Altered Fatty Acid Metabolism Research Articles

Associations of per- and polyfluoroalkyl substances with human milk metabolomic profiles in a rural North American cohort.

Per- and polyfluoroalkyl substances (PFAS) are a class of persistent synthetic chemicals that are found in human milk and are associated with negative health effects. Research suggests that PFAS affect both lactation and the human metabolome. We measured perfluorooctanoate (PFOA) and perfluorooctane sulfonate (PFOS) in the milk of 425 participants from the New Hampshire Birth Cohort Study using liquid chromatography-tandem mass spectrometry (LC-MS/MS). A nontargeted metabolomics assay was performed using LC with high-resolution MS, and metabolites were identified based on in-house database matching. We observed six metabolic profiles among our milk samples using self-organizing maps, and multinomial logistic regression was used to identify sociodemographic and perinatal predictors of these profiles, including infant sex, parity, participant body mass index, participant age, education, race, smoking status, gestational weight gain, and infant age at time of milk collection. Elevated PFOA was associated with profiles containing higher amounts of triglyceride fatty acids, glycerophospholipids and sphingolipids, and carnitine metabolites, as well as lower amounts of lactose and creatine phosphate. Lower concentrations of milk PFOS were associated with lower levels of fatty acids. Our findings suggest that elevated PFOA in human milk is related to metabolomic profiles consistent with enlarged milk fat globule membranes and altered fatty acid metabolism. Further, our study supports the theory that PFAS share mammary epithelial membrane transport mechanisms with fatty acids and associate with metabolic markers of reduced milk production.

Omics studies in Behçet's disease.

In this review, we aimed to highlight recent findings from "-omics" studies in Behçet's disease. Recent genomic studies in Behçet's disease identified possible risk loci associated with Behçet's disease related uveitis, neurologic involvement and gastrointestinal involvement. Additionally, sex-specific genetic effects were determined in Behçet's disease. Transcriptomic analyses of immune cells in Behçet's disease revealed that key inflammatory pathways such as NF-κB and MAPK have roles in Behçet's disease pathogenesis. Proteomic studies have highlighted the role of immune cell derived extracellular vesicles and identified potential biomarkers for vascular involvement and examined HLA I-bound immunopeptidomes. Metabolomics studies are still limited, but recent research has pointed to alterations in fatty acid metabolism and lipid profiles in Behçet's disease patient. Omics studies have gained importance in the field of Behçet's disease through the generation of large data sets and efforts to extend their application are intensifying. These studies can provide opportunities for understanding Behçet's disease pathogenesis when they lead to testable hypotheses. Current challenges include the choice of appropriately homogeneous patient and control groups, effective data management and sharing, high cost and a rapidly increasing gap between the wealth of observational data generated and the relative paucity of controlled experimental efforts that could lead to mechanistic understanding.

Palmitoleic and oleic fatty acids as biomarkers for coronary heart disease: A predictive model.

saturated and unsaturated fatty acid showed a significant link with coronary artery health and disease. This study aimed to compare plasma levels of unsaturated fatty acids (UFAs) between individuals with coronary heart disease (CHD) and those without. It also investigated the association between specific UFA ratios and the presence or severity of acute coronary syndrome (ACS). Additionally, the study explored the potential of UFAs as biomarkers for assessing CHD risk or disease severity. Patients suspected of coronary heart disease (CHD) at Northern Jiangsu People's Hospital were categorized by coronary angiography into non-CHD (53 cases) and CHD (182 cases). The CHD group was divided into non-acute coronary syndrome (non-ACS) (40 cases) and ACS (142 cases) subgroups. The ACS group was further classified into unstable angina (61 cases), non-ST-elevation myocardial infarction (NSTEMI) (40 cases), and ST-elevation myocardial infarction (STEMI) (41 cases). Lipid profiles, myocardial injury markers, and fourteen unsaturated fatty acids were analyzed using liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS). The CHD group had significantly higher triglycerides (TG), palmitoleic acid (PA), oleic acid (OA), docosahexaenoic acid (DHA), ω-6 fatty acids, and a higher ω-6/ω-3 ratio, but lower ω-3 fatty acids compared to non-CHD. In ACS, PA, LA, OA, and the ω-6/ω-3 ratio were elevated, while EPA and HDL were reduced. Logistic regression identified TG, ω-6/ω-3 ratio, PA, OA, and ω-6 fatty acids as risk factors, with ω-3 fatty acids being protective. PA was protective, while OA posed risk. A combined PA and OA model had a diagnostic efficacy (AUC 0.746). Altered fatty acid metabolism in CHD patients, particularly PA and OA, offers potential as biomarkers. The ω-6/ω-3 ratio is crucial for cardiovascular health.

Metabolomic Profiling of Open-Angle Glaucoma Etiologic Endotypes: Tohoku Multi-Omics Glaucoma Study.

The purpose of this study was to investigate biologically meaningful endotypes of open-angle glaucoma (OAG) by applying unsupervised machine learning to plasma metabolites. This retrospective longitudinal cohort study enrolled consecutive patients aged ≥20 years with OAG at Tohoku University Hospital from January 2017 to January 2020. OAG was confirmed based on comprehensive ophthalmic examinations. Among the 523 patients with OAG with available clinical metabolomic data, 173 patients were longitudinally followed up for ≥2 years, with available data from ≥5 reliable visual field (VF) tests without glaucoma surgery. We collected fasting blood samples and clinical data at enrollment and nuclear magnetic resonance spectroscopy to profile 45 plasma metabolites in a targeted approach. After computing a distance matrix of preprocessed metabolites with Pearson distance, gap statistics determined the optimal number of OAG endotypes. Its risk factors, clinical presentations, metabolomic profiles, and progression rate of sector-based VF loss were compared across endotypes. Five distinct OAG endotypes were identified. The highest-risk endotype (endotype B) showed a significant faster progression of central VF loss (P = 0.007). Compared with patients with other endotypes, those with endotype B were more likely to have a high prevalence of dyslipidemia, cold extremities, oxidative stress, and low OAG genetic risk scores. Pathway analysis of metabolomic profiles implicated altered fatty acid and ketone body metabolism in this endotype, with 34 differentially enriched pathways (false discovery rate [FDR] < 0.05). Integrated metabolomic profiles identified five distinct etiologic endotypes of OAG, suggesting pathological mechanisms related with a high-risk group of central vision loss progression in the Japanese population.

Transcriptomic profiling reveals potential regulatory genes and molecular mechanisms of residual feed intake in Jian carp (Cyprinus carpio var. Jian)

Feed efficiency is one of the most important economic traits in animal production. Improving feed efficiency through genetic selection or other approaches will reduce production costs and mitigate environmental impacts. Residual feed intake (RFI) has some advantages over traditional feed efficiency metrics as a selection criterion for improving feed efficiency, because it is not a ratio and unrelated to growth. In this study, high RFI (HRFI) and low RFI (LRFI) Jian carp (Cyprinus carpio var. Jian) were tested for feed efficiency traits and serum biochemical indices. No significant differences were observed in the growth rates between HRFI and LRFI group, but daily feed intake of LRFI was significantly lower than that of the HRFI group. The results indicated that significantly higher content of triglyceride (TG) and total cholesterol (T-CHO) in the LRFI group was significantly correlated with RFI. We also selected HRFI and LRFI carp for transcriptomic analysis to determine differentially expressed genes (DEGs) in the liver tissues of 12 individuals. A total of 830 DEGs were identified between HRFI and LRFI group, of which 486 genes were up-regulated and 344 genes were down-regulated. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis revealed that DEGs were mainly enriched in fatty acid metabolism, ErbB signaling pathway, phosphatidylinositol signaling system, and autophagy. Lipid metabolism and autophagy-related genes, were considered candidate genes that played a crucial role in regulating feed efficiency. Taken together, these results indicated that differences in RFI affect Jian carp metabolism and cell fate, and that alterations in fatty acid metabolism and autophagy are key physiological modes of regulation in low RFI Jian carp. Our data provide valuable candidate genes and candidate pathways, which will help to study the molecular mechanisms of feed efficiency in carp.

Low temperature conditioning and nitric oxide treatment reduced chilling injury and altered fatty acid metabolism of flat peaches

Low-temperature conditioning is a recognized method for alleviating chilling injuries in flat peaches. However, long-term low-temperature storage can mitigate volatile organic compounds, thereby limiting fruit availability. To improve the supply of flat peaches, we investigated the combined effects of low-temperature conditioning and nitric oxide treatment on various parameters including physiological quality, volatile organic compounds, fatty acids, associated enzymes, and genes involved in the fatty acid pathway with the transcriptome sequencing analysis. The results indicated that low-temperature conditioning coordinated with 10 µL L−1 nitric oxide treatment possessed higher firmness and vitamin C content and restricted the content of malonaldehyde and relative electrical conductivity, thus maintaining the overall quality of flat peaches. In the study, 10 µL L−1 nitric oxide was employed for subsequent experiments. Moreover, higher contents of volatile organic compounds were supported by increased contents of palmitic acid, stearic acid, oleic acid, linoleic acid, linolenic acid, alcohol dehydrogenase, hydroperoxide lyase, and up-regulated genes of LOX2, LOX3, LOX6, ADH2, and ADH3. In summary, nitric oxide treatment effectively facilitated the recovery of volatile organic compounds in flat peaches during cold storage. Therefore, low-temperature conditioning and nitric oxide treatment can be a promising strategy to prevent the loss of volatile organic compounds by modulating the fatty acid pathway and associated genes.

Metabolomic Profile Alterations Associated with the SLC16A11 Risk Haplotype Following a Lifestyle Intervention in People With Prediabetes

BackgroundA risk haplotype in SLC16A11 characterized by alterations in fatty acid metabolism emerged as a genetic risk factor associated with increased susceptibility to type 2 diabetes (T2D) in Mexican population. Its role on treatment responses is not well understood. ObjectivesWe aimed to determine the impact of the risk haplotype on the metabolomic profile during a lifestyle intervention (LSI). MethodsWe recruited Mexican-mestizo individuals with ≥1 prediabetes criteria according to the American Diabetes Association with a body mass index between 25 and 45 kg/m2. We conducted a 24-wk quasiexperimental LSI study for diabetes prevention. Here, we compared longitudinal plasma liquid chromatography/mass spectrometry metabolomic changes between carriers and noncarriers. We analyzed the association of risk haplotype with metabolites leveraging repeated assessments using multivariable-adjusted linear mixed models. ResultsBefore the intervention, carriers (N = 21) showed higher concentrations of hippurate, C16 carnitine, glycine, and cinnamoylglycine. After 24 wk of LSI, carriers exhibited a deleterious metabolomic profile. This profile was characterized by increased concentrations of hippurate, cinnamoglycine, xanthosine, N-acetylputrescine, L-acetylcarnitine, ceramide (d18:1/24:1), and decreased concentrations of citrulline and phosphatidylethanolamine. These metabolites were associated with higher concentrations of total cholesterol, triglycerides, and low density lipoprotein cholesterol. The effect of LSI on the risk haplotype was notably more pronounced in its impact on 2 metabolites: methylmalonylcarnitine (β: −0.56; P-interaction = 0.014) and betaine (β: −0.64; P-interaction = 0.017). Interestingly, lower consumption across visits of polyunsaturated (β: −0.038; P = 0.017) fatty acids were associated with higher concentrations of methylmalonylcarnitine. Covariates for adjustment across models included age, sex, genetic ancestry principal components, and body mass index. ConclusionsOur study highlights the persistence of deleterious metabolomic patterns associated with the risk haplotype before and during a 24-wk LSI. We also emphasize the potential regulatory role of polyunsaturated fatty acids on methylmalonylcarnitine concentrations suggesting a route for improving interventions for individuals with high-genetic risk.

Lipid Regulatory Element Interact with CD44 on Mitochondrial Bioenergetics in Bovine Adipocyte Differentiation and Lipometabolism.

The CD44 gene is a critical factor in animal physiological processes and has been shown to affect insulin resistance and fat accumulation in mammals. Nevertheless, little research has been conducted on its precise functions in lipid metabolism and adipogenic differentiation in beef cattle. This study analyzed the expression of CD44 and miR-199a-3p during bovine preadipocyte differentiation. The luciferase reporter assay demonstrated that CD44 was a direct target of miR-199a-3p. Increased accumulation of lipid droplets and triglyceride levels, altered fatty acid metabolism, and accelerated preadipocyte differentiation were all caused by the upregulation of miR-199a-3p or a reduction in CD44 expression. CD44 knockdown upregulated the expression of adipocyte-specific genes (LPL and FABP4) and altered the levels of lipid metabolites (SOPC, l-arginine, and heptadecanoic acid). Multiomics highlights enriched pathways involved in energy metabolism (MAPK, cAMP, and calcium signaling) and shifts in mitochondrial respiration and glycolysis, indicating that CD44 plays a regulatory role in lipid metabolism. The findings show that intracellular lipolysis, glycolysis, mitochondrial respiration, fat deposition, and lipid droplet composition are all impacted by miR-199a-3p, which modulates CD44 in bovine adipocytes.

Circulating plasma fibronectin affects tissue insulin sensitivity, adipocyte differentiation, and transcriptional landscape of adipose tissue in mice.

Plasma fibronectin (pFN) is a hepatocyte-derived circulating extracellular matrix protein that affects cell morphology, adipogenesis, and insulin signaling of adipocytes invitro. In this study, we show pFN accrual to adipose tissue and its contribution to tissue homeostasis in mice. Hepatocyte-specific conditional Fn1 knockout mice (Fn1-/-ALB) show a decrease in adipose tissue FN levels and enhanced insulin sensitivity of subcutaneous (inguinal), visceral (epididymal) adipose tissue on a normal diet. Diet-induced obesity model of the Fn1-/-ALB mouse showed normal weight gain and whole-body fat mass, and normal adipose tissue depot volumes and unaltered circulating leptin and adiponectin levels. However, Fn1-/-ALB adipose depots showed significant alterations in adipocyte size and gene expression profiles. The inguinal adipose tissue on a normal diet, which had alterations in fatty acid metabolism and thermogenesis suggesting browning. The presence of increased beige adipocyte markers Ucp1 and Prdm16 supported this. In the inguinal fat, the obesogenic diet resulted in downregulation of the browning markers and changes in gene expression reflecting development, morphogenesis, and mesenchymal stem cell maintenance. Epididymal adipose tissue showed alterations in developmental and stem cell gene expression on both diets. The data suggests a role for pFN in adipose tissue insulin sensitivity and cell profiles.

Neoadjuvant aromatase inhibitor therapy for ER+ breast cancer: The NAOMI trial.

e12646 Background: Neoadjuvant Endocrine Therapy (NET) is an effective and well tolerated treatment for locally advanced ER+ breast cancer (BC) yet it is underutilized. It can induce comparable clinical response rates to chemotherapy but not pathologic complete response. There is a knowledge gap regarding its effect on residual cancer cells and fatty acid oxidation which is essential for survival of dormant ER+BC cells after estrogen withdrawal in vitro. The NAOMI trial is a study testing the effects of NET with the AI letrozole in early ER+ BC. It aimed to assess the effect of letrozole on residual cancer cells as well as markers of mitochondrial and fatty acid metabolism. Herein we present the results of the molecular and clinical analyses. Methods: NAOMI is a phase II single-arm open-label study with use of letrozole for 4 to 12 weeks prior to surgical resection. Eligible patients were women over 18 years of age, post-menopausal, with stage I-III ER+, HER2- BC. Exclusion criteria included prior ET use or other neoadjuvant options. The primary objective was to assess whether residual cancer cells exhibit upregulation of the fatty acid transporter CPT1A compared to baseline. Secondary objectives included the proportion of subjects who had clinical response and whether residual cancer cells exhibit markers of altered mitochondrial and fatty acid metabolism compared to baseline tumors. Protocol was amended to include adherence rates to adjuvant AI. Results: A total of 77 women have consented to study participation since December 2022 including 57 evaluable patients. Molecular analyses were performed on diagnostic and post-letrozole tumor specimens from the first 33 patients. Immunohistochemistry was done using antibodies against Ki67, CPT1A, FASN, perilipin, CD36, and MT-CO2. CPT1A histoscore between baseline and post letrozole specimens were similar (paired t-test p=0.2636). Markers of altered mitochondrial and fatty acid metabolism including MT-CO2, CD36, FASN, Perilipin were unchanged when comparing pre and post-AI tissues. Post hoc comparisons of changes in Ki67 (marker of biological response to letrozole) vs. changes in metabolic markers were performed. Ki67+ cells were substantially decreased during neoadjuvant letrozole therapy (paired t-test p&lt;0.0001). Linear regression analysis of residual tumor cell proliferation [post-letrozole log2(Ki67+1)] vs. letrozole-induced change in log2(MT-CO2) showed that tumors with more residual cell proliferation had greater levels of MT-CO2 (p=0.0278). Patients enrolled in NAOMI had a rate of adherence to adjuvant ET of 82%, higher than historical averages. Conclusions: NET is associated with a decrease in Ki67+ breast cancer cells however it has minimal impact on fatty acid and mitochondrial metabolism. It is suggested to increase adherence to adjuvant ET. Additional studies are planned to elucidate mechanisms of resistance in those samples that did not show a decrease in Ki67. Clinical trial information: NCT04568616 .

Exploring the Metabolic Effects of a Herbal Remedy of Asarum sieboldii, Platycodon grandiflorum, and Cinnamomum cassia Extracts: Unraveling Its Therapeutic Potential as a Topical Application for Atopic Dermatitis Treatment.

Our previous study demonstrated that our novel herbal remedy, a mixture of Asarum sieboldii, Platycodon grandiflorum, and Cinnamomum Cassia extracts, exhibits a therapeutic effect in 1-chloro-2,4-dinitrobenzene (DNCB)-induced mice by inhibiting the Th-2 inflammatory response upon oral administration. It also ameliorated imbalances in lipid metabolism related to the skin barrier function in keratinocytes, indicating its potential as a topical agent. This study aims to further investigate the therapeutic effects and metabolic mechanisms of its topical application. The anti-atopic effect was evaluated using dermatitis scores, histopathological analysis, and immune cell factors in DNCB-induced mice. Metabolomic profiling of serum and lesional skin was conducted to elucidate the metabolic mechanisms. The topical application significantly reduced dermatitis scores, mast cell infiltration, and serum levels of immunoglobulin E (IgE), IFN-γ, interleukin (IL)-4, IL-17, and thymic stromal lymphopoietin (TSLP), demonstrating its effectiveness in treating atopic dermatitis (AD). Serum metabolomics revealed alterations in fatty acid metabolism related to the pro-inflammatory response. In lesional skin, metabolic markers associated with oxidative stress, immune regulation, and AD symptoms were restored. This study demonstrated its potential as a topical agent in suppressing Th-2 inflammatory responses and improving metabolic abnormalities related to AD symptoms, providing crucial insights for developing natural AD treatments.

Physical inactivity following volumetric muscle loss results in a divergence between whole-body and cellular metabolic dysfunction

Volumetric muscle loss (VML) is the frank loss of muscle due to injury or surgery and is characterized by whole-body and cellular metabolic dysfunction. Following VML, prolonged bedrest and life-long disability may worsen metabolic dysfunction. This work aimed to elucidate the impact of VML and physical inactivity on the whole-body, cellular, and metabolomic environment of the remaining uninjured muscle. Adult male C57BI/6J mice (n=40) underwent unilateral VML to the posterior hindlimb compartment or served as age-matched injury naïve controls, then were randomized to standard or restricted activity cages for 8-wks. Physical activity, whole-body metabolism, and glucose tolerance were evaluated at 6- and 7-wks post-VML, respectively. Small molecule metabolites and lipids were measured using liquid chromatography-couple and flow injection tandem mass spectrometry. Differences were evaluated by two-way ANOVA with Tukey’s HSD post hoc. Inactivity following VML resulted in ~7% decrease in 24-hr metabolic rate compared to VML alone (p=0.032). Regardless of injury, 24-hr RER was ~5% greater following inactivity (p=0.001). Over 24 hrs, carbohydrate oxidation was ~23% greater with injury and inactivity (p=0.001); lipid oxidation was largely unchanged (p≥0.068). Change in RER (ΔRER) was ~93% greater in VML-injured mice (p=0.030). Physical activity can influence whole-body metabolism, and inactivity post-VML results in greater whole-body carbohydrate usage. Regardless of activity, blood glucose levels were lower following injury (p&lt;0.001). Adiponectin was greater in VML-injured muscles (p&lt;0.001), which may explain enhanced whole-body glucose tolerance post-VML. Protein expression of localized metabolic signals revealed muscle GLUT4, fatty acid binding protein 4, acetyl-CoA carboxylase (ACC), phosphorylated ACC (pACC) and liver fatty acid synthase (FAS) were unaffected by injury and inactivity (p≥0.117). Muscles of inactive, VML-injured mice exhibited a greater pACC:ACC ratio (p=0.046), suggesting decreased fatty acid synthesis. No effect of injury or inactivity was observed in circulating leptin (p≥0.188). Beta-hydroxyacyl CoA dehydrogenase activity was decreased following injury, suggesting a diminished capacity to oxidize fatty acids (p=0.033). Inactivity alone did not alter the metabolome. Injury resulted in 54 significantly expressed metabolites and/or ratios. The combination of injury and inactivity produced a similar response as VML alone, with 91% of metabolites and/or ratios commonly expressed between groups. Similar metabolite expressions following VML with and without inactivity indicate VML injury alone is regulating an altered metabolome. Collectively, although there was no substantial impact of inactivity on whole-body metabolic dysfunction above VML alone, metabolic changes in VML-injured muscles suggests functional alterations in fatty acid metabolism with inactivity. If the ability to oxidize fatty acids is exhausted following VML, resulting accumulation of triglycerides may contribute to metabolic disease often observed with physical inactivity. Continued work to elucidate mechanisms and functional aspects of fatty acid oxidation following VML is needed. W81XWH-20-1-0885 and R01-AR078903 to JAC &amp; SMG. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

JAK/STAT Inhibition Normalizes Lipid Composition in 3D Human Epidermal Equivalents Challenged with Th2 Cytokines.

Derangement of the epidermal barrier lipids and dysregulated immune responses are key pathogenic features of atopic dermatitis (AD). The Th2-type cytokines interleukin IL-4 and IL-13 play a prominent role in AD by activating the Janus Kinase/Signal Transduction and Activator of Transcription (JAK/STAT) intracellular signaling axis. This study aimed to investigate the role of JAK/STAT in the lipid perturbations induced by Th2 signaling in 3D epidermal equivalents. Tofacitinib, a low-molecular-mass JAK inhibitor, was used to screen for JAK/STAT-mediated deregulation of lipid metabolism. Th2 cytokines decreased the expression of elongases 1, 3, and 4 and serine-palmitoyl-transferase and increased that of sphingolipid delta(4)-desaturase and carbonic anhydrase 2. Th2 cytokines inhibited the synthesis of palmitoleic acid and caused depletion of triglycerides, in association with altered phosphatidylcholine profiles and fatty acid (FA) metabolism. Overall, the ceramide profiles were minimally affected. Except for most sphingolipids and very-long-chain FAs, the effects of Th2 on lipid pathways were reversed by co-treatment with tofacitinib. An increase in the mRNA levels of CPT1A and ACAT1, reduced by tofacitinib, suggests that Th2 cytokines promote FA beta-oxidation. In conclusion, pharmacological inhibition of JAK/STAT activation prevents the lipid disruption caused by the halted homeostasis of FA metabolism.

C6orf15 promotes liver metastasis via WNT/β-catenin signalling in colorectal cancer

BackgroundColon cancer ranks third among global tumours and second in cancer-related mortality, prompting an urgent need to explore new therapeutic targets. C6orf15 is a novel gene that has been reported only in Sjogren’s syndrome and systemic lupus erythematosus patients. We found a close correlation between increased C6orf15 expression and the occurrence of colon cancer. The aim of this study was to explore the potential of C6orf15 as a therapeutic target for colorectal cancer.MethodRNA-seq differential expression analysis of the TCGA database was performed using the R package ‘limma.’ The correlation between target genes and survival as well as tumour analysis was analysed using GEPIA. Western blot and PCR were used to assess C6orf15 expression in colorectal cancer tissue samples. Immunofluorescence and immunohistochemistry were used to assess C6orf15 subcellular localization and tissue expression. The role of C6orf15 in liver metastasis progression was investigated via a mouse spleen infection liver metastasis model. The association of C6orf15 with signalling pathways was assessed using the GSEA-Hallmark database. Immunohistochemistry (IHC), qPCR and western blotting were performed to assess the expression of related mRNAs or proteins. Biological characteristics were evaluated through cell migration assays, MTT assays, and Seahorse XF96 analysis to monitor fatty acid metabolism.ResultsC6orf15 was significantly associated with liver metastasis and survival in CRC patients as determined by the bioinformatic analysis and further verified by immunohistochemistry (IHC), qPCR and western blot results. The upregulation of C6orf15 expression in CRC cells can promote the nuclear translocation of β-catenin and cause an increase in downstream transcription. This leads to changes in the epithelial–mesenchymal transition (EMT) and alterations in fatty acid metabolism, which together promote liver metastasis of CRC.ConclusionOur study identified C6orf15 as a marker of liver metastasis in CRC. C6orf15 can activate the WNT/β-catenin signalling pathway to promote EMT and fatty acid metabolism in CRC.

Limitations in metabolic plasticity after traumatic injury are only moderately exacerbated by physical activity restriction

Following traumatic musculoskeletal injuries, prolonged bedrest and loss of physical activity may limit muscle plasticity and drive metabolic dysfunction. One specific injury, volumetric muscle loss (VML), results in frank loss of muscle and is characterized by whole-body and cellular metabolic dysfunction. However, how VML and restricted physical activity limit plasticity of the whole-body, cellular, and metabolomic environment of the remaining uninjured muscle remains unclear. Adult mice were randomized to posterior hindlimb compartment VML or were age-matched injury naïve controls, then randomized to standard or restricted activity cages for 8-wks. Activity restriction in naïve mice resulted in ~5% greater respiratory exchange ratio (RER); combined with VML, carbohydrate oxidation was ~23% greater than VML alone, but lipid oxidation was largely unchanged. Activity restriction combined with VML increased whole-body carbohydrate usage. Together there was a greater pACC:ACC ratio in the muscle remaining, which may contribute to decreased fatty acid synthesis. Further, β-HAD activity normalized to mitochondrial content was decreased following VML, suggesting a diminished capacity to oxidize fatty acids. The muscle metabolome was not altered by the restriction of physical activity. The combination of VML and activity restriction resulted in similar ( ~ 91%) up- and down-regulated metabolites and/or ratios, suggesting that VML injury alone is regulating changes in the metabolome. Data supports possible VML-induced alterations in fatty acid metabolism are exacerbated by activity restriction. Collectively, this work adds to the sequalae of VML injury, exhausting the ability of the muscle remaining to oxidize fatty acids resulting in a possible accumulation of triglycerides.

Longitudinal aortic strain, ventriculo-arterial coupling and fatty acid oxidation: novel insights into human cardiovascular aging.

Aging-induced aortic stiffness has been associated with altered fatty acid metabolism. We studied aortic stiffness using cardiac magnetic resonance (CMR)-assessed ventriculo-arterial coupling (VAC) and novel aortic (AO) global longitudinal strain (GLS) combined with targeted metabolomic profiling. Among community older adults without cardiovascular disease, VAC was calculated as aortic pulse wave velocity (PWV), a marker of arterial stiffness, divided by left ventricular (LV) GLS. AOGLS was the maximum absolute strain measured by tracking the phasic distance between brachiocephalic artery origin and aortic annulus. In 194 subjects (71 ± 8.6 years; 88 women), AOGLS (mean 5.6 ± 2.1%) was associated with PWV (R = -0.3644, p < 0.0001), LVGLS (R = 0.2756, p = 0.0001) and VAC (R = -0.3742, p <0.0001). Stiff aorta denoted by low AOGLS <4.26% (25th percentile) was associated with age (OR 1.13, 95% CI 1.04-1.24, p = 0.007), body mass index (OR 1.12, 95% CI 1.01-1.25, p = 0.03), heart rate (OR 1.04, 95% CI 1.01-1.06, p = 0.011) and metabolites of medium-chain fatty acid oxidation: C8 (OR 1.005, p = 0.026), C10 (OR 1.003, p = 0.036), C12 (OR 1.013, p = 0.028), C12:2-OH/C10:2-DC (OR 1.084, p = 0.032) and C16-OH (OR 0.82, p = 0.006). VAC was associated with changes in long-chain hydroxyl and dicarboxyl carnitines. Multivariable models that included acyl-carnitine metabolites, but not amino acids, significantly increased the discrimination over clinical risk factors for prediction of AOGLS (AUC [area-under-curve] 0.73 to 0.81, p = 0.037) and VAC (AUC 0.78 to 0.87, p = 0.0044). Low AO GLS and high VAC were associated with altered medium-chain and long-chain fatty acid oxidation, respectively, which may identify early metabolic perturbations in aging-associated aortic stiffening. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02791139.

Differential Disruption of Glucose and Lipid Metabolism Induced by Phthalates in Human Hepatocytes and White Adipocytes.

Phthalic acid esters (PAEs), commonly used as plasticizers, are pervasive in the environment, leading to widespread human exposure. The association between phthalate exposure and metabolic disorders has been increasingly recognized, yet the precise biological mechanisms are not well-defined. In this study, we explored the effects of monoethylhexyl phthalate (MEHP) and monocyclohexyl phthalate (MCHP) on glucose and lipid metabolism in human hepatocytes and adipocytes. In hepatocytes, MEHP and MCHP were observed to enhance lipid uptake and accumulation in a dose-responsive manner, along with upregulating genes involved in lipid biosynthesis. Transcriptomic analysis indicated a broader impact of MEHP on hepatic gene expression relative to MCHP, but MCHP particularly promoted the expression of the gluconeogenesis key enzymes G6PC and FBP1. In adipocytes, MEHP and MCHP both increased lipid droplet formation, mimicking the effects of the Peroxisome proliferator-activated receptor γ (PPARγ) agonist rosiglitazone (Rosi). Transcriptomic analysis revealed that MEHP predominantly altered fatty acid metabolism pathways in mature adipocytes (MA), whereas MCHP exhibited less impact. Metabolic perturbations from MEHP and MCHP demonstrate shared activation of the PPARs pathway in hepatocytes and adipocytes, but the cell-type discrepancy might be attributed to the differential expression of PPARγ. Our results indicate that MEHP and MCHP disrupt glucose and lipid homeostasis in human liver and adipose through mechanisms that involve the PPAR and adenosine monophosphate-activated protein kinase (AMPK) signaling pathways, highlighting the nuanced cellular responses to these environmental contaminants.

PPARα Agonism Enhances Immune Response to Radiotherapy While Dietary Oleic Acid Results in Counteraction.

Head and neck cancer (HNC) improvements are stagnant, even with advances in immunotherapy. Our previous clinical trial data show that altered fatty acid (FA) metabolism correlates with outcome. We hypothesized that pharmacologic and dietary modulation of FA catabolism will affect therapeutic efficacy. We performed in vivo and in vitro experiments using PPARα agonism with fenofibrate (FF) or high oleic acid diets (OAD) with radiotherapy, generating metabolomic, proteomic, stable isotope tracing, extracellular flux analysis, and flow-cytometric data to investigate these alterations. FF improved antitumor efficacy of high dose per fraction radiotherapy in HNC murine models, whereas the OAD reversed this effect. FF-treated mice on the control diet had evidence of increased FA catabolism. Stable isotope tracing showed less glycolytic utilization by ex vivo CD8+ T cells. Improved efficacy correlated with intratumoral alterations in eicosanoid metabolism and downregulated mTOR and CD36. Metabolic intervention with increased FA catabolism improves the efficacy of HNC therapy and enhances antitumoral immune response.

Association between polyunsaturated fatty acids in adipose tissue and mortality of colorectal cancer patients

IntroductionNutritional intake and dysregulation of fatty acid metabolism play a role in the progression of various tumors, but the consumption of fatty acids is difficult to assess accurately with dietary questionnaires. Biomarkers can objectively assess intake, storage and bioavailability. ObjectiveWe studied the association between the polyunsaturated fatty acid (PUFA) composition of abdominal subcutaneous adipose tissue (good indicator of dietary intake over 2–3 years) and all-cause mortality. MethodsIn the multicenter AGARIC study, samples from 203 patients with colorectal cancer (CRC) undergoing curative surgery, were harvested from subcutaneous adipose tissue, which were then analyzed for PUFA composition. ResultsAfter a median follow-up of 45 months, 76 patients died. These patients were more often men (72.4% versus 57.5%, P = 0.04), diabetic (32.9% versus 13.4%, P = 0.001), old (median: 74.5 versus 66.6 years, P < 0.001) and with high alcohol consumption (47.4% versus 30.7%, P = 0.005). An increased risk of death was observed with higher levels of 20:2 ω-6 (hazard ratiotertile3 vstertile1 (HRT3vsT1) 2.12; 95% confidence interval (CI) 1.01–4.42; p-trend = 0.04), 22:4 ω-6 (HRT3vsT1 = 3.52; 95% CI = 1.51–8.17; p-trend = 0.005), and 22:5 ω-6 (HRT3vsT1 = 3.50; 95% CI = 1.56–7.87; p-trend = 0.002). Conversely, the risk of death seemed lower when higher concentrations of 18:3 ω-6 (HRT3vsT1 = 0.52; 95% CI = 0.27–0.99; p-trend = 0.04) and the essential fatty acid, α-linolenic acid 18:3 ω-3 (HRT3vsT1 = 0.47; 95% CI = 0.24–0.93; p-trend = 0.03) were observed. ConclusionThe risk of death was increased in CRC patients with higher concentrations of certain ω-6 PUFAs and lower concentrations of α-linolenic acid in their subcutaneous adipose tissue. These results reflect dietary habits and altered fatty acid metabolism. Our exploratory results warrant confirmation in larger studies with further exploration of the mechanisms involved.

Hepatocellular carcinoma cells induce γδ T cells through metabolic reprogramming into tumor-progressive subpopulation.

Tumor immune microenvironment (TIME) is a tiny structure that contains multiple immune cell components around tumor cells, which plays an important role in tumorigenesis, and is also the potential core area of activated immunotherapy. How immune cells with tumor-killing capacity in TIME are hijacked by tumor cells during the progression of tumorigenesis and transformed into subpopulations that facilitate cancer advancement is a question that needs to be urgently addressed nowadays. γδ T cells (their T cell receptors are composed of γ and δ chains), a unique T cell subpopulation distinguished from conventional αβ T cells, are involved in a variety of immune response processes through direct tumor-killing effects and/or indirectly influencing the activity of other immune cells. However, the presence of γδ T cells in the tumor microenvironment (TME) has been reported to be associated with poor prognosis in some tumors, suggesting that certain γδ T cell subsets may also have pro-tumorigenic effects. Recent studies have revealed that metabolic pathways such as activation of glycolysis, increase of lipid metabolism, enhancement of mitochondrial biosynthesis, alterations of fatty acid metabolism reshape the local TME, and immune cells trigger metabolic adaptation through metabolic reprogramming to meet their own needs and play the role of anti-tumor or immunosuppression. Combining previous studies and our bioinformatics results, we hypothesize that γδT cells compete for resources with hepatocellular carcinoma (HCC) cells by means of fatty acid metabolic regulation in the TME, which results in the weakening or loss of their ability to recognize and kill HCC cells through genetic and epigenetic alterations, thus allowing γδT cells to be hijacked by HCC cells as a subpopulation that promotes HCC progression.