scholarly journals De novo synthesized polyunsaturated fatty acids operate as both host immunomodulators and nutrients for Mycobacterium tuberculosis

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Thomas Laval ◽  
Laura Pedró-Cos ◽  
Wladimir Malaga ◽  
Laure Guenin-Macé ◽  
Alexandre Pawlik ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Mycobacterium Tuberculosis ◽  
Transcriptional Activation ◽  
De Novo ◽  
Axenic Culture ◽  
Innate Immune Responses ◽  
Primary Mouse ◽  
Mouse Macrophages ◽  
Successful Control

Successful control of Mycobacterium tuberculosis (Mtb) infection by macrophages relies on immunometabolic reprogramming, where the role of fatty acids (FAs) remains poorly understood. Recent studies unraveled Mtb's capacity to acquire saturated and monounsaturated FAs via the Mce1 importer. However upon activation, macrophages produce polyunsaturated FAs (PUFAs), mammal-specific FAs mediating the generation of immunomodulatory eicosanoids. Here, we asked how Mtb modulates de novo synthesis of PUFAs in primary mouse macrophages and whether this benefits host or pathogen. Quantitative lipidomics revealed that Mtb infection selectively activates the biosynthesis of w6 PUFAs upstream of the eicosanoid precursor arachidonic acid (AA), via transcriptional activation of Fads2. Inhibiting FADS2 in infected macrophages impaired their inflammatory and antimicrobial responses but had no effect on Mtb growth in mice. Using a click-chemistry approach, we found that Mtb efficiently imports w6 PUFAs via Mce1 in axenic culture, including AA. Further, Mtb preferentially internalized AA over all other FAs within infected macrophages, by mechanisms partially depending on Mce1 and supporting intracellular persistence. Notably, IFNγ repressed de novo synthesis of AA by infected mouse macrophages and restricted AA import by intracellular Mtb. Together, these findings identify AA as a major FA substrate for intracellular Mtb, whose mobilization by innate immune responses is opportunistically hijacked by the pathogen and downregulated by IFNγ.

scholarly journals De novo synthesized polyunsaturated fatty acids operate as both host immunomodulators and nutrients for Mycobacterium tuberculosis

2021 ◽  
Author(s):  
Thomas Laval ◽  
Laura Pedró-Cos ◽  
Wladimir Malaga ◽  
Laure Guenin-Macé ◽  
Alexandre Pawlik ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Mycobacterium Tuberculosis ◽  
Immune Responses ◽  
Biosynthetic Pathway ◽  
De Novo ◽  
Axenic Culture ◽  
Pufa Biosynthesis ◽  
Successful Control

Successful control of Mycobacterium tuberculosis (Mtb) infection by macrophages relies on immunometabolic reprogramming, where the role of fatty acids (FAs) remains poorly understood. Recent studies unraveled Mtb's capacity to acquire saturated and monounsaturated FAs via the Mce1 importer. However, upon activation macrophages produce polyunsaturated FAs (PUFAs), mammal-specific FAs mediating the generation of key immunomodulatory eicosanoids. Here, we asked whether PUFA biosynthesis is modulated in Mtb-infected macrophages and benefits host or pathogen. Quantitative lipidomics revealed that Mtb infection activates the early PUFA biosynthetic pathway for production of eicosanoids. While PUFA synthesis blockade significantly impaired the inflammatory and antimicrobial responses of infected macrophages, it had no effect on Mtb growth in vivo. Using a click-chemistry approach, we found that Mtb efficiently imports PUFAs of the w6 subset via Mce1 in axenic culture, including the eicosanoid precursor arachidonic acid (AA). Notably, Mtb preferentially internalized AA over all other FAs in infected macrophages, but AA import by intracellular Mtb was largely independent from Mce1 and correlated with elevated AA levels within macrophages. Together, these findings reveal PUFAs as novel FA substrates for Mtb. They suggest that Mtb's import of infection-induced PUFAs may counteract their stimulatory effect on anti-mycobacterial immune responses.

Regulation Of The Fatty Acid Composition Of Platelet Phospholipids

1981 ◽  
Author(s):  
M L McKean ◽  
J B Smith ◽  
M J Silver
Keyword(s):  
Fatty Acids ◽  
Fatty Acid Composition ◽  
Fatty Acid ◽  
Acid Composition ◽  
Unsaturated Fatty Acids ◽  
De Novo ◽  
Membrane Phospholipids ◽  
De Novo Biosynthesis ◽  
Coa Transferase

The fatty acid composition of cell membrane phospholipids does not remain constant after de novo biosynthesis, but undergoes continual remodelling. One of the major routes for remodelling probably includes the deacylation-reacylation steps of the Lands Pathway. This has been shown to be important for the incorporation of long chain, polyunsaturated fatty acids into phospholipids by liver and brain. An understanding of the mechanisms involved in these processes in platelets is especially important in light of the large stores of arachidonic acid (AA) in platelet phospholipids and the role of AA in hemostasis and thrombosis. Previous results from this laboratory have shown that the turnover of radioactive AA, 8,11,14-eicosatrienoic and 5,8,11,14,17-eicosapentaenoic acids in the phospholipids of resting platelets is more rapid than the turnover of radioactive C16 and C18 saturated and unsaturated fatty acids. However, little is known about how fatty acids, especially AA and its homologues, are incorporated into platelet phospholipids during de novo biosynthesis or how they are exchanged during remodelling.At least three enzymes are involved in the deacylation- reacylation of phospholipids: phospholipase A2; acyl CoA synthetase; and acyl CoA transferase. We have studied acyl CoA transferase and have found considerable activity in human platelet membranes. Experiments are in progress to determine the substrate specificity and other properties of this enzyme.

Prolonged Laboratory Maintenance of Toxoplasma gondii Tachyzoites in Co-cultivation with the Bovine Theileria annulata-Infected Lymphoblastoids

2021 ◽  
Author(s):  
Vahid Nasiri
Keyword(s):  
Toxoplasma Gondii ◽  
Calf Serum ◽  
Axenic Culture ◽  
Theileria Annulata ◽  
Primary Mouse ◽  
Mouse Macrophages ◽  
Culture Suspension ◽  
Cultivation Process ◽  
Laboratory Maintenance

Background and Aims: In most of the studies, Toxoplasma gondii is maintained in laboratory mice or studied in vitro using non-lymphoid cell lines or primary mouse macrophages. The target of our research was to design a new axenic culture of Toxoplasma gondii tachyzoites to providing a sufficient quantity of them. Material and Methods: Theileria annulata-infected lymphoblastoids, which had been maintained up to 260 sub-cultures to attenuate the Theileria annulata, were evaluated for their suitability to the cultivation of Toxoplasma gondii tachyzoites. This cultivation process was carried out continuously for up to 10 passages, and after each 5 sub-culture, 0.1 ml of culture suspension (1×106 tachyzoites) was inoculated to each BALB/c mouse. Results: It was observed that the tachyzoites have attacked the lympho blastoids, multiplied inside them, and many fresh tachyzoites with typical shape and gliding movement were present in the culture suspension. In all processes of cultivation, the pathogenesis of parasites remained stable, and they were able to proliferate in mice and eventually lead to the death of the animals. Conclusions: We describe here a new protocol for prolonged maintenance of tachyzoites of Toxoplasma gondii, which is more efficient (both in terms of yield and cost (it does not need fetal calf serum)) than other traditional methods for maintenance of the parasite.

scholarly journals Distinct role of nuclear receptor corepressor 1 regulated de novo fatty acids synthesis in liver regeneration and hepatocarcinogenesis in mice

Hepatology ◽  
2018 ◽  
Vol 67 (3) ◽  
pp. 1071-1087 ◽  
Author(s):  
Qing Ou-Yang ◽  
Xi-Meng Lin ◽  
Yan-Jing Zhu ◽  
Bo Zheng ◽  
Liang Li ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Liver Regeneration ◽  
Nuclear Receptor ◽  
De Novo ◽  
Nuclear Receptor Corepressor ◽  
Distinct Role

scholarly journals Role of superoxide dismutase in survival of Leishmania within the macrophage

2003 ◽  
Vol 369 (3) ◽  
pp. 447-452 ◽  
Author(s):  
Sanjay GHOSH ◽  
Srikanta GOSWAMI ◽  
Samit ADHYA
Keyword(s):  
Superoxide Dismutase ◽  
Antisense Rna ◽  
Axenic Culture ◽  
Free Radical Damage ◽  
Enhanced Sensitivity ◽  
Mouse Macrophages ◽  
Parasite Survival ◽  
Radical Damage ◽  
Genus Leishmania

Intracellular parasitic protozoans of the genus Leishmania depend for their survival on the elaboration of enzymic and other mechanisms for evading toxic free-radical damage inflicted by their phagocytic macrophage host. One such mechanism may involve superoxide dismutase (SOD), which detoxifies reactive superoxide radicals produced by activated macrophages, but the role of this enzyme in parasite survival has not yet been demonstrated. We have cloned a SOD gene from L. tropica and generated SOD-deficient parasites by expressing the corresponding antisense RNA from an episomal vector. Such parasites have enhanced sensitivity to menadione and hydrogen peroxide in axenic culture, and a markedly reduced survival in mouse macrophages. These results indicate that SOD is a major determinant of intracellular survival of Leishmania.

scholarly journals Reprogramming of fatty acid metabolism in cancer

2019 ◽  
Vol 122 (1) ◽  
pp. 4-22 ◽  
Author(s):  
Nikos Koundouros ◽  
George Poulogiannis
Keyword(s):  
Fatty Acids ◽  
Fatty Acid ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Fatty Acid Metabolism ◽  
Acid Metabolism ◽  
De Novo ◽  
Great Promise ◽  
Molecular Heterogeneity

AbstractA common feature of cancer cells is their ability to rewire their metabolism to sustain the production of ATP and macromolecules needed for cell growth, division and survival. In particular, the importance of altered fatty acid metabolism in cancer has received renewed interest as, aside their principal role as structural components of the membrane matrix, they are important secondary messengers, and can also serve as fuel sources for energy production. In this review, we will examine the mechanisms through which cancer cells rewire their fatty acid metabolism with a focus on four main areas of research. (1) The role of de novo synthesis and exogenous uptake in the cellular pool of fatty acids. (2) The mechanisms through which molecular heterogeneity and oncogenic signal transduction pathways, such as PI3K–AKT–mTOR signalling, regulate fatty acid metabolism. (3) The role of fatty acids as essential mediators of cancer progression and metastasis, through remodelling of the tumour microenvironment. (4) Therapeutic strategies and considerations for successfully targeting fatty acid metabolism in cancer. Further research focusing on the complex interplay between oncogenic signalling and dysregulated fatty acid metabolism holds great promise to uncover novel metabolic vulnerabilities and improve the efficacy of targeted therapies.

scholarly journals The peroxisomal transporter ABCD3 plays a major role in dicarboxylic fatty acid metabolism

2021 ◽  
Author(s):  
Pablo Ranea-Robles ◽  
Hongjie Chen ◽  
Brandon Stauffer ◽  
Chunli Yu ◽  
Dipankar Bhattacharya ◽  
...  
Keyword(s):  
Fatty Acids ◽  
De Novo ◽  
Ketone Bodies ◽  
De Novo Lipogenesis ◽  
Lipid Homeostasis ◽  
Hepatic Cholesterol Synthesis ◽  
Specific Subset

Peroxisomes metabolize a specific subset of fatty acids, which include dicarboxylic fatty acids (DCAs) generated by ω-oxidation. Data obtained in vitro suggest that the peroxisomal transporter ABCD3 (also known as PMP70) mediates the transport of DCAs into the peroxisome, but in vivo evidence to support this role is lacking. In this study, we studied an Abcd3 KO mouse model generated by CRISPR-Cas9 technology using targeted and untargeted metabolomics, histology, immunoblotting, and stable isotope tracing technology. We show that ABCD3 functions in DCA metabolism and uncover a novel role for this peroxisomal transporter in lipid metabolic homeostasis. The Abcd3 KO mouse presents with lipodystrophy, increased circulating free fatty acids, decreased ketone bodies, enhanced hepatic cholesterol synthesis and decreased hepatic de novo lipogenesis. Moreover, our study suggests that DCAs are metabolized by mitochondrial β-oxidation when ABCD3 is not functional, reflecting the importance of the metabolic compartmentalization and communication between peroxisomes and mitochondria. In summary, this study provides data on the role of the peroxisomal transporter ABCD3 in hepatic lipid homeostasis and DCA metabolism, and the consequences of peroxisomal dysfunction for the liver.

Abstract 401: The Lineage-specific Transcription Factor PU.1 Prevents Heterochromatinization of Macrophage-specific Genes During Hematopoietic Differentiation

2015 ◽  
Vol 35 (suppl_1) ◽  
Author(s):  
Monique Floer ◽  
Mohita Tagore ◽  
Michael J McAndrew ◽  
Alison Gjidoda
Keyword(s):  
Transcription Factor ◽  
Nucleosome Occupancy ◽  
Specific Gene ◽  
Macrophage Differentiation ◽  
Regulatory Regions ◽  
Specific Transcription Factor ◽  
Primary Mouse ◽  
Mouse Macrophages ◽  
Cell Type Specific

We are using a quantitative approach to determine the fractional occupancy of nucleosomes at gene regulatory regions (i.e. enhancers and promoters) in primary mouse macrophages. This has allowed us to determine the dynamics of nucleosome removal at regulatory regions upon pro-inflammatory gene induction (Gjidoda, A. et al. 2014 Nucleosomes are stably evicted from enhancers but not promoters upon induction of certain pro-inflammatory genes in mouse macrophages. PLoS ONE 9(4): e93971). Moreover, we are interested in understanding how an accessible chromatin architecture is established at regulatory regions during macrophage differentiation, so that the transcriptional machinery can be recruited to these sites in mature cells. These studies have shown that the lineage-specific transcription factor PU.1 has to be present in hematopoietic progenitors to mark macrophage-specific genes for later induction. Using a previously established macrophage differentiation system from a PU.1-/- mouse as well as primary macrophages, we find that in the absence of PU.1 binding to the enhancer of a macrophage-specific gene, the enhancer is bound by PRC2 as cells are differentiated into mature macrophages. This leads to wrapping of the whole gene locus into heterochromatin, which is associated with tri-methylation of H3K27 and increased nucleosome occupancy. Our results show that one role of lineage-specific transcription factors is to prevent heterochromatinization of cell-type specific genes during differentiation to allow their expression in mature cells.

scholarly journals Role of lipids on elongation of the preimplantation conceptus in ruminants

Reproduction ◽  
2016 ◽  
Vol 152 (4) ◽  
pp. R115-R126 ◽  
Author(s):  
Eduardo S Ribeiro ◽  
José E P Santos ◽  
William W Thatcher
Keyword(s):  
Fatty Acids ◽  
Lipid Metabolism ◽  
Cell Biology ◽  
De Novo ◽  
Dynamic Changes ◽  
Expression Of Genes ◽  
Trophectoderm Cells ◽  
Conceptus Development ◽  
Elongation Phase

Elongation of the preimplantation conceptus is a prerequisite for successful pregnancy in ruminants and depends on histotroph secretion by the endometrium. Lipids are an essential component of the histotroph, and recent studies indicate that lipids have important roles in the elongation phase of conceptus development. The onset of elongation is marked by dynamic changes in the transcriptome of trophectoderm cells, which are associated with lipid metabolism. During elongation, the trophectoderm increases transcript expression of genes related to uptake, metabolism andde novobiosynthesis of fatty acids and prostaglandins. Expression of the genePPARGincreases substantially, and activation of the transcription factor PPARG by binding of lipid ligands appears to be crucial for the coordination of cell biology during elongation. Lipids accumulated in the epithelial cells of the endometrium during diestrus are likely the most important source of fatty acids for utilization by the conceptus and become available in the uterine lumen through exporting of exosomes, microvesicles, carrier proteins and lipoproteins. Targeting of uterine lipid metabolism and PPARG activity during preimplantation conceptus development through nutraceutical diets may be a good strategy to improve pregnancy survival and reproductive efficiency in ruminants.

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