Biology subjects

Clish, C. B.

Publications and source records attributed to Clish, C. B..

At least 37 records · Page 2Linked to original sources

bioRxiv2023

Metabolic Reprogramming of the Neovascular Niche Promotes Regenerative Angiogenesis in Proliferative Retinopathy

Healthy blood vessels supply neurons to preserve metabolic function. In blinding ischemic proliferative retinopathies (PRs), pathological neovascular tufts often emerge in lieu of needed physiological neuroretina revascularization. We show that metabolic shifts in the neurovascular niche define this angiogenic dichotomy between healthy and diseased blood vessel growth. Fatty acid oxidation (FAO) metabolites accumulated in human and murine retinopathy samples. Neovascular tufts with a distinct single-cell transcriptional signature highly expressed FAO enzymes. The deletion of Sirt3, an FAO regulator, shifted the neurovascular niche metabolism from FAO to glycolysis and suppressed tuft formation. This metabolic transition increased Vegf expression in astrocytes and reprogrammed pathological EC to a physiological phenotype, hastening vascular regeneration of the ischemic retina. Our findings identify SIRT3 as a metabolic switch in the neurovascular niche, offering a new therapeutic target for optimizing ischemic tissue revascularization. HighlightsO_LIPathological EC favor FAO over glycolysis. C_LIO_LIUnique signature for pathological EC found in proliferative retinopathy model. C_LIO_LISirt3 deletion shifts astrocytes and EC metabolism from FAO to glycolysis. C_LIO_LIMetabolic reprogramming of the vascular niche enhances physiological revascularization. C_LI Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=83 SRC="FIGDIR/small/566898v1_ufig1.gif" ALT="Figure 1"> View larger version (21K): org.highwire.dtl.DTLVardef@70020eorg.highwire.dtl.DTLVardef@19719acorg.highwire.dtl.DTLVardef@1168ddeorg.highwire.dtl.DTLVardef@1bc25e0_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

bioRxiv2023

Lac-Phe mediates the anti-obesity effect of metformin

Metformin is a widely prescribed anti-diabetic medicine that also reduces body weight. The mechanisms that mediate metformins effects on energy balance remain incompletely defined. Here we show that metformin is a powerful pharmacological inducer of the anorexigenic metabolite Lac-Phe in mice as well as in two independent human cohorts. In cell culture, metformin drives Lac-Phe biosynthesis via inhibition of complex I, increased glycolytic flux, and intracellular lactate mass action. Other biguanides and structurally distinct inhibitors of oxidative phosphorylation also increase Lac-Phe levels in vitro. Genetic ablation of CNDP2, the principal biosynthetic enzyme for Lac-Phe, in mice renders animals resistant to metformins anorexigenic and anti-obesity effects. Mediation analyses also support a role for Lac-Phe in metformins effect on body mass index in humans. These data establish the CNDP2/Lac-Phe pathway as a critical mediator of the effects of metformin on energy balance.

physiology↗

bioRxiv2023

Beneficial metabolic effects of PAHSAs depend on the gut microbiota in diet-induced obese mice

Dietary lipids play an essential role in regulating the function of the gut microbiota and gastrointestinal tract, and these luminal interactions contribute to mediating host metabolism. PAHSAs are a class of lipids with anti-diabetic and anti-inflammatory properties, but whether the gut microbiota contributes to their beneficial effects on host metabolism is unknown. Here, we report that treating high fat diet (HFD)-fed germ-free mice with PAHSAs does not improve insulin sensitivity. However, transfer of feces from PAHSA-treated, but not Vehicle-treated, chow-fed mice increases insulin-sensitivity in HFD-fed germ free mice. Thus, the gut microbiota is necessary for and can transmit the insulin-sensitizing effects of PAHSAs in HFD-fed germ-free mice. Functional analyses of the cecal metagenome and lipidome of PAHSA-treated mice identified multiple lipid species that associate with the gut commensal Bacteroides thetaiotaomicron (Bt) and with insulin sensitivity resulting from PAHSA treatment. Bt supplementation in HFD-fed female mice prevented weight gain, reduced adiposity, improved glucose tolerance, fortified the colonic mucus barrier and reduced systemic inflammation versus chow-fed controls, effects that were not observed in HFD-fed male mice. Furthermore, ovariectomy partially reversed the beneficial Bt effects on host metabolism, indicating a role for sex hormones in mediating probiotic effects. Altogether, these studies highlight the fact that lipids can modulate the gut microbiota resulting in improvement in host metabolism and that PAHSA-induced changes in the microbiota result in at least some of their insulin-sensitizing effects in female mice.

physiology↗

bioRxiv2023

Identification and targeting of microbial putrescine acetylation in bloodstream infections

The growth of antimicrobial resistance (AMR) has highlighted an urgent need to identify bacterial pathogenic functions that may be targets for clinical intervention. Although severe bacterial infections profoundly alter host metabolism, prior studies have largely ignored alterations in microbial metabolism in this context. Performing metabolomics on patient and mouse plasma samples, we identify elevated levels of bacterially-derived N- acetylputrescine during gram-negative bloodstream infections (BSI), with higher levels associated with worse clinical outcomes. We discover that SpeG is the bacterial enzyme responsible for acetylating putrescine and show that blocking its activity reduces bacterial proliferation and slows pathogenesis. Reduction of SpeG activity enhances bacterial membrane permeability and results in increased intracellular accumulation of antibiotics, allowing us to overcome AMR of clinical isolates both in culture and in vivo. This study highlights how studying pathogen metabolism in the natural context of infection can reveal new therapeutic strategies for addressing challenging infections.

microbiology↗

bioRxiv2023

Multi-omics characterization of partial chemical reprogramming reveals evidence of cell rejuvenation

Partial reprogramming by cyclic short-term expression of Yamanaka factors holds promise for shifting cells to younger states and consequently delaying the onset of many diseases of aging. However, the delivery of transgenes and potential risk of teratoma formation present challenges for in vivo applications. Recent advances include the use of cocktails of compounds to reprogram somatic cells, but the characteristics and mechanisms of partial cellular reprogramming by chemicals remain unclear. Here, we report a multi-omics characterization of partial chemical reprogramming in fibroblasts from young and aged mice. We measured the effects of partial chemical reprogramming on the epigenome, transcriptome, proteome, phosphoproteome, and metabolome. At the transcriptome, proteome, and phosphoproteome levels, we saw widescale changes induced by this treatment, with the most notable signature being an upregulation of mitochondrial oxidative phosphorylation. Furthermore, at the metabolome level, we observed a reduction in the accumulation of aging-related metabolites. Using both transcriptomic and epigenetic clock-based analyses, we show that partial chemical reprogramming reduces the biological age of mouse fibroblasts. We demonstrate that these changes have functional impacts, as evidenced by changes in cellular respiration and mitochondrial membrane potential. Taken together, these results illuminate the potential for chemical reprogramming reagents to rejuvenate aged biological systems and warrant further investigation into adapting these approaches for in vivo age reversal.

molecular biology↗

bioRxiv2023

Eclipse: Alignment of Two or More Nontargeted LC-MS Metabolomics Datasets using Directed Subalignments

Nontargeted LC-MS metabolomics datasets contain a wealth of information but present many challenges during analysis and processing. Often, two or more independently processed datasets must be aligned to form a complete dataset, but no available software meets our needs. For this, we have created an open-source Python package called Eclipse. Eclipse uses a novel graph-based subalignment approach to handle complex matching scenarios that arise from n>2 datasets. Eclipse is open source (https://github.com/broadinstitute/bmxp) and can be installed via "pip install bmxp".

bioinformatics↗

bioRxiv2023

Early cellular and molecular signatures correlate with severity of West Nile Virus infection

Infection with West Nile Virus (WNV) can drive a wide range of responses, from asymptomatic to flu-like symptoms/fever or severe cases of encephalitis and death. To identify cellular and molecular signatures distinguishing WNV severity, we employed systems profiling of peripheral blood from asymptomatic and severely ill individuals infected with WNV. We interrogated immune responses longitudinally from acute infection through convalescence at 3 months and 1 year employing multiplexed single cell protein and transcriptional profiling (CyTOF and Seq-Well) complemented with matched serum proteomics and metabolomics. At the acute time point, we detected both an elevated proportion of pro-inflammatory markers in innate immune cell types and reduced frequency of regulatory T cell activity in participants with severe infection compared to those with asymptomatic infection. Single-cell transcriptomics of paired samples revealed that asymptomatic donors had higher expression of genes associated with innate immune pathways, in particular anti-inflammatory CD16+ monocytes at the acute time point. A multi-omics analysis identified factors--beyond those from individual analyses--that distinguished immune state trajectory between severity groups. Here we highlighted the potential of systems immunology using multiple cell-type and cell-state-specific analyses to identify correlates of infection severity and host cellular activity contributing to an effective anti-viral response.

immunology↗

bioRxiv2023

Screening in serum-derived medium reveals differential response to compounds targeting metabolism

INTRODUCTION INTRODUCTION RESULTS DISCUSSION KEY RESOURCES TABLE CONTACT FOR REAGENT AND... EXPERIMENTAL MODEL AND SUBJECT... METHOD DETAILS QUANTIFICATION AND STATISTICAL... Data resources DATA AND SOFTWARE AVAILABILITY AUTHOR CONTRIBUTIONS DECLARATION OF INTERESTS REFERENCES Studies of cancer cells in standard culture conditions have long been used as a tractable tool for drug discovery. Cell culture provides unparalleled experimental flexibility, scalability, and low cost to identify and understand the response to cancer therapeutics; however, drug responses in culture are not always predictive of drug response in animal models or in patients1 ...

cancer biology↗

bioRxiv2023

FALCON systematically interrogates free fatty acid biology and identifies a novel mediator of lipotoxicity

Cellular exposure to free fatty acids (FFA) is implicated in the pathogenesis of obesity-associated diseases. However, studies to date have assumed that a few select FFAs are representative of broad structural categories, and there are no scalable approaches to comprehensively assess the biological processes induced by exposure to diverse FFAs circulating in human plasma. Furthermore, assessing how these FFA- mediated processes interact with genetic risk for disease remains elusive. Here we report the design and implementation of FALCON (Fatty Acid Library for Comprehensive ONtologies) as an unbiased, scalable and multimodal interrogation of 61 structurally diverse FFAs. We identified a subset of lipotoxic monounsaturated fatty acids (MUFAs) with a distinct lipidomic profile associated with decreased membrane fluidity. Furthermore, we developed a new approach to prioritize genes that reflect the combined effects of exposure to harmful FFAs and genetic risk for type 2 diabetes (T2D). Importantly, we found that c-MAF inducing protein (CMIP) protects cells from exposure to FFAs by modulating Akt signaling and we validated the role of CMIP in human pancreatic beta cells. In sum, FALCON empowers the study of fundamental FFA biology and offers an integrative approach to identify much needed targets for diverse diseases associated with disordered FFA metabolism. HighlightsO_LIFALCON (Fatty Acid Library for Comprehensive ONtologies) enables multimodal profiling of 61 free fatty acids (FFAs) to reveal 5 FFA clusters with distinct biological effects C_LIO_LIFALCON is applicable to many and diverse cell types C_LIO_LIA subset of monounsaturated FAs (MUFAs) equally or more toxic than canonical lipotoxic saturated FAs (SFAs) leads to decreased membrane fluidity C_LIO_LINew approach prioritizes genes that represent the combined effects of environmental (FFA) exposure and genetic risk for disease C_LIO_LIC-Maf inducing protein (CMIP) is identified as a suppressor of FFA-induced lipotoxicity via Akt-mediated signaling C_LI

cell biology↗

bioRxiv2022

Effectors enabling adaptation to mitochondrial complex I loss in Hurthle cell carcinoma

Oncocytic (Hurthle cell) carcinoma of the thyroid (HCC) is genetically characterized by complex I mitochondrial DNA mutations and widespread chromosomal losses. Here, we utilize RNA-seq and metabolomics to identify candidate molecular effectors activated by these genetic drivers. We find glutathione biosynthesis, amino acid metabolism, mitochondrial unfolded protein response, and lipid peroxide scavenging, a safeguard against ferroptosis, to be increased in HCC. A CRISPR-Cas9 knockout screen in a new HCC model reveals which pathways are key for fitness, and highlights loss of GPX4, a defense against ferroptosis, as a strong liability. Rescuing complex I redox activity with the yeast NADH dehydrogenase (NDI1) in HCC cells diminishes ferroptosis sensitivity, while inhibiting complex I in normal thyroid cells augments ferroptosis induction. Our work demonstrates unmitigated lipid peroxide stress to be an HCC vulnerability that is mechanistically coupled to the genetic loss of mitochondrial complex I activity. SignificanceOncocytic (Hurthle cell) carcinoma of the thyroid (HCC) is a unique tumor with a remarkable accumulation of mitochondria. HCC harbors unique genetic alterations, including mitochondrial DNA (mtDNA) mutations in complex I genes and widespread loss-of-heterozygosity in the nuclear DNA. With less favorable clinical outcomes, new therapies for HCC are needed, especially since these tumors show intrinsic resistance to radioactive iodine, which is one of the main treatments for metastatic well-differentiated thyroid cancer. An absence of authentic HCC cell lines and animal models has hindered the mechanistic understanding of this disease and slowed therapeutic progress. In this study, we describe the transcriptomic and metabolomic landscape of HCC and present new HCC models that recapitulate key mtDNA and nuclear DNA alterations. A targeted CRISPR-Cas9 knockout screen in an HCC cell line highlights the molecular programs nominated by our -omics profiling that are required for cell fitness. This screen suggests that lipid peroxide scavenging, a defense system against an iron-dependent form of cell death known as ferroptosis, is a vulnerability in HCC that is coupled to complex I loss, and that targeting this pathway may help patients with HCC.

cancer biology↗

bioRxiv2022

Human hematopoietic stem cell vulnerability to ferroptosis

Hematopoietic stem cells (HSCs) have a number of unique physiologic adaptations that enable lifelong maintenance of blood cell production, including a highly regulated rate of protein synthesis. Yet the precise vulnerabilities that arise from such adaptations have not been fully characterized. Here, inspired by a bone marrow failure disorder due to loss of the histone deubiquitinase MYSM1, characterized by selectively disadvantaged HSCs, we show how reduced protein synthesis in HSCs results in increased ferroptosis. HSC maintenance can be fully rescued by blocking ferroptosis, despite no alteration in protein synthesis rates. Importantly, this selective vulnerability to ferroptosis not only underlies HSC loss in MYSM1 deficiency, but also characterizes a broader liability of human HSCs. Increasing protein synthesis rates via MYSM1 overexpression makes HSCs less susceptible to ferroptosis, more broadly illuminating the selective vulnerabilities that arise in somatic stem cell populations as a result of physiologic adaptations.

genetics↗

bioRxiv2022

Plasma and ovarian metabolomics responses to chronic stress in female mice

BackgroundChronic stress may affect metabolism of amino acids, lipids, and other small molecule metabolites, but these alterations may differ depending on tissue evaluated. We examined metabolomic changes in plasma and ovarian tissue samples from female mice due to chronic stress exposure. MethodsAt 12 weeks old, healthy, female, C57 black mice were randomly assigned to three weeks of chronic stress using daily restraint (2 hours/day; n=9) or normal care (n=10). Metabolomic profiling was conducted on plasma and ovarian tissues. Using the Wilcoxon Rank Test, Metabolite Set Enrichment Analysis, and Differential Network Analysis we identified metabolomic alterations occurring in response to restraint stress. All p-values were corrected for multiple testing using the false discovery rate approach. ResultsIn plasma, individual lysophosphatidylcholines (positively) and the metabolite classes carnitines (positively), diacylglycerols and triacylglycerols (inversely) were associated with restraint stress (adjusted-ps<0.2). In contrast, diacylglycerols and triacylglycerols were increased while carnitines were decreased in ovarian tissue from stressed mice (adjusted-ps<0.2). However, several metabolites (cholesteryl esters, phosphatidylcholines/ phosphatidylethanolamines plasmalogens and multiple amino acids) were consistently inversely associated with restraint stress in plasma and ovarian tissue (adjusted-ps<0.2). ConclusionWe identified differences in multiple lipid and amino acid metabolites in plasma and ovarian tissue of female mice after exposure to chronic stress. Some affected metabolites (primarily triacylglycerols and diacylglycerols) exhibited opposite associations with chronic stress in plasma (a marker of systemic influences) versus in ovarian tissue (representing local changes), suggesting research to understand the biological impact of chronic stress needs to consider both systemic and tissue-specific alterations.

animal behavior and cognition↗

bioRxiv2021

Mct11 deficiency alters hepatic glucose metabolism and energy homeostasis

Genetic variation at the SLC16A11 locus contributes to the disproportionate impact of type 2 diabetes (T2D) on Latino populations. We recently demonstrated that T2D risk variants reduce SLC16A11 liver expression and function of MCT11, the monocarboxylate transporter encoded by the SLC16A11 gene. Here, we show that SLC16A11 expression within the liver is primarily localized to the low oxygen pericentral region, and that T2D risk variants disrupt oxygen-regulated SLC16A11 expression in human hepatocytes. Under physiologic oxygen conditions, MCT11 deficiency alters hepatocyte glucose metabolism, resulting in elevated intracellular lactate and a metabolic shift toward triacylglycerol accumulation. We also demonstrate an impact of Mct11 deficiency on glucose and lipid metabolism in Slc16a11 knockout mice, which display physiological changes that are observed in individuals with T2D. Our findings provide mechanistic insight into how SLC16A11 disruption impacts hepatic energy metabolism and T2D risk, and highlight MCT11-mediated regulation of lactate levels as a potential therapeutic target.

genetics↗

bioRxiv2021

Human gut bacteria produce TH17-modulating bile acid metabolites

The microbiota plays a pivotal role in gut immune homeostasis. Bacteria influence the development and function of host immune cells, including T helper cells expressing interleukin-17a (TH17 cells). We previously reported that the bile acid metabolite 3-oxolithocholic acid (3-oxoLCA) inhibits TH17 cell differentiation1. While it was suggested that gut-residing bacteria produce 3-oxoLCA, the identity of such bacteria was unknown. Furthermore, it was not clear whether 3-oxoLCA and other immunomodulatory bile acids are associated with gut inflammatory pathologies in humans. Using a high-throughput screen, we identified human gut bacteria and corresponding enzymes that convert the secondary bile acid lithocholic acid into 3-oxoLCA as well as the abundant gut metabolite isolithocholic acid (isoLCA). Like 3-oxoLCA, isoLCA suppressed TH17 differentiation by inhibiting ROR{gamma}t (retinoic acid receptor-related orphan nuclear receptor {gamma}t), a key TH17 cell-promoting transcription factor. Levels of both 3-oxoLCA and isoLCA and the 3-hydroxysteroid dehydrogenase (3-HSDH) genes required for their biosynthesis were significantly reduced in patients with inflammatory bowel diseases (IBD). Moreover, levels of these bile acids were inversely correlated with expression of TH17 cell-associated genes. Overall, our data suggest that bacterially produced TH17 cell-inhibitory bile acids may reduce the risk of autoimmune and inflammatory disorders such as IBD.

immunology↗

bioRxiv2020

Metabolomic profiling identifies complex lipid species associated with response to weight loss interventions

Obesity is an epidemic internationally. While weight loss interventions are efficacious, they are compounded by heterogeneity with regards to clinically relevant metabolic responses. Thus, we sought to identify metabolic pathways and biomarkers that distinguish individuals with obesity who would most benefit from a given type of intervention. Liquid chromatography mass spectrometry-based profiling was used to measure 765 metabolites in baseline plasma from three different weight loss studies: WLM (behavioral intervention, N=443), STRRIDE-PD (exercise trial, N=163), and CBD (surgical cohort, N=125). The primary outcome was percent change in insulin resistance (as measured by the Homeostatic Model Assessment of Insulin Resistance [%{Delta}HOMA-IR]) over the intervention. Overall, 92 individual metabolites were associated with %{Delta}HOMA-IR after adjustment for multiple comparisons. Concordantly, the most significant metabolites were triacylglycerols (TAGs; p=2.3e-5) and diacylglycerols (DAGs; p=1.6e-4), with higher TAG and DAG levels associated with a greater improvement in HOMA-IR. In tests of heterogeneity, 50 metabolites changed differently between weight loss interventions; we found amino acids, peptides, and their analogues to be most significant (4.7e-3) in this category. Our results highlight novel metabolic pathways associated with heterogeneity in response to weight loss interventions, and related biomarkers which could be used in future studies of personalized approaches to weight loss interventions.

physiology↗

bioRxiv2020

Adaptation of pancreatic cancer cells to nutrient deprivation is reversible and requires glutamine synthetase stabilization by mTORC1

Pancreatic ductal adenocarcinoma (PDA) is a lethal, therapy-resistant cancer that thrives in a highly desmoplastic, nutrient-deprived microenvironment. Several studies investigated the effects of depriving PDA of either glucose or glutamine alone. However, the consequences on PDA growth and metabolism of limiting both preferred nutrients have remained largely unknown. Here, we report the selection for clonal human PDA cells that survive and adapt to limiting levels of both glucose and glutamine. We find that adapted clones exhibit increased growth in vitro and enhanced tumor-forming capacity in vivo. Mechanistically, adapted clones share common transcriptional and metabolic programs, including amino acid use for de novo glutamine and nucleotide synthesis. They also display enhanced mTORC1 activity that prevents the proteasomal degradation of glutamine synthetase (GS), the rate-limiting enzyme for glutamine synthesis. This phenotype is notably reversible, with PDA cells acquiring alterations in open chromatin upon adaptation. Silencing of GS suppresses the enhanced growth of adapted cells and mitigates tumor growth. These findings identify non-genetic adaptations to nutrient deprivation in PDA and highlight GS as a dependency that could be targeted therapeutically in pancreatic cancer patients. SignificancePancreatic ductal adenocarcinoma (PDA) is a highly lethal malignancy with no effective therapies. PDA aggressiveness partly stems from its ability to grow within a uniquely dense stroma restricting nutrient access. This study demonstrates that PDA clones that survive chronic nutrient deprivation acquire reversible non-genetic adaptations allowing them to switch between metabolic states optimal for growth under nutrient-replete or nutrient-deprived conditions. One contributing factor to this adaptation mTORC1 activation, which stabilizes glutamine synthetase (GS) necessary for glutamine generation in nutrient-deprived cancer cells. Our findings imply that although total GS levels may not be a prognostic marker for aggressive disease, GS inhibition is of high therapeutic value, as it targets specific cell clusters adapted to nutrient starvation, thus mitigating tumor growth.

cancer biology↗

bioRxiv2019

EDEM3 modulates plasma triglyceride level through its regulation of LRP1 expression

Human genetics studies have uncovered genetic variants that can be used to guide biological research and prioritize molecular targets for therapeutic intervention for complex diseases and metabolic conditions. We have identified a missense variant (P746S) in EDEM3 associated with lower blood triglyceride (TG) levels in >300,000 individuals. Functional analyses in cell and mouse models show that EDEM3 deficiency strongly increased the uptake of very low-density lipoprotein and thereby reduced the plasma TG level, as a result of up-regulated expression of LRP1 receptor. We demonstrate that EDEM3 deletion up-regulated the pathways for RNA and ER protein processing and transport, and consequently increased the cell surface mannose-containing glycoproteins, including LRP1. Metabolomics analyses reveal a cellular TG accumulation under EDEM3 deficiency, a profile consistent with individuals with carrying EDEM3 P746S. Our study identifies EDEM3 as a regulator of blood TG, and targeted inhibition of EDEM3 may provide a complementary approach for lowering elevated blood TG concentrations.

genetics↗

bioRxiv2019

A prospective analysis of circulating plasma metabolomics and ovarian cancer risk

We assessed the association of pre-diagnostic plasma metabolites (N=420) with ovarian cancer risk. We included 252 cases and 252 matched controls from the Nurses Health Studies. Multivariable logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) comparing the 90th-10th percentile in metabolite levels, using permutation tests to account for testing multiple correlated hypotheses. Weighted gene co-expression network analysis (WGCNA) modules (n=10) and metabolite set enrichment analysis (MSEA; n=23) were also evaluated. Pseudouridine had the strongest statistical association with ovarian cancer risk overall (OR=2.56, 95%CI=1.48-4.45; p=0.001/adjusted-p=0.15). C36:2 phosphatidylcholine (PC) plasmalogen had the strongest statistical association with lower risk (OR=0.11, 95%CI=0.03-0.35; p<0.001/adjusted-p=0.06) and pseudouridine with higher risk (OR=9.84, 95%CI=2.89-37.82; p<0.001/adjusted-p=0.07) of non-serous tumors. Seven WGCNA modules and 15 classes were associated with risk at FDR[≤]0.20. Triacylglycerols (TAGs) showed heterogeneity by tumor aggressiveness (case-only heterogeneity-p<0.0001). TAG association with risk overall and serous tumors differed by acyl carbon content and saturation. Pseudouridine may be a novel risk factor for ovarian cancer. TAGs may also be important, particularly for rapidly fatal tumors, with associations differing by structural features. Validation in independent prospective studies and complementary experimental work to understand biological mechanisms is needed.

epidemiology↗