Changes In Fatty Acid Metabolism Research Articles

2-[18F]Fluoropropionic Acid PET Imaging of Doxorubicin-induced Cardiotoxicity.

Purpose Treatment of pediatric cancers with doxorubicin is a common and predictable cause of cardiomyopathy. Early diagnosis of treatment-induced cardiotoxicity and intervention are major determinants for the prevention of advanced disease. The onset of cardiomyopathies is often accompanied by profound changes in lipid metabolism, including an enhanced uptake of short-chain fatty acids (SCFA). Therefore, we explored the utility of 2-[ 18 F]fluoropropionic acid ([ 18 F]FPA), an SCFA analog, as an imaging biomarker of cardiac injury in mice exposed to doxorubicin. Procedures : Cardiotoxicity and cardiac dysfunction were induced in mice by an 8-dose regimen of doxorubicin (cumulative dose 24 mg/kg) administered over 14 days. The effects of doxorubicin exposure were assessed by measurement of heart weights, left ventricular ejection fractions, and blood cardiac troponin levels. Whole body and cardiac [ 18 F]FPA uptakes were determined by PET and tissue gamma counting in the presence or absence of AZD3965, a pharmacological inhibitor of monocarboxylate transporter 1 (MCT1). Radiation absorbed doses were estimated using tissue time-activity concentrations. Results Significantly higher cardiac [ 18 F]FPA uptake was observed in doxorubicin-treated animals. This uptake remained constant from 30 min to 120 min post-injection. Pharmacological inhibition of MCT1-mediated transport by AZD3965 selectively decreased the uptake of [ 18 F]FPA in tissues other than the heart. Co-administration of [ 18 F]FPA and AZD3965 enhanced the imaging contrast of the diseased heart while reducing overall exposure to radioactivity. Conclusions [ 18 F]FPA, especially when co-administered with AZD3965, is a new tool for imaging changes in fatty acid metabolism occurring in response to doxorubicin-induced cardiomyopathy by PET.

Dynamic variations of plasma and urine metabolic profiles in left anterior descending coronary artery ligation-induced myocardial infarction rats and the regulatory effects of Chinese patent medicine Xin-Ke-Shu

Myocardial infarction (MI) is one of the most severe cardiovascular diseases (CVD). Traditional Chinese medicines have unique advantages in the treatment of CVD, with Xin-Ke-Shu (XKS) being a commonly used Chinese patent medicine for the prevention and treatment of MI patients. This study aimed to investigate the dynamic metabolic profiles of plasma and urine in left anterior descending coronary artery ligation (LAD) -induced MI rats at days 3, 12, and 21 after surgery, and to evaluate the regulatory effects of XKS at these time points using ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS) metabolomics. The metabolic profiles of plasma and urine in the LAD-induced MI rats showed significant variations at days 3, 12, and 21 after MI. We identified a total of 23 plasma metabolites and 12 urine metabolites as potential pathological markers related to MI progression. These metabolites were mainly involved in pathways such as TCA cycle, arachidonic acid metabolism, glutathione metabolism, glycerophospholipid metabolism, sphingolipid metabolism, and fatty acid metabolism, all of which were associated with imbalance of myocardial energy metabolism, oxidative stress, and calcium overload. Disturbances in the TCA cycle, arachidonic acid metabolism, glutathione metabolism, and purine metabolism in plasma and urine were observed as early as day 3 after MI. By day 12, we noted significant changes in fatty acid metabolism in plasma and urine, along with notable alterations in sphingolipid metabolism in plasma. Disorders in plasma glycerophospholipid metabolism were first evident at day 12 and reached their peak severity by day 21. Treatments with XKS significantly regulated the disturbances in the plasma and urine metabolic profiles of MI rats at days 3, 12, and 21, with medium dose of XKS displaying a particularly strong regulatory effect, especially at day 12. Our study demonstrates that host metabolism undergoes dynamical changes following MI with most metabolic disorders manifesting in the early stage of MI. XKS effectively regulates nearly all of these disturbances and can be administered as soon as possible after MI. These findings provide valuable insights into the metabolic progression of MI and highlight the therapeutic potential of XKS in the treatment of MI.

Metabolic revitalization: exploring erythrocyte fatty acid profile following laparoscopic sleeve gastrectomy.

Obesity is linked to metabolic disorders. Bariatric surgery offers a promising therapeutic approach, but its impact on fatty acid (FA) profiles within erythrocytes and the associated clinical implications remain underexplored. This study aimed to assess changes in erythrocytes' membranes FA after Laparoscopic Sleeve Gastrectomy (LSG) and to correlate these alterations with clinical parameters. Sixty-one patients with morbid obesity undergoing LSG and 32 healthy controls were enrolled. Erythrocytes' membranes FA were analyzed using gas chromatography. Clinical parameters were assessed, including BMI, blood pressure, and multiple biochemistry markers. Bariatric intervention reduced BMI (41.1 to 32.0) and fat mass (54.1 to 35.2kg). Also, other anthropometric parameters improved significantly. Favorable changes in FA metabolism post LSG, potentially leading to a reduction in cardiovascular disease (CVD) risk, were observed. The OMEGA-3 Index (1.8 vs 3.0), and the eicosapentaenoic/arachidonic (0.1 vs 0.2) FA ratio increased after surgery. The dynamics of metabolism post-LSG, assessed by exploring the ratios of erythrocytes' FA concentration in baseline and 6 months after the surgery, with the corresponding ratios calculated for clinical parameters, evidenced the impact of linoleic (LA) on obesity reduction. The LA ratios increased along with the reduction of BMI (r=-0.32), fat mass (r=-0.39), and waist circumference (r=-0.33) proportions. The opposite relations of LA were held with Excess Weight Loss percentage (r=0.49), and Excess BMI Loss percentage (r=0.5). The study underscores distinct post-LSG changes in erythrocytes' FA profiles potentially associated with reduced weight and BMI, improved inflammatory status, and lowered CVD risk.

Application of microdialysis combined with lipidomics to analyze fatty acid metabolic changes in the disease process of rheumatoid arthritis

Rheumatoid arthritis (RA) is a metabolically active disease, with shifts in fatty acid metabolism during disease progression profoundly affecting the systemic inflammatory response. Altered fatty acid biomarker metabolism may be a key target for the treatment of RA. To investigate the changes of fatty acid metabolism in RA, collagen-induced arthritis (CIA) model was established. Microdialysis sampling was utilized to overcome the characteristic of occlusive joint cavity in vivo synovial fluid (SF) sampling. Lipidomic methods were established with the UHPLC-Orbitrap Exploris120 platform, and lipid measurements were performed on serum and SF samples. Then, multivariate statistical analyses were performed to detect changes in lipid metabolites induced by CIA. Consequently, a total of 22 potential biomarkers associated with differential fatty acids were screened and identified in serum, and 13 were identified in SF. Notably, alterations were observed in metabolites such as Hexadecanoic acid, Octadecanoic acid, Arachidonic acid, (+/-)11,12-EpETrE, DHA, DPA, Myristic acid, Suberic acid, and others. This study explored a new mechanism of the RA disease process from the perspective of fatty acid metabolism. It provided a new strategy for experimental research on determining the optimal time for establishing CIA model and screening clinical diagnostic biomarkers.

Change in prostate tissue gene expression following finasteride or doxazosin administration in the medical therapy for prostatic symptoms (MTOPS) study

Benign prostatic hyperplasia (BPH) may decrease patient quality of life and often leads to acute urinary retention and surgical intervention. While effective treatments are available, many BPH patients do not respond or develop resistance to treatment. To understand molecular determinants of clinical symptom persistence after initiating BPH treatment, we investigated gene expression profiles before and after treatments in the prostate transitional zone of 108 participants in the Medical Therapy of Prostatic Symptoms (MTOPS) Trial. Unsupervised clustering revealed molecular subgroups characterized by expression changes in a large set of genes associated with resistance to finasteride, a 5α-reductase inhibitor. Pathway analyses within this gene cluster found finasteride administration induced changes in fatty acid metabolism, amino acid metabolism, immune response, steroid hormone metabolism, and kinase activity within the transitional zone. We found that patients without this transcriptional response were highly likely to develop clinical progression, which is expected in 13.2% of finasteride-treated patients. Importantly, a patient’s transcriptional response to finasteride was associated with their pre-treatment kinase expression. Further, we identified novel expression signatures of finasteride resistance among the transcriptionally responded patients. These patients showed different gene expression profiles at baseline and increased prostate transitional zone volume compared to the patients who responded to the treatment. Our work suggests molecular mechanisms of clinical resistance to finasteride treatment that could be potentially helpful for personalized BPH treatment as well as new drug development to increase patient drug response.

Mitochondria and Lipid Droplets: Focus on the Molecular Structure of Contact Sites in the Pathogenesis of Metabolic Syndrome.

Metabolic syndrome (MetS) is a complex of serious pathologies with a high prevalence worldwide. Disruption of mitochondrial biogenesis and its interaction with other cell organelles plays an important role in the development of MetS. Studies have revealed the phenotypic and functional heterogeneity of mitochondria that exist within a single cell and can regulate metabolic signaling pathways, influencing the development of metabolic diseases. Excessive intake of fatty acids leads to changes in fatty acid metabolism that affect the biology of important cell organelles - the lipid droplets, whose specific biology is not fully understood. Perhaps targeted molecular genetic stimulation aimed at regulating the contact between mitochondria and lipids can break the vicious cycle of inflammation in MetS and restore normal cell function, reducing the risk of developing concomitant pathologies. The review describes potential (promising) therapeutic molecular targets associated with mitochondria and lipid droplets, focusing on the proteins involved in their contact and emphasizing their role in the pathogenesis of MetS.

Accounting for NAD Concentrations in Genome-Scale Metabolic Models Captures Important Metabolic Alterations in NAD-Depleted Systems.

Nicotinamide adenine dinucleotide (NAD) is a ubiquitous molecule found within all cells, acting as a crucial coenzyme in numerous metabolic reactions. It plays a vital role in energy metabolism, cellular signaling, and DNA repair. Notably, NAD levels decline naturally with age, and this decline is associated with the development of various age-related diseases. Despite this established link, current genome-scale metabolic models, which offer powerful tools for understanding cellular metabolism, do not account for the dynamic changes in NAD concentration. This impedes our understanding of a fluctuating NAD level's impact on cellular metabolism and its contribution to age-related pathologies. To bridge this gap in our knowledge, we have devised a novel method that integrates altered NAD concentration into genome-scale models of human metabolism. This approach allows us to accurately reflect the changes in fatty acid metabolism, glycolysis, and oxidative phosphorylation observed experimentally in an engineered human cell line with a compromised level of subcellular NAD.

Abstract 6544: Targeting resistance mechanisms to AR-targeted therapy in prostate cancer through inhibition of CREBBP/EP300

Abstract Standard initial treatment for men with metastatic prostate cancer involves targeting the androgen receptor (AR) with androgen deprivation therapy or androgen-receptor signaling inhibitors. Resistance eventually develops, such as through AR-activating alterations, leaving few targeted options for patients. Here, we utilize data from 4,509 prostate cancer patients with longitudinal clinical and DNA/RNA sequencing data to elucidate mechanisms of resistance and identify potential therapeutic vulnerabilities in resistant disease. By constructing comprehensive regulatory networks, termed hybrid networks, built across different disease stages, combining features from WGCNA, causal mediation analysis, probabilistic causal network inference, and public knowledge graphs, we uncover subnetworks strongly associated with disease progression and resistance. These subnetworks reflect biological processes for cell cycle, E2F, DNA repair, MYC, and AR, comprehensively identifying broad transcriptional changes that drive disease progression and resistance. Selected subnetwork scores, derived from RNA expression, were significantly associated with outcomes in both the hormone-sensitive and castration-resistant settings, demonstrating that the subnetworks capture early and late resistance. The hybrid networks identified the transcriptional co-activators CREBBP and EP300 as key modulators of these subnetworks, suggesting that targeting CREBBP/EP300 may be effective in treating both early and late-stage disease. Prostate cancer cell lines were treated with FT-6876, a small molecule inhibitor of CREBBP/EP300, and growth inhibition was measured in both enzalutamide sensitive and resistant cell lines, covering a wide range of resistance mechanisms. The selected subnetworks were enriched for genes down-regulated following treatment with FT-6876, suggesting that targeting CREBBP/P300 addresses multiple resistance-related pathways. Differential changes in protein abundance and protein acetylation between enzalutamide sensitive and resistant cell lines identified changes in fatty acid metabolism as a common, downstream event in response to treatment with FT-6876, suggesting an additional mechanism for response to FT-6876. Together, our integrated theoretical and experimental analyses support the hypothesis that targeting CREBBP/EP300 may provide therapeutic benefits to prostate cancer patients. Further, the subnetworks identified may serve as mechanistically-informed biomarkers for identifying patients who may benefit from inhibition of CREBBP/EP300. Citation Format: Bonnie V. Dougherty, Beatrice C. Thomas, Alice M. Walsh, Veronica Calvo, Kathryne E. Ware, Andrew J. Armstrong, Jens Renstrup, Jason A. Somarelli, Eric E. Schadt. Targeting resistance mechanisms to AR-targeted therapy in prostate cancer through inhibition of CREBBP/EP300 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6544.

Inflammaging and fatty acid oxidation in monocytes and macrophages.

Fatty acid oxidation (FAO), primarily known as β-oxidation, plays a crucial role in breaking down fatty acids within mitochondria and peroxisomes to produce cellular energy and preventing metabolic dysfunction. Myeloid cells, including macrophages, microglia, and monocytes, rely on FAO to perform essential cellular functions and uphold tissue homeostasis. As individuals age, these cells show signs of inflammaging, a condition that includes a chronic onset of low-grade inflammation and a decline in metabolic function. These lead to changes in fatty acid metabolism and a decline in FAO pathways. Recent studies have shed light on metabolic shifts occurring in macrophages and monocytes during aging, correlating with an altered tissue environment and the onset of inflammaging. This review aims to provide insights into the connection of inflammatory pathways and altered FAO in macrophages and monocytes from older organisms. We describe a model in which there is an extended activation of receptor for advanced glycation end products, nuclear factor-κB (NF-κB) and the nod-like receptor family pyrin domain containing 3 inflammasome within macrophages and monocytes. This leads to an increased level of glycolysis, and also promotes pro-inflammatory cytokine production and signaling. As a result, FAO-related enzymes such as 5' AMP-activated protein kinase and peroxisome proliferator-activated receptor-α are reduced, adding to the escalation of inflammation, accumulation of lipids, and heightened cellular stress. We examine the existing body of literature focused on changes in FAO signaling within macrophages and monocytes and their contribution to the process of inflammaging.

Newly isolated Lactobacillus paracasei strain modulates lung immunity and improves the capacity to cope with influenza virus infection

BackgroundThe modulation of immune responses by probiotics is crucial for local and systemic immunity. Recent studies have suggested a correlation between gut microbiota and lung immunity, known as the gut–lung axis. However, the evidence and mechanisms underlying this axis remain elusive.ResultsIn this study, we screened various Lactobacillus (L.) strains for their ability to augment type I interferon (IFN-I) signaling using an IFN-α/β reporter cell line. We identified L. paracasei (MI29) from the feces of healthy volunteers, which showed enhanced IFN-I signaling in vitro. Oral administration of the MI29 strain to wild-type B6 mice for 2 weeks resulted in increased expression of IFN-stimulated genes and pro-inflammatory cytokines in the lungs. We found that MI29-treated mice had significantly increased numbers of CD11c+PDCA-1+ plasmacytoid dendritic cells and Ly6Chi monocytes in the lungs compared with control groups. Pre-treatment with MI29 for 2 weeks resulted in less weight loss and lower viral loads in the lung after a sub-lethal dose of influenza virus infection. Interestingly, IFNAR1−/− mice did not show enhanced viral resistance in response to oral MI29 administration. Furthermore, metabolic profiles of MI29-treated mice revealed changes in fatty acid metabolism, with MI29-derived fatty acids contributing to host defense in a Gpr40/120-dependent manner.ConclusionsThese findings suggest that the newly isolated MI29 strain can activate host defense immunity and prevent infections caused by the influenza virus through the gut–lung axis.AkUk8chsowdrEnMNpQUQ-XVideo

Altered markers of mitochondrial function in adults with autism spectrum disorder.

Previous research suggests potential mitochondrial dysfunction and changes in fatty acid metabolism in a subgroup of individuals with autism spectrum disorder (ASD), indicated by higher lactate, pyruvate levels, and mitochondrial disorder prevalence. This study aimed to further investigate potential mitochondrial dysfunction in ASD by assessing blood metabolite levels linked to mitochondrial metabolism. Blood levels of creatine kinase (CK), alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate, pyruvate, free and total carnitine, as well as acylcarnitines were obtained in 73 adults with ASD (47 males, 26 females) and compared with those of 71 neurotypical controls (NTC) (44 males, 27 females). Correlations between blood parameters and psychometric ASD symptom scores were also explored. Lower CK (pcorr = 0.045) levels were found exclusively in males with ASD compared to NTC, with no such variation in females. ALT and AST levels did not differ significantly between both groups. After correction for antipsychotic and antidepressant medication, CK remained significant. ASD participants had lower serum lactate levels (pcorr = 0.036) compared to NTC, but pyruvate and carnitine concentrations showed no significant difference. ASD subjects had significantly increased levels of certain acylcarnitines, with a decrease in tetradecadienoyl-carnitine (C14:2), and certain acylcarnitines correlated significantly with autistic symptom scores. We found reduced serum lactate levels in ASD, in contrast to previous studies suggesting elevated lactate or pyruvate. This difference may reflect the focus of our study on high-functioning adults with ASD, who are likely to have fewer secondary genetic conditions associated with mitochondrial dysfunction. Our findings of significantly altered acylcarnitine levels in ASD support the hypothesis of altered fatty acid metabolism in a subset of ASD patients.

Functional and molecular profiling of hematopoietic stem cells during regeneration

Hematopoietic stem cells (HSCs) enable hematopoietic stem cell transplantation (HCT) through their ability to replenish the entire blood system. Proliferation of HSCs is linked to decreased reconstitution potential, and a precise regulation of actively dividing HSCs is thus essential to ensure long-term functionality. This regulation becomes important in the transplantation setting where HSCs undergo proliferation followed by a gradual transition to quiescence and homeostasis. While mouse HSCs have been well studied during homeostatic conditions, the mechanisms regulating HSC activation during stress remain unclear. Here, we analyzed the different phases of regeneration following transplantation. We isolated bone marrow from mice at eight time points after transplantation and examined the reconstitution dynamics and transcriptional profiles of stem and progenitor populations. We found that regenerating HSCs initially produced rapidly expanding progenitors and displayed distinct changes in fatty acid metabolism and glycolysis. Moreover, we observed molecular changes in cell cycle, MYC and mTOR signaling in both HSCs and the progenitor subsets. We used a decay rate model to fit the temporal transcription profiles of regenerating HSCs and identified genes with progressively decreased or increased expression after transplantation. These genes overlapped to a large extent with published gene sets associated with key aspects of HSC function demonstrating the potential of this data set as a resource for identification of novel HSC regulators. Taken together, our study provides a detailed functional and molecular characterization of HSCs at different phases of regeneration and identifies a gene set associated with the transition from proliferation to quiescence.

Auricularia auricula polysaccharides attenuate obesity in mice through gut commensal Papillibacter cinnamivorans

IntroductionAuricularia auricula is a well-known traditional edible and medical fungus with high nutritional and pharmacological values, as well as metabolic and immunoregulatory properties. Nondigestible fermentable polysaccharides are identified as primary bioactive constituents of Auricularia auricula extracts. However, the exact mechanisms underlying the effects of Auricularia auricula polysaccharides (AAP) on obesity and related metabolic endpoints, including the role of the gut microbiota, remain insufficiently understood. MethodsThe effects of AAP on obesity were assessed within high-fat diet (HFD)-based mice through obesity trait analysis and metabolomic profiling. To determine the mechanistic role of the gut microbiota in observed anti-obesogenic effects AAP, faecal microbiota transplantation (FMT) and pseudo-germ-free mice model treated with antibiotics were also applied, together with 16S rRNA genomic-derived taxonomic profiling. ResultsHigh-fat diet (HFD) murine exposure to AAP thwarted weight gains, reduced fat depositing and enhanced glucose tolerance, together with upregulating thermogenesis proteomic biomarkers within adipose tissue. Serum metabolome indicated these effects were associated with changes in fatty acid metabolism. Intestine-dwelling microbial population assessments discovered that AAP selectively enhanced Papillibacter cinnamivorans, a commensal bacterium with reduced presence in HFD mice. Notably, HFD mice treated with oral formulations of P. cinnamivorans attenuated obesity, which was linked to decreased intestinal lipid transportation and hepatic thermogenesis. Mechanistically, it was demonstrated that P. cinnamivorans regulated intestinal lipids metabolism and liver thermogenesis by reducing the proinflammatory response and gut permeability in a JAK-STAT signaling-related manner. ConclusionDatasets from the present study show that AAP thwarted dietary-driven obesity and metabolism-based disorders by regulating intestinal lipid transportation, a mechanism that is dependent on the gut commensal P. cinnamivorans. These results indicated AAP and P. cinnamivorans as newly identified pre- and probiotics that could serve as novel therapeutics against obesity.

1611-P: Assessment of Fatty Acid Uptake by PET/MRI Imaging Under Fasting and Postprandial Conditions—A Repeatability Study in People with T2DM and Obesity

Background: Changes in fatty acid metabolism are an important component of the pathogenesis of type 2 diabetes mellitus (T2DM). Fatty acid uptake in tissues can be measured with positron emission tomography (PET) imaging, employing the fatty acid analogue 18F-FTHA radiotracer. We aimed to evaluate the repeatability of assessments of fatty acid uptake in tissues with a new whole-body PET/MRI (magnetic resonance) imaging method in people with obesity with or without T2DM. Methods: 17 completers underwent 4 repeated examinations under standardised conditions, twice under fasting and twice postprandially (PP). Tissue-specific fatty acid uptake (FAU) and uptake rate was measured using 18F-FTHA and dynamic whole-body PET/MRI in skeletal muscle, subcutaneous and visceral adipose tissues (SAT, VAT), myocardium and brain. Free fatty acid levels were measured over time. The repeatability of PET measurements under fasting, and under PP, was assessed by calculating the intraclass correlation coefficient (ICC 2,1) along with its 95 % confidence intervals; ICC ≥ 0.75 indicates excellent, 0.6 - 0.74 good, 0.4 - 0.59 fair and <0.4 poor reliability. Results: In the fasted state, repeatability of the net uptake rate in muscle tissue was found to be excellent, ICC 0.91 (0.78 - 0.96) and good in myocardium, ICC 0.64 (0.27-0.86). Repeatability of FAU in other tissues was at least fair (ICC SAT 0.80 (0.54-0.91), VAT 0.64 (0.27-0.85), brain 0.75 (0.46-0.90). In the PP experiments, variability increased especially for the FAU estimates, but the repeatability of the uptake rate was acceptable (ICC >0.4) for most investigated tissues, and good for muscle (ICC 0.73 (0.42-0.89). Conclusion: 18F-FTHA-PET/MRI provides information on tissue-specific fatty acid uptake with good reliability, and excellent repeatability for the muscle under fasting. The method has potential to provide insights in monitoring and evaluating treatment effects in interventional trials. Disclosure I.Laitinen: Employee; Antaros Medical. T.Coskun: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company. Z.Milicevic: Employee; Eli Lilly and Company. L.Johansson: Employee; Antaros Medical, Stock/Shareholder; Antaros Medical. P.Nuutila: None. S.Ekström: Employee; Antaros Medical. H.Haraldsson: Employee; Antaros Medical. S.Pierrou: Stock/Shareholder; AstraZeneca. K.Kalliokoski: Consultant; Synektik S.A., Stock/Shareholder; Faron Pharmaceuticals Oy, CRST Oy. M.Kiugel: None. M.Scheinin: Consultant; Orion Pharma, Employee; Clinical Research Services Turku - CRST Oy, Other Relationship; Antaros Medical AB, Biogen, Boehringer Ingelheim International GmbH, Falk GmbH and Co Kg, Imbria, Novartis AG, Novo Nordisk A/S, Provention Bio, Inc., Stock/Shareholder; Clinical Research Services Turku - CRST Oy. S.Southekal: Employee; Eli Lilly and Company. M.Lu: None.

Fatty acid desaturation by stearoyl-CoA desaturase-1 controls regulatory T cell differentiation and autoimmunity

The imbalance between pathogenic and protective T cell subsets is a cardinal feature of autoimmune disorders such as multiple sclerosis (MS). Emerging evidence indicates that endogenous and dietary-induced changes in fatty acid metabolism have a major impact on both T cell fate and autoimmunity. To date, however, the molecular mechanisms that underlie the impact of fatty acid metabolism on T cell physiology and autoimmunity remain poorly understood. Here, we report that stearoyl-CoA desaturase-1 (SCD1), an enzyme essential for the desaturation of fatty acids and highly regulated by dietary factors, acts as an endogenous brake on regulatory T-cell (Treg) differentiation and augments autoimmunity in an animal model of MS in a T cell-dependent manner. Guided by RNA sequencing and lipidomics analysis, we found that the absence of Scd1 in T cells promotes the hydrolysis of triglycerides and phosphatidylcholine through adipose triglyceride lipase (ATGL). ATGL-dependent release of docosahexaenoic acid enhanced Treg differentiation by activating the nuclear receptor peroxisome proliferator-activated receptor gamma. Our findings identify fatty acid desaturation by SCD1 as an essential determinant of Treg differentiation and autoimmunity, with potentially broad implications for the development of novel therapeutic strategies and dietary interventions for autoimmune disorders such as MS.

Intestinal dysbiosis exacerbates the pathogenesis of psoriasis-like phenotype through changes in fatty acid metabolism

The intestinal microbiota has been associated with host immunity as well as psoriasis; however, the mechanism of intestinal microbiota regulating psoriasis needs to be demonstrated systematically. Here, we sought to examine its role and mechanism of action in the pathogenesis of psoriasis. We found that the severity of psoriasis-like skin phenotype was accompanied by changes in the composition of the intestinal microbiota. We performed co-housing and fecal microbial transplantation (FMT) experiments using the K14-VEGF transgenic mouse model of psoriasis and demonstrated that the transfer of intestinal microbiota from mice with severe psoriasis-like skin phenotype exacerbated psoriasiform skin inflammation in mice with mild symptoms, including increasing the infiltration and differentiation of Th17, and increased the abundance of Prevotella, while decreasing that of Parabacteroides distasonis, in the colon. These alterations affected fatty acid metabolism, increasing the abundance of oleic and stearic acids. Meanwhile, gentamicin treatment significantly reduced the abundance of Prevotella and alleviated the psoriasis-like symptoms in both K14-VEGF mice and imiquimod (IMQ)-induced psoriasis-like mice. Indeed, administration of oleic and stearic acids exacerbated psoriasis-like symptoms and increased Th17 and monocyte-derived dendritic cell infiltration in the skin lesion areas in vivo, as well as increased the secretion of IL-23 by stimulating DCs in vitro. At last, we found that, treatment of PDE-4 inhibitor alleviated psoriasis-like phenotype of K14-VEGF mice accompanied by the recovery of intestinal microbiota, including the decrease of Prevotella and increase of Parabacteroides distasonis. Overall, our findings reveal that the intestinal microbiota modulates host metabolism and psoriasis-like skin inflammation in mice, suggesting a new target for the clinical diagnosis and treatment of psoriasis.

AKT/PACS2 Participates in Renal Vascular Hyperpermeability by Regulating Endothelial Fatty Acid Oxidation in Diabetic Mice.

Diabetes is a chronic metabolic disorder that can cause many microvascular and macrovascular complications, including diabetic nephropathy. Endothelial cells exhibit phenotypic and metabolic diversity and are affected by metabolic disorders. Whether changes in endothelial cell metabolism affect vascular endothelial function in diabetic nephropathy remains unclear. In diabetic mice, increased renal microvascular permeability and fibrosis, as well as increased MAMs and PACS2 in renal endothelial cells, were observed. Mice lacking PACS2 improved vascular leakage and glomerulosclerosis under high fat diet. In vitro, PACS2 expression, VE-cadherin internalization, fibronectin production, and Smad-2 phosphorylation increased in HUVECs treated with high glucose and palmitic acid (HGHF). Pharmacological inhibition of AKT significantly reduced HGHF-induced upregulation of PACS2 and p-Smad2 expression. Blocking fatty acid β-oxidation (FAO) ameliorated the impaired barrier function mediated by HGHF. Further studies observed that HGHF induced decreased FAO, CPT1α expression, ATP production, and NADPH/NADP+ ratio in endothelial cells. However, these changes in fatty acid metabolism were rescued by silencing PACS2. In conclusion, PACS2 participates in renal vascular hyperpermeability and glomerulosclerosis by regulating the FAO of diabetic mice. Targeting PACS2 is potential new strategy for the treatment of diabetic nephropathy.

A novel fatty acid metabolism-related gene signature predicts the prognosis, tumor immune properties, and immunotherapy response of colon adenocarcinoma patients.

Colon adenocarcinoma (COAD) has a high incidence and death rate. Despite the fact that change in fatty acid metabolism promotes tumor growth and metastasis to the greatest degree among metabolite profiles, a thorough investigation on the involvement of fatty acid metabolism‐related genes (FAMRGs) in COAD has yet not been conducted. Here, the clinical data as well as the gene expression profiles were extracted from The Cancer Genome Atlas (TCGA) database. Based on the FAMRG expression data and clinical information, a FAMRG risk signature was developed using LASSO as well as multivariate and univariate Cox regression analyses. Then, the nomogram was used to create a customized prognostic prediction model, and the calibration and receiver operating characteristic curves were used to evaluate the nomogram's prediction performance and discriminative capability. Lastly, a number of studies were conducted to assess the influence of independent FAMRGs on COAD, including unsupervised cluster analysis, functional analysis, and drug sensitivity analysis. Three hundred and sixty‐seven patients were included in this study, and a 12‐FAMRG risk signature was discovered in the training cohort based on a detailed examination of the FAMRGs expression data and clinical information. After that, risk scores were computed to classify patients into low or high‐risk groups, and the Kaplan–Meier curve analysis revealed that patients in the low‐risk group exhibited an elevated overall survival (OS) rate. The FAMRG was shown to be substantially correlated with prognosis in multivariate Cox regression analysis and was validated using the validation dataset. Then, using the clinical variables and risk signature, we developed and validated a prediction nomogram for OS. Functional characterization showed a strong correlation between this signature and immune cell infiltration and immune modulation. Additionally, by evaluating the GDSC database, it was determined that the high‐risk group exhibited medication resistance to many chemotherapeutic and targeted medicines, including VX.680, gemcitabine, doxorubicin, and paclitaxel. Overall, we have revealed the significance of a FAMRG risk signature for predicting the prognosis and response to immunotherapy in COAD, and our findings might contribute to an enhanced comprehension of metabolic pathways and the future development of innovative COAD therapeutic methods.

Fatty Acid Metabolism and Idiopathic Pulmonary Fibrosis.

Fatty acid metabolism, including the de novo synthesis, uptake, oxidation, and derivation of fatty acids, plays several important roles at cellular and organ levels. Recent studies have identified characteristic changes in fatty acid metabolism in idiopathic pulmonary fibrosis (IPF) lungs, which implicates its dysregulation in the pathogenesis of this disorder. Here, we review the evidence for how fatty acid metabolism contributes to the development of pulmonary fibrosis, focusing on the profibrotic processes associated with specific types of lung cells, including epithelial cells, macrophages, and fibroblasts. We also summarize the potential therapeutics that target this metabolic pathway in treating IPF.

A Matched Case-Control Study of Noncholesterol Sterols and Fatty Acids in Chronic Hemodialysis Patients.

Dyslipidemia is common among patients on hemodialysis, but its etiology is not fully understood. Although changes in cholesterol homeostasis and fatty acid metabolism play an important role during dialysis, the interaction of these metabolic pathways has yet to be studied in sufficient detail. In this study, we enrolled 26 patients on maintenance hemodialysis treatment (high-volume hemodiafiltration, HV HDF) without statin therapy (17 men/9 women) and an age/gender-matched group of 26 individuals without signs of nephropathy. The HV-HDF group exhibited more frequent signs of cardiovascular disease, disturbed saccharide metabolism, and altered lipoprotein profiles, manifesting in lower HDL-C, and raised concentrations of IDL-C and apoB-48 (all p < 0.01). HV-HDF patients had higher levels of campesterol (p < 0.01) and β-sitosterol (p = 0.06), both surrogate markers of cholesterol absorption and unchanged lathosterol concentrations. Fatty acid (FA) profiles were changed mostly in cholesteryl esters, with a higher content of saturated and n-3 polyunsaturated fatty acids (PUFA) in the HV-HDF group. However, n-6 PUFA in cholesteryl esters were less abundant (p < 0.001) in the HV-HDF group. Hemodialysis during end-stage kidney disease induces changes associated with higher absorption of cholesterol and disturbed lipoprotein metabolism. Changes in fatty acid metabolism reflect the combined effect of renal insufficiency and its comorbidities, mostly insulin resistance.