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The metabolism of polyunsaturated fatty acids (PUFAs) plays an important role in male reproduction. Linoleic and alpha-linolenic acids need to be provided in the diet and they are converted into long chain polyunsaturated fatty acids by steps of elongation and desaturation, exerted by elongases 2 (ELOVL2) and 5 (ELOVL5) and Δ5- (FADS1) and Δ6-desaturase (FADS2). This study aims to assess the gene expression and localization of enzymes involved in the synthesis of n-3 and n-6 long-chain PUFAs in control rabbits and those fed diets containing 10% extruded flaxseed. Enzyme and PUFA localization were assessed in the testes and epididymis by immunofluorescence. Testes showed high gene expression of FADS2, ELOVL2 and ELOVL5 and low expression of FADS1. Intermediate metabolites, enzymes and final products were differently found in Leydig, Sertoli and germinal cells. FADS2 was localized in interstitial cells and elongated spermatids; ELOVL5 in meiotic cells; FADS1 was evident in interstitial tissue, Sertoli cells and elongated spermatids; ELOVL2 in interstitial cells. Epididymal vesicles were positive for FADS1, ELOVL2 and ELOVL5 as well as docosahexaenoic, eicosapentaenoic, and arachidonic acids. This knowledge of fatty acids (FA) metabolism in spermatogenesis and the influence of diet on FA profile could help identify causes of male infertility, suggesting new personalized therapy.

Germinal center B cells (GCBCs) are critical for generating long-lived humoral immunity. How GCBCs meet the energetic challenge of rapid proliferation is poorly understood. Dividing lymphocytes typically rely on aerobic glycolysis over oxidative phosphorylation for energy. Here we report that GCBCs are exceptional among proliferating B and T cells, as they actively oxidize fatty acids (FAs) and conduct minimal glycolysis. In vitro, GCBCs had a very low glycolytic extracellular acidification rate but consumed oxygen in response to FAs. [ 13 C 6 ]-glucose feeding revealed that GCBCs generate significantly less phosphorylated glucose and little lactate. Further, GCBCs did not metabolize glucose into tricarboxylic acid (TCA) cycle intermediates. Conversely, [ 13 C 16 ]-palmitic acid labeling demonstrated that GCBCs generate most of their acetyl-CoA and acetylcarnitine from FAs. FA oxidation was functionally important, as drug-mediated and genetic dampening of FA oxidation resulted in a selective reduction of GCBCs. Hence, GCBCs appear to uncouple rapid proliferation from aerobic glycolysis. Germinal center B cells can undergo rapid proliferation. Shlomchik and colleagues show that germinal center B cells, unlike other rapidly proliferating cells, do not depend on glycolysis, but rather increase their peroxisome content and rewire their cellular metabolism to exclusively utilize fatty acid oxidation for their energetic needs.

Ferroptosis is an iron-dependent regulated necrosis mediated by lipid peroxidation. Cancer cells survive under metabolic stress conditions by altering lipid metabolism, which may alter their sensitivity to ferroptosis. However, the association between lipid metabolism and ferroptosis is not completely understood. In this study, we found that the expression of elongation of very longchain fatty acid protein 5 (ELOVL5) and fatty acid desaturase 1 (FADS1) is up-regulated in mesenchymal-type gastric cancer cells (GCs), leading to ferroptosis sensitization. In contrast, these enzymes are silenced by DNA methylation in intestinal-type GCs, rendering cells resistant to ferroptosis. Lipid profiling and isotope tracing analyses revealed that intestinal-type GCs are unable to generate arachidonic acid (AA) and adrenic acid (AdA) from linoleic acid. AA supplementation of intestinal-type GCs restores their sensitivity to ferroptosis. Based on these data, the polyunsaturated fatty acid (PUFA) biosynthesis pathway plays an essential role in ferroptosis; thus, this pathway potentially represents a marker for predicting the efficacy of ferroptosis-mediated cancer therapy.

Low temperature (LT) restricts the growth and development of pitaya, therefore mitigating these detrimental LT-induced effects is of significant agricultural and economic importance in subtropical regions. This study investigated the effects of exogenous salicylic acid (SA, 2 mM) on the antioxidant system, fatty acid components, degree of unsaturation, and fatty acid desaturases (FADs) gene expression in pitaya seedlings (‘Taiwan No. 6’) under LT stress. LT stress increased reactive oxygen species (ROS), malondialdehyde (MDA), and relative electrical conductivity (REC), causing visible chilling injury (CI = 0.63). Crucially, LT also elevated saturated fatty acids (C12:0, C16:0, C18:0, C22:0) and decreased unsaturated fatty acids (C16:1, C18:2). This reduced the unsaturation ratio (UFA/SFA) and double bond index (DBI), compromising membrane stability and increasing permeability. However, SA application effectively mitigated these effects. SA improved peroxidase (POD) and catalase (CAT) activities, scavenging ROS and preventing oxidative damage. Crucially, SA upregulated the expression of genes encoding stearoyl-ACP desaturase (SAD) and fatty acid desaturases (FAD) enzymes, such as HuSAD2 , HuFAD2 , HuFAD4 , HuFAD6 . Consequently, SA increased unsaturated fatty acid proportions (C16:1, C18:2), UFA/SFA, and DBI. This restored membrane stability and integrity, lowered MDA, REC, and markedly reduced CI (to 0.38). This study demonstrates, for the first time in pitaya, that exogenous SA enhances cold resistance by activating antioxidant systems and regulating HuSADs and HuFADs gene expression to maintain membrane fatty acid unsaturation.

Glioblastoma (GBM) is an aggressive tumor with a dismal prognosis. Neural stem-like cells contribute to GBM’s poor prognosis by driving drug resistance and maintaining cellular heterogeneity. GBM neural stem-like cells express high levels of brain fatty acid-binding protein (FABP7), which binds to polyunsaturated fatty acids (PUFAs) ω-6 arachidonic acid (AA) and ω-3 docosahexaenoic acid (DHA). Similar to brain, GBM tissue is enriched in AA and DHA. However, DHA levels are considerably lower in GBM tissue compared to adult brain. Therefore, it is possible that increasing DHA content in GBM, particularly in neural stem-like cells, might have therapeutic value. Here, we examine the fatty acid composition of patient-derived GBM neural stem-like cells grown as neurosphere cultures. We also investigate the effect of AA and DHA treatment on the fatty acid profiles of GBM neural stem-like cells with or without FABP7 knockdown. We show that DHA treatment increases DHA levels and the DHA:AA ratio in GBM neural stem-like cells, with FABP7 facilitating the DHA uptake. We also found that an increased uptake of DHA inhibits the migration of GBM neural stem-like cells. Our results suggest that increasing DHA content in the GBM microenvironment may reduce the migration/infiltration of FABP7-expressing neural stem-like cancer cells.

There is mounting evidence that diets supplemented with polyunsaturated fatty acids (PUFA) can impact brain biology and functions. This study investigated whether moderately high-fat diets differing in n-6/n-3 fatty acid ratio could impact fatty acid composition in regions of the brain linked to various psychopathologies. Adult male Sprague Dawley rats consumed isocaloric diets (35% kcal from fat) containing different ratios of linoleic acid (n-6) and alpha-linolenic acid (n-3) for 2 months. It was found that the profiles of PUFA in the prefrontal cortex, hippocampus, and hypothalamus reflected the fatty acid composition of the diet. In addition, region-specific changes in saturated fatty acids and monounsaturated fatty acids were detected in the hypothalamus, but not in the hippocampus or prefrontal cortex. This study in adult rats demonstrates that fatty acid remodeling in the brain by diet can occur within months and provides additional evidence for the suggestion that diet could impact mental health.

Background Breast cancer (BRCA) is a malignancy originating in the breast cells, characterized by a poor overall survival rate. Post-resection, chemotherapy is commonly recommended as a primary therapeutic approach; however, its efficacy remains limited. Recent advancements in lipidomics and metabolomics have provided new insights into the intricate landscape of fatty acid metabolism (FAM) and the fatty acid lipidome in both health and disease. A growing body of evidence suggests that dysregulations in FAM and fatty acid levels play a significant role in cancer initiation and progression. Despite these advances, the precise mechanisms through which FAM mediates the anti-cancer effects of lobaplatin in BRCA remain poorly understood and warrant further investigation. Methods GEO and TCGA data were classified into two types. We aimed to show how FAMGs influence immune function, immune checkpoints, and m6a in BRCA. A co-expression analysis discovered that gene expression is strongly connected to pyroptosis. The TCGA gathered information about mRNAsi, gene mutations, CNV, and clinical features. Results In the low-risk group, overall survival (OS) is longer. GSEA was utilized to identify immune and tumor-related pathways. Most of the FAMG-derived prognostic signatures predominantly modulate immunological and oncogenic signaling pathways, including the Wnt, neurotrophin, chemokine, and calcium signaling cascades. Among the genes involved are CEL, WT1, and ULBP2. Expression levels varied as well. The prognostic model, CNVs, single nucleotide polymorphism (SNP), and drug sensitivity all pointed to the gene. Conclusions The primary objective of this study is to identify and validate BRCA-associated FAMGs that can serve as prognostic indicators and provide insights into immune system function, while also offering evidence to support the development of fatty acid metabolism-related molecularly targeted therapeutics. Consequently, FAMGs and their interactions with the immune system, as well as their role in BRCA, may emerge as promising therapeutic targets.

Longer-chain polyunsaturated fatty acids (LCPUFAs) ≥20 carbons long are required for leukocyte function. These can be obtained from the diet, but there is some evidence that leukocytes can convert essential fatty acids (EFAs) into LCPUFAs. We used stable isotope tracers to investigate LCPUFA biosynthesis and the effect of different EFA substrate ratios in human T lymphocytes. CD3 + T cells were incubated for up to 48 h with or without concanavalin A in media containing a 18:2n-6:18:3n-3 (EFA) ratio of either 5:1 or 8:1 and [ 13 C]18:3n-3 plus [d 5 ]18:2n-6. Mitogen stimulation increased the amounts of 16:1n-7, 18:1n-9, 18:2n-6, 20:3n-6, 20:4n-6, 18:3n-3, and 20:5n-3 in T cells. Expression of the activation marker CD69 preceded increased FADS2 and FADS1 mRNA expression and increased amounts of [d 5 ]20:2n-6 and [ 13 C]20:3n-3 at 48 h. In addition, 22-carbon n-6 or n-3 LCPUFA synthesis was not detected, consistent with the absence of ELOVL2 expression. An EFA ratio of 8:1 reduced 18:3n-3 conversion and enhanced 20:2n-6 synthesis compared to a 5:1 ratio. Here, [d 5 ]9- and [d 5 ]-13-hydroxyoctadecadienoic (HODE) and [ 13 C]9- and [ 13 C]13-hydroxyoctadecatrienoic acids (HOTrE) were the major labelled oxylipins in culture supernatants; labelled oxylipins ≥20 carbons were not detected. An EFA ratio of 8:1 suppressed 9- and 13-HOTrE synthesis, but there was no significant effect on 9- and 13-HODE synthesis. These findings suggest that partitioning of newly assimilated EFA between LCPUFA synthesis and hydroxyoctadecaenoic acid may be a metabolic branch point in T-cell EFA metabolism that has implications for understanding the effects of dietary fats on T lymphocyte function.

Renal cell carcinoma is characterized by a poor prognosis. Recently, renal cell carcinoma has been recognized as a metabolic disease associated with fatty acid metabolic reprogramming, although in-depth studies on this topic are still lacking. We found that fatty acid metabolism reprogramming in renal cell carcinoma is primarily characterized by high expression of FABP1 . FABP1 + tumors significantly impact survival and display distinct differentiation trajectories compared to other tumor subclusters. They show elevated expression of angiogenesis and cell migration signals, with PLG-PLAT-mediated interactions with endothelial cells notably enhanced. Spatial transcriptomics show a prominent co-localization of FABP1 + tumors with endothelial cells, and their spatial distribution closely aligns with that of PLAT + endothelial cells. FABP1 + tumors exhibit a unique pattern in spatial transcriptomics, enriched in Extracellular Matrix and angiogenesis-related pathways. Through receptor-ligand interaction analysis, a novel PLG-PLAT functional axis was found between tumor epithelial cells and endothelial cells. Based on results of experiments, we infer that FABP1 + tumors can promote plasmin-related tumor angiogenesis by triggering the PLG-PLAT signaling axis. Finally, utilizing preclinical models, we suggest that targeting the FABP1-PLG-PLAT axis may serve as promising strategy enhancing the sensitivity of Tyrosine Kinase Inhibitor therapy.

A new study shows that reduced fat metabolism in renal tubule cells contributes to kidney fibrosis. Renal fibrosis is the histological manifestation of a progressive, usually irreversible process causing chronic and end-stage kidney disease. We performed genome-wide transcriptome studies of a large cohort ( n = 95) of normal and fibrotic human kidney tubule samples followed by systems and network analyses and identified inflammation and metabolism as the top dysregulated pathways in the diseased kidneys. In particular, we found that humans and mouse models with tubulointerstitial fibrosis had lower expression of key enzymes and regulators of fatty acid oxidation (FAO) and higher intracellular lipid deposition compared to controls. In vitro experiments indicated that inhibition of FAO in tubule epithelial cells caused ATP depletion, cell death, dedifferentiation and intracellular lipid deposition, phenotypes observed in fibrosis. In contrast, restoring fatty acid metabolism by genetic or pharmacological methods protected mice from tubulointerstitial fibrosis. Our results raise the possibility that correcting the metabolic defect in FAO may be useful for preventing and treating chronic kidney disease.