Complex Alterations of Fatty Acid Metabolism and Phospholipidome Uncovered in Isolated Colon Cancer Epithelial Cells.
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SUBMITTER: Hofmanova J
PROVIDER: S-EPMC8268957 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:IntroductionA methyl donor depleted (MDD) diet dramatically suppresses intestinal tumor development in Apc-mutant mice, but the mechanism of this prevention is not entirely clear.ObjectivesWe sought to gain insight into the mechanisms of cancer suppression by the MDD diet and to identify biomarkers of cancer risk reduction.MethodsA plasma metabolomic analysis was performed on ApcΔ14/+ mice maintained on either a methyl donor sufficient (MDS) diet or the protective MDD diet. A group of MDS animals was also pair-fed with the MDD mice to normalize caloric intake, and another group was shifted from an MDD to MDS diet to determine the durability of the metabolic changes.ResultsIn addition to the anticipated changes in folate one-carbon metabolites, plasma metabolites related to fatty acid metabolism were generally decreased by the MDD diet, including carnitine, acylcarnitines, and fatty acids. Some fatty acid selectivity was observed; the levels of cancer-promoting arachidonic acid and 2-hydroxyglutarate were decreased by the MDD diet, whereas eicosapentaenoic acid (EPA) levels were increased. Machine-learning elastic net analysis revealed a positive association between the fatty acid-related compounds azelate and 7-hydroxycholesterol and tumor development, and a negative correlation with succinate and β-sitosterol.ConclusionMethyl donor restriction causes dramatic changes in systemic fatty acid metabolism. Regulating fatty acid metabolism through methyl donor restriction favorably effects fatty acid profiles to achieve cancer protection.
| S-EPMC8416812 | biostudies-literature
Project description:Background & aimsIntestinal barrier alterations are associated with fatty liver (FL) and metabolic syndrome (MetS), but microRNA (miR) signaling pathways in MetS-FL pathogenesis remain unclear. This study investigates an epithelial-focused miR network in colorectal cell models based on the previously reported MetS-FL miR trio of hsa-miR-142-3p, hsa-miR-18b, and hsa-miR-890.MethodsEach miR mimic construct of MetS-FL miR trio was transfected into human colorectal cells, CRL-1790 or Caco-2. Global miRNome changes posttransfection were profiled (nCounter® Human v3 miRNA, NanoString Technologies). Changes in barrier (transepithelial electrical resistance, TEER) and epithelial cell junction structure (Occludin and Zona Occludens-1/ZO-1 immunofluorescence staining-confocal microscopy) were examined pre- and posttransfection in Caco-2 cell monolayers. A signaling network was constructed from the MetS-FL miR trio, MetS-FL miR-induced colorectal miRNome changes, ZO-1, and Occludin.ResultsTransfection of CRL-1790 cells with each MetS-FL miR mimic led to global changes in the cellular miRNome profile, with 288 miRs being altered in expression by more than twofold. Eleven miRs with known cytoskeletal and metabolic roles were commonly altered in expression by all three miR mimics. Transfection of Caco-2 cell monolayers with each MetS-FL miR mimic induced barrier-associated TEER variations and led to structural modifications of ZO-1 and Occludin within epithelial cell junctions. Pathway analysis incorporating the MetS-FL miR trio, eleven common target miRs, ZO-1, and Occludin revealed a signaling network centered on TNF and AKT2, which highlights injury, inflammation, and hyperplasia.ConclusionsColon-specific changes in epithelial barriers, cell junction structure, and a miRNome signaling network are described from functional studies of a MetS-FL miR trio signature.
| S-EPMC6174781 | biostudies-literature
Project description:The effects of obesity surgery on serum and adipose tissue fatty acid (FA) profile and FA metabolism may modify the risk of obesity-related diseases.We measured serum (n=122) and adipose tissue (n=24) FA composition and adipose tissue mRNA expression of genes regulating FA metabolism (n=100) in participants of the Kuopio Obesity Surgery Study (KOBS, age 47.2±8.7 years, BMI 44.6±6.0, 40 men, 82 women) before and one year after obesity surgery. As part of the surgery protocol, all the subjects were instructed to add sources of unsaturated fatty acids, such as rapeseed oil and fatty fish, into their diet. The results were compared with changes in serum FA composition in 122 subjects from the Finnish Diabetes Prevention study (DPS) (age 54.3±7.1 years, BMI 32.2±4.6, 28 men, 94 women).The proportion of saturated FAs decreased and the proportion of n-3 and n-6 FAs increased in serum triglycerides after obesity surgery (all P<0.002). Weight loss predicted changes in quantitative amounts of saturated FAs, monounsaturated FAs, n-3 and n-6 FAs in triglycerides (P<0.002 for all). Moreover, the changes in adipose tissue FAs reflected the changes in serum FAs, and some of the changes were associated with mRNA expression of elongases and desaturases in adipose tissue (all P<0.05). In line with this the estimated activity of elongase (18:1 n-7/16:1 n-7) increased significantly after obesity surgery in all lipid fractions (all P<4 × 10-7) and the increase in the estimated activity of D5D in triglycerides was associated with higher weight loss (r=0.415, P<2 × 10-6). Changes in serum FA profile were similar after obesity surgery and lifestyle intervention, except for the change in the absolute amounts of n-3 FAs between the two studies (P=0.044).Beneficial changes in serum and adipose tissue FAs after obesity surgery could be associated with changes in endogenous metabolism and diet.
| S-EPMC5637104 | biostudies-literature
Project description:The metabolism of polyunsaturated fatty acids (PUFAs) remains poorly characterized in ovarian tissues of patients with polycystic ovary syndrome (PCOS). This study aimed to explore alterations in the levels of PUFAs and their metabolites in serum and ovarian tissues in a PCOS rat model treated with a high-fat diet and andronate. Levels of PUFAs and their metabolites were measured using gas/liquid chromatography-mass spectrometry after the establishment of a PCOS rat model. Only 3 kinds of PUFAs [linoleic acid, arachidonic acid (AA) and docosahexaenoic acid] were detected in both the circulation and ovarian tissues of the rats, and their concentrations were lower in ovarian tissues than in serum. Moreover, significant differences in the ovarian levels of AA were observed between control, high-fat diet-fed and PCOS rats. The levels of prostaglandins, AA metabolites via the cyclooxygenase (COX) pathway, in ovarian tissues of the PCOS group were significantly increased compared to those in the controls. Further studies on the mechanism underlying this phenomenon showed a correlation between decreased expression of phosphorylated cytosolic phospholipase A2 (p-cPLA2) and increased mRNA and protein expression of COX2, potentially leading to a deeper understanding of altered AA and prostaglandin levels in ovarian tissues of PCOS rats.
| S-EPMC6010729 | biostudies-literature
Project description:Zoledronate is a bisphosphonate that is widely used in the treatment of metabolic bone diseases. However, zoledronate induces significant nephrotoxicity associated with acute tubular necrosis and renal fibrosis when administered intravenously. There is speculation that zoledronate-induced nephrotoxicity may result from its pharmacological activity as an inhibitor of the mevalonate pathway but the molecular mechanisms are not fully understood. In this report, human proximal tubular HK-2 cells and mouse models were combined to dissect the molecular pathways underlying nephropathy caused by zoledronate treatments. Metabolomic and proteomic assays revealed that multiple cellular processes were significantly disrupted, including the TGFβ pathway, fatty acid metabolism and small GTPase signaling in zoledronate-treated HK-2 cells (50 μM) as compared with those in controls. Zoledronate treatments in cells (50 μM) and mice (3 mg/kg) increased TGFβ/Smad3 pathway activation to induce fibrosis and kidney injury, and specifically elevated lipid accumulation and expression of fibrotic proteins. Conversely, fatty acid transport protein Slc27a2 deficiency or co-administration of PPARA agonist fenofibrate (20 mg/kg) prevented zoledronate-induced lipid accumulation and kidney fibrosis in mice, indicating that over-expression of fatty acid transporter SLC27A2 and defective fatty acid β-oxidation following zoledronate treatments were significant factors contributing to its nephrotoxicity. These pharmacological and genetic studies provide an important mechanistic insight into zoledronate-associated kidney toxicity that will aid in development of therapeutic prevention and treatment options for this nephropathy.
| S-EPMC5773652 | biostudies-literature
Project description:Retinoic acid receptor responder 1 (RARRES1) is silenced in many cancers and is differentially expressed in metabolism associated diseases, such as hepatic steatosis, hyperinsulinemia and obesity. Here we report a novel function of RARRES1 in metabolic reprogramming of epithelial cells. Using non-targeted LC-MS, we discovered that RARRES1 depletion in epithelial cells caused a global increase in lipid synthesis. RARRES1-depleted cells rewire glucose metabolism by switching from aerobic glycolysis to glucose-dependent de novo lipogenesis (DNL). Treatment with fatty acid synthase (FASN) inhibitor, C75, reversed the effects of RARRES1 depletion. The increased DNL in RARRES1-depleted normal breast and prostate epithelial cells proved advantageous to the cells during starvation, as the increase in fatty acid availability lead to more oxidized fatty acids (FAO), which were used for mitochondrial respiration. Expression of RARRES1 in several common solid tumors is also contextually correlated with expression of fatty acid metabolism genes and fatty acid-regulated transcription factors. Pathway enrichment analysis led us to determine that RARRES1 is regulated by peroxisome proliferating activated receptor (PPAR) signaling. These findings open up a new avenue for metabolic reprogramming and identify RARRES1 as a potential target for cancers and other diseases with impaired fatty acid metabolism.
| S-EPMC6296515 | biostudies-literature
Project description:Background Cancer metabolism is largely altered compared to normal cells. This study aims to explore critical metabolism pathways in colon adenocarcinoma (COAD), and reveal the possible mechanism of their role in cancer progression. Methods Expression data and sequencing data of COAD samples were obtained from The Cancer Genome Atlas and Gene Expression Omnibus databases. The expression profiles between tumor and normal samples were compared to identify differential metabolism pathways through single sample gene set enrichment analysis. Results Fatty acid synthesis was identified as a key metabolism pathway in COAD. Based on fatty acid-related lncRNAs, two molecular subtypes (C1 and C2) were defined. C2 subtype with worse prognosis had higher immune infiltration and higher expression of immune checkpoints. Five transcription factors (TFs) including FOS, JUN, HIF1A, STAT3 and STAT2 were highly expressed in C2 subtype. Five fatty acid-related lncRNAs were identified to be biomarkers for predicting COAD prognosis. Finally, further experients showed that knockdown of lncRNA PAXIP1-AS1 decreased the triglyceride content and the fatty acid synthase and acetyl-CoA carboxylase 1 expressions, which suggested that lncRNA PAXIP1-AS1 plays an important role in fatty acid metabolism of COAD. Conclusions This study demonstrated that fatty acid synthesis was greatly altered in COAD. Fatty acid-related lncRNAs were speculated to be involved in cancer progression through associating with TFs. The five screened TFs may serve as new drug targets for treating COAD. Supplementary Information The online version contains supplementary material available at 10.1186/s13062-022-00332-y.
| S-EPMC9331591 | biostudies-literature
Project description:Background: Fatty acid metabolism (FAM), as a hallmark of caner, plays important roles in tumor initiation and carcinogenesis. However, the significance of fatty acid metabolism-related genes in colon adenocarcinoma (COAD) are largely unknown. Methods: RNA sequencing data and clinical information were downloaded from the Cancer Genome Atlas (TCGA) cohort. Univariate and multivariate Cox regression analyses were utilized to construct a fatty acid metabolism-related gene signature. Kaplan-Meier survival and receiver operating characteristic (ROC) analyses were used to verify the performance of this signature. GEO datasets were applied to validate the signature. Maftools package was utilized to analyze the mutation profiles of this signature. Correlation between the risk signature and stemness scores was compared by RNA stemness score (RNAss). Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) and gene set variation analysis (GSVA) were performed to explore the potential functions and signaling pathways. Immune landscape of the signature was explored by analyzing different immune cells infiltration, immune functions and microsatellite instability. A nomogram was constructed by combining the risk signature and multiple clinical factors. Expression levels and prognostic values of the risk genes were revealed in the cancer genome atlas and GEO databases. Moreover, the expression the risk genes were measured in cell lines using real time quantitative PCR (qRT-PCR). Results: Eight fatty acid metabolism-related genes (CD36, ENO3, MORC2, PTGR1, SUCLG2, ELOVL3, ELOVL6 and CPT2) were used to construct a risk signature. This signature demonstrated better prognostic value than other clinicopathological parameters, with AUC value was 0.734 according to the cancer genome atlas database. There was negative correlation between the riskscore and RNA stemness score. The patients in the high-risk group demonstrated higher infiltration of M0 macrophages, and less infiltration of activated CD4 memory T cells and Eosinophils. There were more MSI patients in the high-risk group than those in the low-risk group (38% vs. 30%). The risk scores of patients in the MSI group were slightly higher than those in the microsatellite stability group. Gene ontology, kyoto encyclopedia of genes and genomes and gene set variation analysis enrichment analyses showed that several metabolism-related functions and signaling pathways were enriched. A nomogram showed good predictive capability of the signature. Moreover, qRT-PCR revealed upregulated expression of ENO3, MORC2, SUCLG2 and ELOVL6, and downregulated expression of CPT2 in all examined colon adenocarcinoma cell lines. Conclusion: This study provided novel insights into a fatty acid metabolism-related signature in the prognosis an immune landscape of colon adenocarcinoma patients.
| S-EPMC9780302 | biostudies-literature
Project description:BackgroundBone is a metabolically active tissue containing different cell types acting as endocrine targets and effectors. Further, bone is a dynamic depot for calcium, phosphorous and other essential minerals. The tissue matrix is subjected to a constant turnover in response to mechanical/endocrine stimuli. Bone turnover demands high energy levels, making fatty acids a crucial source for the bone cells. However, the current understanding of bone cell metabolism is poor. This is partly due to bone matrix complexity and difficulty in small molecules extraction from bone samples. This study aimed to evaluate the effect of metabolite sequestering from a protein-dominated matrix to increase the quality and amount of metabolomics data in discovering small molecule patterns in pathological conditions.MethodsHuman bone samples were collected from 65 to 85 years old (the elderly age span) patients who underwent hip replacement surgery. Separated cortical and trabecular bone powders were treated with decalcifying, enzymatic (collagenase I and proteinase K) and solvent-based metabolite extraction protocols. The extracted mixtures were analyzed with the high-resolution mass spectrometry (HRMS). Data analysis was performed with XCMS and MetaboAnalystR packages.ResultsFast enzymatic treatment of bone samples before solvent addition led to a significantly higher yield of metabolite extraction. Collagenase I and proteinase K rapid digestion showed more effectiveness in cortical and trabecular bone samples, with a significantly higher rate (2.2 folds) for collagenase I. Further analysis showed significant enrichment in pathways like de novo fatty acid biosynthesis, glycosphingolipid metabolism and fatty acid oxidation-peroxisome.ConclusionThis work presents a novel approach for bone sample preparation for HRMS metabolomics. The disruption of bone matrix conformation at the molecular level helps the molecular release into the extracting solvent and, therefore, can lead to higher quality results and trustable biomarker discovery. Our results showed β-oxidation alteration in the aged bone sample. Future work covering more patients is worthy to identify the effective therapeutics to achieve healthy aging.
| S-EPMC10858523 | biostudies-literature
Project description:BackgroundAberrant fatty acid (FA) metabolism is a unique vulnerability of cancer cells and may present a promising target for cancer therapy. Our study aims to elucidate the molecular mechanisms by which NKX2-8 deletion reprogrammed FA metabolism-induced chemoresistance in epithelial ovarian cancer (EOC).MethodsThe deletion frequency and expression of NKX2-8 in 144 EOC specimens were assayed using Fluorescence in situ hybridization and immunochemical assays. The effects of NKX2-8 deletion and the fatty acid oxidation (FAO) antagonist Perhexiline on chemoresistance were examined by Annexin V and colony formation in vitro, and via an intraperitoneal tumor model in vivo. The mechanisms of NKX2-8 deletion in reprogrammed FA metabolism was determined using Chip-seq, metabolomic analysis, FAO assays and immunoprecipitation assays.FindingsNKX2-8 deletion was correlated with the overall and relapse-free survival of EOC patients. NKX2-8 inhibited the FAO pathway by epigenetically suppressing multiple key components of the FAO cascade, including CPT1A and CPT2. Loss of NKX2-8 resulted in reprogramming of FA metabolism of EOC cells in an adipose microenvironment and leading to platinum resistance. Importantly, pharmacological inhibition of FAO pathway using Perhexiline significantly counteracted NKX2-8 deletion-induced chemoresistance and enhanced platinum's therapeutic efficacy in EOC.InterpretationOur results demonstrate that NKX2-8 deletion-reprogrammed FA metabolism contributes to chemoresistance and Perhexiline might serve as a potential tailored treatment for patients with NKX2-8-deleted EOC. FUND: This work was supported by Natural Science Foundation of China; Guangzhou Science and Technology Plan Projects; Natural Science Foundation of Guangdong Province; The Fundamental Research Funds for the Central Universities.
| S-EPMC6562195 | biostudies-literature