- livers revealed a mitochondrial dysfunction signature. Seahorse flux analysis in primary hepatocytes and differentiated skeletal muscle myotubes confirmed impaired respiratory capacity, with a shift from oxidative phosphorylation to glycolytic ATP production. This metabolic rewiring was associated with enhanced insulin sensitivity and increased glucose uptake in skeletal muscle. Under metabolic stress, IRP1 deficiency altered the redox balance of mitochondrial iron, resulting in inefficient energy production and accumulation of amino acids and metabolites in skeletal muscle, rendering them unavailable for hepatic gluconeogenesis. These findings identify IRP1 as a critical regulator of systemic energy homeostasis.

pathology↗

bioRxiv2025

Adaptive thermogenesis reprograms the behavioural and metabolic responses to protein restriction for successful amino acid homeostasis

Reduced protein intake is proposed to contribute to the obesity epidemic, but existing murine models of protein restriction do not promote obesity, limiting insight into underlying mechanisms. Here we show that mice self-select a consistent daily protein intake, independent of energy needs. Under mild protein restriction (7-10% protein), mice exhibit hyperphagia and increased adiposity. This hyperphagic response is blunted at thermoneutrality, leading to loss of lean mass and body weight. Protein-restricted mice also fail to exhibit protein preference at thermoneutrality, despite elevated circulating FGF21 levels. Circulating levels of essential amino acids (AAs) are tightly regulated during protein restriction at 22{degrees}C, but this regulation is lost at 28{degrees}C. Metabolomic and transcriptional analyses revealed a role for hepatic and brown fat AA-derived acylcarnitines and N-acetyl AAs in buffering free AA levels for the maintenance of AA homeostasis at 22{degrees}C, but these pathways are blunted at thermoneutrality. Thus, the behavioural and metabolic adaptations to protein restriction rely on coordinated peripheral and central mechanisms, modulated by ambient temperature. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=63 SRC="FIGDIR/small/667623v1_ufig1.gif" ALT="Figure 1"> View larger version (19K): org.highwire.dtl.DTLVardef@1d1a9e1org.highwire.dtl.DTLVardef@1e7f3b5org.highwire.dtl.DTLVardef@131276borg.highwire.dtl.DTLVardef@130757_HPS_FORMAT_FIGEXP M_FIG C_FIG

physiology↗

bioRxiv2024

Early life milk diets shape infant gut microbiota: evidence of microbial plasticity in response to breast and formula milk.

In early life, diet plays a key role in shaping the infant microbiota, yet the impact of breast milk and formula on microbial ecosystems at different stages of infant development remains poorly understood. Here, we performed static batch culture experiments using infant faecal samples at ages 1, 12 and 18 months of age, supplemented with either breast milk or formula for 48 hours. We further removed small metabolites (e.g. small carbohydrates, proteins and lipids) from breast and formula milk through dialysis and also added this to the static batch cultures with faecal samples from each infant. Our results show that the one-month-old faecal microbiota exhibited the greatest sensitivity to dietary intervention, with significant changes in microbial composition, metabolites and lipids, particularly in response to formula supplementation. In contrast, the microbiota at 12 months displayed increased stability, while the 18-month-old infant samples were the most resilient to different dietary supplementation. We also observed that triglyceride (TG46:1) was produced in the youngest infant samples but consumed by the older infant microbiota, suggesting a shift in metabolic interactions as the gut microbiota diversifies with age. Metabolite profiles linked to KEGG pathways further indicated the older infants diverse microbiotas had greater functional capacity in comparison to the one-month-old infant, particularly in response to breast milk. Fewer overall metabolic pathways were affected when the infant samples were grown in formula. Collectively, our data underscores the importance of early life diet in shaping microbiota profiles, with more stable microbial dynamics in more mature gut ecosystems, in response to dietary changes which are also associated with downstream functional (i.e. metabolite/lipid) readouts. Notably, the removal of small metabolites from breast milk by dialysis highlighted the potential role of milk lipids in promoting growth of foundational microbiota members like Bifidobacterium. Our data, along with further studies, are required to probe the mechanisms by which specific nutrients, particularly lipids, modulate microbial composition and support infant health during the first 2 years of life.

microbiology↗

bioRxiv2024

Damaging mutations in LXRα uncouple lipogenesis from hepatotoxicity and implicate hepatic cholesterol sensing in human liver health

The nuclear receptor Liver X Receptor- (LXR) activates lipogenic gene expression in hepatocytes. Its inhibition has therefore been proposed as a strategy to treat metabolic-dysfunction-associated steatotic liver disease (MASLD). In order to understand the impact of reducing LXR activity on human health we first examined the association between the carriage of rare loss of function mutations in NR1H3 (encoding LXR) and metabolic and hepatic phenotypes. We identified 63 rare predicted damaging variants in the ligand binding domain of LXR in 454,787 participants in UK Biobank. On functional characterisation, 42 of these were found to be severely impaired. Consistent with loss of the lipogenic actions of LXR, carriers of damaging mutations in LXR had reduced serum triglycerides ({beta}=-0.13 s.d. {+/-}0.03, P=2.7x10-5, N(carriers)=971). Surprisingly, these carriers also had elevated concentrations of serum liver enzymes (e.g. ALT: {beta}=0.17s.d. {+/-}0.03, P=1.1x10-8, N(carriers)=972) with a 35% increased risk of clinically significant elevations in ALT (OR=1.32, 95%CI:1.15-1.53, P=1.2x10-4, N(carriers)=972), suggestive of hepatotoxicity. We generated a knock-in mouse carrying one of the most severely damaging mutations (Nr1h3 p.W441R) which we demonstrated to have dominant negative properties. Homozygous knock-in mice rapidly developed severe hepatitis and fibrotic liver injury following exposure to western diet despite markedly reduced steatosis, liver triglycerides and lipogenic gene expression. This phenotype was completely rescued by viral over-expression of wildtype LXR specifically in hepatocytes, indicating a cell-autonomous effect of the mutant on hepatocyte health. While homozygous LXR knockout mice showed some evidence of hepatocyte injury under similar dietary conditions, the phenotype of the LXRW441R/W441R mouse was much more severe, suggesting that dominant negative mutations that actively co-repress target genes can result in pathological impacts significantly more severe than those seen with simple absence of the receptor. In summary, our results show that loss of function mutations in LXR occur in at least 1/450 people and are associated with evidence of liver dysfunction. These findings implicate LXR in the maintenance of human liver health, identify a new murine model of rapidly progressive fibrotic liver disease and caution against LXR antagonism as a therapeutic strategy for MASLD.

genetics↗

bioRxiv2023

ZFP57 is a regulator of postnatal growth and life-long health

Early-life factors, including nutrition, shape long-term health outcomes. Despite the essential role of lactation in maternal nutritional support, the influence of epigenetic factors on lactation and postnatal growth remains poorly understood. Zinc-finger protein 57 (ZFP57), is an epigenetic regulator of genomic imprinting, a process that directs gene expression based on parental origin, playing a vital role in mammalian prenatal growth. Here, we identify a novel function of ZFP57 in regulating the mammary gland, where it serves as a key modulator of postnatal resource control, independently of imprinted genes. ZFP57 influences multiple aspects of mammary gland function, including ductal branching and cellular homeostasis. Its absence leads to significant differential gene expression, related to alveologenesis, lactogenesis and milk synthesis, associated with delayed lactation and altered milk composition. This results in life-long impacts on offspring including the development of metabolic syndrome. Cross-fostering reveals intricate dynamics between mother and offspring during lactation. Pups raised by a dam of a different genotype than their birth mother exhibit exacerbated metabolic features in adulthood, providing additional insight into the programming of offspring long-term health by maternal context. This study deepens our understanding of the interplay between epigenetic factors, lactation, and postnatal resource control and identifies ZFP57 as a major regulator of both pre and postnatal resource control in mammals.

developmental biology↗

bioRxiv2023

A co-ordinated transcriptional programme in the maternal liver supplies LC-PUFAs to the conceptus using phospholipids

Essential fatty acids (EFAs) and their derivatives, the long and very long chain polyunsaturated fatty acids (LC-PUFAs), are preferentially transported by the mother to the fetus. Failure to supply EFAs is strongly linked with stillbirth, fetal growth restriction, and impaired neurodevelopmental outcomes. However, dietary supplementation during pregnancy is unable to simply reverse these outcomes, suggesting imperfectly understood interactions between dietary EFA intake and the molecular mechanisms of maternal supply. Here we combine untargeted lipidomics with transcriptional profiling of healthy and genetically-manipulated murine models to understand the maternal adaptations required to provide LC-PUFAs to the developing fetus. We discovered a late pregnancy-specific, selective activation of the Liver X Receptor signalling pathway which dramatically increases maternal supply of LC-PUFAs within circulating phospholipids. Crucially, genetic ablation of this pathway in the mother reduced LC-PUFA accumulation by the fetus. Overall our work suggests new molecular strategies for improving maternal-fetal transfer of these important lipids.

physiology↗

bioRxiv2021

Placental polyamines regulate acetyl-coA and histone acetylation in a sex-dependent manner

Fetal sex differences play an important role in the pathophysiology of several placenta-related pregnancy complications. We previously reported that the maternal circulating level of a polyamine metabolite was altered in a fetal sex-specific manner, and was associated with pre-eclampsia and fetal growth restriction. Here we show that placental polyamine metabolism is altered in these disorders and that polyamines influence widespread changes in gene expression by regulating the availability of acetyl-CoA which is necessary for histone acetylation. Sex differences in polyamine metabolism are associated with escape from X chromosome inactivation of the gene encoding the enzyme spermine synthase in female placentas, as evidenced by biallelic expression of the gene in female trophoblasts. Polyamine depletion in primary human trophoblasts impairs glycolysis and mitochondrial metabolism resulting in decreased availability of acetyl-CoA and global histone hypoacetylation, in a sex-dependent manner. Chromatin-immunoprecipitation sequencing and RNA-sequencing identifies downregulation of progesterone biosynthetic pathways as a key target and polyamine depletion reduced progesterone release in male trophoblasts. Collectively, these findings suggest that polyamines regulate placental endocrine function through metabolic regulation of gene expression, and that sex differences in polyamine metabolism due to XCI escape may buffer the effects of placental dysfunction in pregnancy disorders.

physiology↗

bioRxiv2021

Maternal diet-induced obesity during pregnancy alters lipid supply to fetuses and changes the cardiac tissue lipidome in a sex- dependent manner

Maternal obesity during pregnancy has immediate and long-term detrimental effects on the offspring heart. In this study, we characterized the cardiac and circulatory lipid profiles in fetuses of diet-induced obese pregnant mice and established the changes in lipid abundance and fetal cardiac transcriptomics. We used untargeted and targeted lipidomics and transcriptomics to define changes in the serum and cardiac lipid composition and fatty acid metabolism in male and female fetuses. From these analyses we observed: (1) maternal obesity affects the maternal and fetal serum lipidome distinctly; (2) female heart lipidomes are more sensitive to maternal obesity than male fetuses; (3) changes in lipid supply might contribute to early expression of lipolytic genes in mouse hearts exposed to maternal obesity. These results highlight the existence of sexually dimorphic responses of the fetal heart to the same in utero obesogenic environment and identify lipids species that might mediate programming of cardiovascular health.

developmental biology↗

bioRxiv2020

Revealing grand-paternal programming of lipid metabolism using a novel computational tool

While the consequences of poor maternal diet on the offspring’s cardio-metabolic health have been studied in detail, the role of the father’s diet on the health of his offspring is poorly understood. We used a known mouse model to establish the impact of an isocaloric paternal low-protein high-carbohydrate diet on the offspring’s lipid metabolism. Detailed lipid profiles were acquired from F1 neonate (3 weeks), F1 adult (16 weeks) and F2 neonate male and female offspring, in serum, liver, brain, heart and abdominal adipose tissues by Mass Spectrometry and Nuclear Magnetic Resonance. Using a purpose-built computational tool for analysing lipid metabolism as a network, we characterised the number, type and abundance of lipid variables in and between tissues (Lipid Traffic Analysis), finding a variety of alterations associated with paternal diet. These elucidate a mechanism for the defective physiological behaviour of systems at risk of cardio-metabolic disease.Competing Interest StatementThe authors have declared no competing interest.View Full Text

developmental biology↗

bioRxiv2020

Lipid extraction from dried blood spots and dried milk spots for high throughput lipidomics

Dried blood spots (DBS) and dried milk spots (DMS) represent convenient matrices for collecting and storing human samples. However, the use of these sample types for researching lipid metabolism remains relatively poorly explored, and especially the efficiency of lipid extraction is unclear. A visual inspection of punched DBSs after standard extraction suggests that the samples remain largely intact. DMSs comprise a dense aggregate of milk fat globules on one side of the card, suggesting that the lipid fraction may be physically inaccessible. This led us to the hypotheses that decoagulating may facilitate lipid extraction from both DBSs and DMSs. We tested decoagulation using a mixture of strong chaeotropes (guanidine and thiourea) in both DBS and DMS in the context of high throughput lipidomics (96/384w plate). Extraction of lipids from DMSs was tested with established extractions and one novel solvent mixture in a high throughput format. We found that exposure of DBSs to chaeotropes facilitated collection of the lipid fraction but was ineffective for DMSs. The lipid fraction of DMSs was best isolated without water, using a mixture of xylene/methanol/isopropanol (1:2:4). We conclude that decoagulation is essential for efficient extraction of lipids from DBSs and that a non-aqueous procedure using a spectrum of solvents is the best procedure for extracting lipids from DMSs. These methods represent convenient steps that are compatible with the sample structure and type, and with high throughput lipidomics. HighlightsO_LIThe efficiency of lipid extractions on dried milk and dried blood spots was tested C_LIO_LIThe number of lipid variables and the total signal strength were used as objective measures C_LIO_LIDecoagulation of dried blood spots improved extraction efficiency C_LIO_LIA mixture of xylene, methanol and isopropanol isolates the lipid fraction best from DMSs C_LIO_LIAn aqueous extraction using dichloromethane was the most efficient method for isolating lipids from DBSs C_LI

biochemistry↗

bioRxiv2020

Extreme phenotypes define epigenetic and metabolic signatures in cardiometabolic syndrome.

Improving the understanding of cardiometabolic syndrome pathophysiology and its relationship with thrombosis are ongoing healthcare challenges. Using plasma biomarkers analysis coupled with the transcriptional and epigenetic characterisation of cell types involved in thrombosis, obtained from two extreme phenotype groups (obese and lipodystrophy) and comparing these to lean individuals and blood donors, the present study identifies the molecular mechanisms at play, highlighting patterns of abnormal activation in innate immune phagocytic cells and shows that extreme phenotype groups could be distinguished from lean individuals, and from each other, across all data layers. The characterisation of the same obese group, six months after bariatric surgery shows the loss of the patterns of abnormal activation of innate immune cells previously observed. However, rather than reverting to the gene expression landscape of lean individuals, this occurs via the establishment of novel gene expression landscapes. Netosis and its control mechanisms emerge amongst the pathways that show an improvement after surgical intervention. Taken together, by integrating across data layers, the observed molecular and metabolic differences form a disease signature that is able to discriminate, amongst the blood donors, those individuals with a higher likelihood of having cardiometabolic syndrome, even when not presenting with the classic features.

genomics↗