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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.

Interleukin-10 (IL-10) is a key anti-inflammatory cytokine that can limit immune cell activation and cytokine production in innate immune cell types 1 . Loss of IL-10 signalling results in life-threatening inflammatory bowel disease in humans and mice—however, the exact mechanism by which IL-10 signalling subdues inflammation remains unclear 2 – 5 . Here we find that increased saturated very long chain (VLC) ceramides are critical for the heightened inflammatory gene expression that is a hallmark of IL-10 deficiency. Accordingly, genetic deletion of ceramide synthase 2 (encoded by Cers2 ), the enzyme responsible for VLC ceramide production, limited the exacerbated inflammatory gene expression programme associated with IL-10 deficiency both in vitro and in vivo. The accumulation of saturated VLC ceramides was regulated by a decrease in metabolic flux through the de novo mono-unsaturated fatty acid synthesis pathway. Restoring mono-unsaturated fatty acid availability to cells deficient in IL-10 signalling limited saturated VLC ceramide production and the associated inflammation. Mechanistically, we find that persistent inflammation mediated by VLC ceramides is largely dependent on sustained activity of REL, an immuno-modulatory transcription factor. Together, these data indicate that an IL-10-driven fatty acid desaturation programme rewires VLC ceramide accumulation and aberrant activation of REL. These studies support the idea that fatty acid homeostasis in innate immune cells serves as a key regulatory node to control pathologic inflammation and suggests that ‘metabolic correction’ of VLC homeostasis could be an important strategy to normalize dysregulated inflammation caused by the absence of IL-10. IL-10 exerts its anti-inflammatory activity in macrophages by increasing the expression of enzymes that promote fatty acid desaturation and downstream regulation of the transcription factor REL.

Long-chain polyunsaturated fatty acids (LC-PUFAs), particularly the omega-3 LC-PUFAs eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA), and docosahexaenoic acid (DHA), have been associated with beneficial health effects. Consequently, sustainable sources have to be developed to meet the increasing demand for these PUFAs. Here, we demonstrate the design and construction of artificial PUFA biosynthetic gene clusters (BGCs) encoding polyketide synthase-like PUFA synthases from myxobacteria adapted for the oleaginous yeast Yarrowia lipolytica . Genomic integration and heterologous expression of unmodified or hybrid PUFA BGCs yielded different yeast strains with specific LC-PUFA production profiles at promising yield and thus valuable for the biotechnological production of distinct PUFAs. Nutrient screening revealed a strong enhancement of PUFA production, when cells were phosphate limited. This represents, to the best of our knowledge, highest concentration of DHA (16.8 %) in total fatty acids among all published PUFA-producing Y. lipolytica strains. Sustainable sources are needed to meet the demand for long-chain polyunsaturated fatty acids. Here the authors construct an artificial biosynthetic gene cluster in Y. lipolytica capable of producing a high concentration of PUFAs.

Microalgae are the primary producers of carbon in marine ecosystems, fixing carbon and subsequently generating various biomolecules such as carbohydrates, proteins and lipids. Most importantly, microalgae are the generators and main suppliers of ω3 polyunsaturated fatty acids (ω3PUFA) in the marine ecosystem, which have a fundamental importance for the functioning and quality of the whole marine food web. A meta-analysis of over 160 fatty acid profiles of 7 marine phytoplankton phyla reveals not only a phyla-specific, but also a highly class-specific PUFA production of marine phytoplankton. The highest EPA (Eicosapentaenoic acid; 20:5ω3) production per total fatty acids was found in 2 classes of Haptophyta and in Ochrophyta, while Dinophyta and the Haptophyte Emiliana huxleyi show the highest production of DHA (Docosahexaenoic acid; 22:6ω3). An important precursor for EPA, Stearidonic acid (SDA, 18:4ω3) is found in high proportions in Cryptophyta and the Chlorophta class Pyramimonadophyceae. Per unit of carbon, Chlorophyta and Cyanobacteria were the poorest producers of highly unsaturated fatty acids (HUFA). The remaining phyla had a similar HUFA contribution per unit of carbon but with different compositions. The nutritional and environmental effects on the phytoplankton PUFA production is summarized and shows a lowering of the PUFA content under stressful environmental conditions.

In the present two-year study, an attempt was made to estimate the grain yield, grain nutrient uptake, and oil quality of three commonly grown maize (Zea mays L.) hybrids fertilized with varied levels of nitrogen (N), phosphorus (P) and potassium (K). Results obtained from both the experimental years indicated that application of 125% of recommended dose of fertilizer (RDF) recorded maximum grain yield (10.37 t ha-1; 124% higher than control). When compared with 100% RDF, grain yield reduction with nutrient omission was 44% for N omission, 17% for P omission, and 27% for K omission. Nitrogen uptake was increased with increasing NPK levels up to 150% RDF that was statistically at par (p ≥ 0.01) with 125% RDF. Increasing trend in P and K uptake was observed with successive increase in NPK levels up to 125% RDF, above which it declined. The protein content was significantly higher in grains of var. P 3396 with 125% RDF. Nutrient management has significant (p ≤ 0.01) role in the grain oil content. Saturated fatty acids (palmitic, stearic and arachidic acid) content decreased, and unsaturated fatty acid (oleic, linoleic and linolenic acid) increased with increasing NPK levels. The average oleic acid desaturation and linoleic acid desaturation ratios were increased with increasing NPK levels up to 100 and 125% RDF, respectively. However, average monounsaturated fatty acids (MUFA): poly-unsaturated fatty acids (PUFA), saturated: unsaturated as well as linoleic: linolenic acid ratios were increased on receiving 75% RDF, and beyond that it showed decreasing trend. The omission of K had the highest inhibitory effect on corn oil quality followed by N and P omission.

Lipid degradation is generally considered an antagonistic pathway to lipid synthesis, so this pathway is often removed to improve lipid production. In this study, triacylglycerol (TAG) cycling formed by lipid degradation is found to be crucial for long-chain polyunsaturated fatty acid (PUFA) biosynthesis; this result contradicts the notion that lipid degradation is a useless process. Specifically, we demonstrate that TAG cycling promoting PUFA biosynthesis occurred in Yarrowia lipolytica and Mortierella alpina via the desaturase/elongase pathway but not in Schizochytrium sp. with the polyketide synthase (PKS) pathway. Exploiting the TAG cycling mechanism, a strategy of decoupling the TAG biosynthesis and degradation is developed. Using this strategy, the titers of C20:5, C22:5 and prostaglandin F2α (PGF2α) in Y. lipolytica are improved by 116.2%, 99.4% and 41.7%, respectively. Our findings highlight the potential of the TAG cycling for related biochemical synthesis in the construction of excellent oleaginous engineered strains. The authors demonstrate the role and mechanism of triacylglycerol (TAG) cycling in polyunsaturated fatty acid biosynthesis and develop a strategy of decoupling the TAG biosynthesis and degradation to improve related biochemical synthesis.

Atlantic salmon can synthesize polyunsaturated fatty acids (PUFAs), such as eicosapentaenoic acid (20:5n-3), arachidonic acid (20:4n-6) and docosahexaenoic acid (22:6n-3) via activities of very long chain fatty acyl elongases (Elovls) and fatty acyl desaturases (Fads), albeit to a limited degree. Understanding molecular mechanisms of PUFA biosynthesis and regulation is a pre-requisite for sustainable use of vegetable oils in aquafeeds as current sources of fish oils are unable to meet increasing demands for omega-3 PUFAs. By generating CRISPR-mediated elovl2 partial knockout (KO), we have shown that elovl2 is crucial for multi-tissue synthesis of 22:6n-3 in vivo and that endogenously synthesized PUFAs are important for transcriptional regulation of lipogenic genes in Atlantic salmon. The elovl2-KOs showed reduced levels of 22:6n-3 and accumulation of 20:5n-3 and docosapentaenoic acid (22:5n-3) in the liver, brain and white muscle, suggesting inhibition of elongation. Additionally, elovl2-KO salmon showed accumulation of 20:4n-6 in brain and white muscle. The impaired synthesis of 22:6n-3 induced hepatic expression of sterol regulatory element binding protein-1 (srebp-1), fatty acid synthase-b, Δ6fad-a, Δ5fad and elovl5. Our study demonstrates key roles of elovl2 at two penultimate steps of PUFA synthesis in vivo and suggests Srebp-1 as a main regulator of endogenous PUFA synthesis in Atlantic salmon.

Omega-3 long-chain (≥C20) polyunsaturated fatty acids (ω3 LC-PUFA) such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are critical for human health and development [corrected].. Numerous studies have indicated that deficiencies in these fatty acids can increase the risk or severity of cardiovascular, inflammatory and other diseases or disorders. EPA and DHA are predominantly sourced from marine fish although the primary producers are microalgae. Much work has been done to engineer a sustainable land-based source of EPA and DHA to reduce pressure on fish stocks in meeting future demand, with previous studies describing the production of fish oil-like levels of DHA in the model plant species, Arabidopsis thaliana. In this study we describe the production of fish oil-like levels (>12%) of DHA in the oilseed crop species Camelina sativa achieving a high ω3/ω6 ratio. The construct previously transformed in Arabidopsis as well as two modified construct versions designed to increase DHA production were used. DHA was found to be stable to at least the T5 generation and the EPA and DHA were found to be predominantly at the sn-1,3 positions of triacylglycerols. Transgenic and parental lines did not have different germination or seedling establishment rates. DHA can be produced at fish oil-like levels in industrially-relevant oilseed crop species using multi-gene construct designs which are stable over multiple generations. This study has implications for the future of sustainable EPA and DHA production from land-based sources.

Microalgae offer potential for numerous commercial applications, among them the production of long-chain polyunsaturated fatty acids (LC-PUFAs). These valuable fatty acids are important for a variety of nutraceutical and pharmaceutical purposes, and the market for these products is continually growing. An appropriate ratio of LC-PUFA of the ω-3 and ω-6 groups is vital for \"healthy\" nutrition, and adequate dietary intake has strong health benefits in humans. Microalgae of diverse classes are primary natural producers of LC-PUFA. This mini-review presents an introductory overview of LC-PUFA-related health benefits in humans, describes LC-PUFA occurrence in diverse microalgal classes, depicts the major pathways of their biosynthesis in microalgae, and discusses the prospects for microalgal LC-PUFA production.[PUBLICATION ABSTRACT]

Microalgae have a great potential for the production of healthy food and feed supplements. Their ability to convert carbon into high-value compounds and to be cultured in large scale without interfering with crop cultivation makes these photosynthetic microorganisms promising for the sustainable production of lipids. In particular, microalgae represent an alternative source of polyunsaturated fatty acids (PUFAs), whose consumption is related to various health benefits for humans and animals. In recent years, several strategies to improve PUFAs’ production in microalgae have been investigated. Such strategies include selecting the best performing species and strains and the optimization of culturing conditions, with special emphasis on the different cultivation systems and the effect of different abiotic factors on PUFAs’ accumulation in microalgae. Moreover, developments and results obtained through the most modern genetic and metabolic engineering techniques are described, focusing on the strategies that lead to an increased lipid production or an altered PUFAs’ profile. Additionally, we provide an overview of biotechnological applications of PUFAs derived from microalgae as safe and sustainable organisms, such as aquafeed and food ingredients, and of the main techniques (and their related issues) for PUFAs’ extraction and purification from microalgal biomass.