The Immunometabolic Roles of Various Fatty Acids in Macrophages and Lymphocytes

Abstract Cancer cells undergo metabolic reprogramming to support cell proliferation, growth, and dissemination. Alterations in lipid metabolism, and specifically the uptake and synthesis of fatty acids (FAs), comprise one well-documented aspect of this reprogramming. Recent studies have revealed an expanded range of roles played by FA in promoting the aggressiveness of cancer while simultaneously identifying new potential targets for cancer therapy. This article provides a brief review of these advances in our understanding of FA metabolism in cancer, highlighting both recent discoveries and the inherent challenges caused by the metabolic plasticity of cancer cells in targeting lipid metabolism for cancer therapy.

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Role of the AMP-activated protein kinase in regulating fatty acid metabolism during exerciseThis paper is one of a selection of papers published in this Special Issue, entitled 14th International Biochemistry of Exercise Conference – Muscles as Molecular and Metabolic Machines, and has undergone the Journal’s usual peer review process.

Applied Physiology Nutrition and Metabolism ◽

10.1139/h09-009 ◽

2009 ◽

Vol 34 (3) ◽

pp. 315-322 ◽

Cited By ~ 26

Author(s):

Gregory R. Steinberg

Keyword(s):

Skeletal Muscle ◽

Fatty Acids ◽

Adipose Tissue ◽

Fatty Acid ◽

Protein Kinase ◽

Fatty Acid Metabolism ◽

Acid Metabolism ◽

Moderate Intensity ◽

Amp Activated Protein Kinase

During moderate-intensity exercise, fatty acids are the predominant substrate for working skeletal muscle. The release of fatty acids from adipose tissue stores, combined with the ability of skeletal muscle to actively fine tune the gradient between fatty acid and carbohydrate metabolism, depending on substrate availability and energetic demands, requires a coordinated system of metabolic control. Over the past decade, since the discovery that AMP-activated protein kinase (AMPK) was increased in accordance with exercise intensity, there has been significant interest in the proposed role of this ancient stress-sensing kinase as a critical integrative switch controlling metabolic responses during exercise. In this review, studies examining the role of AMPK as a regulator of fatty acid metabolism in both adipose tissue and skeletal muscle during exercise will be discussed. Exercise induces activation of AMPK in adipocytes and regulates triglyceride hydrolysis and esterfication through phosphorylation of hormone sensitive lipase (HSL) and glycerol-3-phosphate acyl-transferase, respectively. In skeletal muscle, exercise-induced activation of AMPK is associated with increases in fatty acid uptake, phosphorylation of HSL, and increased fatty acid oxidation, which is thought to occur via the acetyl-CoA carboxylase-malony-CoA-CPT-1 signalling axis. Despite the importance of AMPK in regulating fatty acid metabolism under resting conditions, recent evidence from transgenic models of AMPK deficiency suggest that alternative signalling pathways may also be important for the control of fatty acid metabolism during exercise.

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Emergence of MicroRNAs as Key Players in Cancer Cell Metabolism

Clinical Chemistry ◽

10.1373/clinchem.2018.299651 ◽

2019 ◽

Vol 65 (9) ◽

pp. 1090-1101 ◽

Cited By ~ 17

Author(s):

Sugarniya Subramaniam ◽

Varinder Jeet ◽

Judith A Clements ◽

Jennifer H Gunter ◽

Jyotsna Batra

Keyword(s):

Fatty Acid ◽

Signaling Pathways ◽

Tumor Cells ◽

Metabolic Pathways ◽

Acid Metabolism ◽

Tca Cycle ◽

Metabolic Reprogramming ◽

Metabolic Adaptation ◽

Novel Therapeutic

AbstractBACKGROUNDMetabolic reprogramming is a hallmark of cancer. MicroRNAs (miRNAs) have been found to regulate cancer metabolism by regulating genes involved in metabolic pathways. Understanding this layer of complexity could lead to the development of novel therapeutic approaches.CONTENTmiRNAs are noncoding RNAs that have been implicated as master regulators of gene expression. Studies have revealed the role of miRNAs in the metabolic reprogramming of tumor cells, with several miRNAs both positively and negatively regulating multiple metabolic genes. The tricarboxylic acid (TCA) cycle, aerobic glycolysis, de novo fatty acid synthesis, and altered autophagy allow tumor cells to survive under adverse conditions. In addition, major signaling molecules, hypoxia-inducible factor, phosphatidylinositol-3 kinase/protein kinase B/mammalian target of rapamycin/phosphatase and tensin homolog, and insulin signaling pathways facilitate metabolic adaptation in tumor cells and are all regulated by miRNAs. Accumulating evidence suggests that miRNA mimics or inhibitors could be used to modulate the activity of miRNAs that drive tumor progression via altering their metabolism. Currently, several clinical trials investigating the role of miRNA-based therapy for cancer have been launched that may lead to novel therapeutic interventions in the future.SUMMARYIn this review, we summarize cancer-related metabolic pathways, including glycolysis, TCA cycle, pentose phosphate pathway, fatty acid metabolism, amino acid metabolism, and other metabolism-related oncogenic signaling pathways, and their regulation by miRNAs that are known to lead to tumorigenesis. Further, we discuss the current state of miRNA therapeutics in the clinic and their future potential.

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Inflammation, obesity, and fatty acid metabolism: influence ofn-3 polyunsaturated fatty acids on factors contributing to metabolic syndrome

Applied Physiology Nutrition and Metabolism ◽

10.1139/h07-087 ◽

2007 ◽

Vol 32 (6) ◽

pp. 1008-1024 ◽

Cited By ~ 55

Author(s):

Lindsay E. Robinson ◽

Andrea C. Buchholz ◽

Vera C. Mazurak

Keyword(s):

Metabolic Syndrome ◽

Fatty Acids ◽

Fatty Acid ◽

Polyunsaturated Fatty Acids ◽

Abdominal Obesity ◽

Fatty Acid Metabolism ◽

Acid Metabolism ◽

Preliminary Evidence ◽

Postprandial Period

Metabolic syndrome (MetS) comprises an array of metabolic risk factors including abdominal obesity, dyslipidemia, hypertension, and glucose intolerance. Individuals with MetS are at elevated risk for diabetes and cardiovascular disease. Central to the etiology of MetS is an interrelated triad comprising inflammation, abdominal obesity, and aberrations in fatty acid metabolism, coupled with the more recently recognized changes in metabolism during the postprandial period. We review herein preliminary evidence regarding the role of dietary n-3 polyunsaturated fatty acids in modulating each of the components of the triad of adiposity, inflammation, and fatty acid metabolism, with particular attention to the role of the postprandial period as a contributor to the pathophysiology of MetS.

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Reprogramming of fatty acid metabolism in cancer

British Journal of Cancer ◽

10.1038/s41416-019-0650-z ◽

2019 ◽

Vol 122 (1) ◽

pp. 4-22 ◽

Cited By ~ 61

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.

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Fatty acid oxidation participates in resistance to nutrient-depleted environments in the insect stages of Trypanosoma cruzi

PLoS Pathogens ◽

10.1371/journal.ppat.1009495 ◽

2021 ◽

Vol 17 (4) ◽

pp. e1009495

Author(s):

Rodolpho Ornitz Oliveira Souza ◽

Flávia Silva Damasceno ◽

Sabrina Marsiccobetre ◽

Marc Biran ◽

Gilson Murata ◽

...

Keyword(s):

Amino Acids ◽

Fatty Acids ◽

Fatty Acid ◽

Trypanosoma Cruzi ◽

Acid Metabolism ◽

De Novo ◽

Tca Cycle ◽

Acid Oxidation ◽

Environmental Cues ◽

Metabolic Fate

Trypanosoma cruzi, the parasite causing Chagas disease, is a digenetic flagellated protist that infects mammals (including humans) and reduviid insect vectors. Therefore, T. cruzi must colonize different niches in order to complete its life cycle in both hosts. This fact determines the need of adaptations to face challenging environmental cues. The primary environmental challenge, particularly in the insect stages, is poor nutrient availability. In this regard, it is well known that T. cruzi has a flexible metabolism able to rapidly switch from carbohydrates (mainly glucose) to amino acids (mostly proline) consumption. Also established has been the capability of T. cruzi to use glucose and amino acids to support the differentiation process occurring in the insect, from replicative non-infective epimastigotes to non-replicative infective metacyclic trypomastigotes. However, little is known about the possibilities of using externally available and internally stored fatty acids as resources to survive in nutrient-poor environments, and to sustain metacyclogenesis. In this study, we revisit the metabolic fate of fatty acid breakdown in T. cruzi. Herein, we show that during parasite proliferation, the glucose concentration in the medium can regulate the fatty acid metabolism. At the stationary phase, the parasites fully oxidize fatty acids. [U-14C]-palmitate can be taken up from the medium, leading to CO2 production. Additionally, we show that electrons are fed directly to oxidative phosphorylation, and acetyl-CoA is supplied to the tricarboxylic acid (TCA) cycle, which can be used to feed anabolic pathways such as the de novo biosynthesis of fatty acids. Finally, we show as well that the inhibition of fatty acids mobilization into the mitochondrion diminishes the survival to severe starvation, and impairs metacyclogenesis.

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COVID-19 infection results in alterations of the kynurenine pathway and fatty acid metabolism that correlate with IL-6 levels and renal status

10.1101/2020.05.14.20102491 ◽

2020 ◽

Cited By ~ 1

Author(s):

Tiffany Thomas ◽

Davide Stefanoni ◽

Julie A Reisz ◽

Travis Nemkov ◽

Lorenzo Bertolone ◽

...

Keyword(s):

Amino Acids ◽

Fatty Acids ◽

Fatty Acid ◽

Fatty Acid Metabolism ◽

Acid Metabolism ◽

Kynurenine Pathway ◽

Clinical Severity ◽

Metabolic Effects ◽

Markers Of Inflammation ◽

Circulating Levels

Previous studies suggest a role for systemic reprogramming of host metabolism during viral pathogenesis to fuel rapidly expanding viral proliferation, for example by providing free amino acids and fatty acids as building blocks. In addition, general alterations in metabolism can provide key understanding of pathogenesis. However, little is known about the specific metabolic effects of SARS-COV-2 infection. The present study evaluated the serum metabolism of COVID-19 patients (n=33), identified by a positive nucleic acid test of a nasopharyngeal swab, as compared to COVID-19-negative control patients (n=16). Targeted and untargeted metabolomics analyses specifically identified alterations in the metabolism of tryptophan into the kynurenine pathway, which is well-known to be involved in regulating inflammation and immunity. Indeed, the observed changes in tryptophan metabolism correlated with serum interleukin-6 (IL-6) levels. Metabolomics analysis also confirmed widespread dysregulation of nitrogen metabolism in infected patients, with decreased circulating levels of most amino acids, except for tryptophan metabolites in the kynurenine pathway, and increased markers of oxidant stress (e.g., methionine sulfoxide, cystine), proteolysis, and kidney dysfunction (e.g., creatine, creatinine, polyamines). Increased circulating levels of glucose and free fatty acids were also observed, consistent with altered carbon homeostasis in COVID-19 patients. Metabolite levels in these pathways correlated with clinical laboratory markers of inflammation and disease severity (i.e., IL-6 and C-reactive protein) and renal function (i.e., blood urea nitrogen). In conclusion, this initial observational study of the metabolic consequences of COVID-19 infection in a clinical cohort identified amino acid metabolism (especially kynurenine and cysteine/taurine) and fatty acid metabolism as correlates of COVID-19, providing mechanistic insights, potential markers of clinical severity, and potential therapeutic targets.

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Role of triglyceride-fatty acid cycle in controlling fat metabolism in humans during and after exercise

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1990.258.2.e382 ◽

1990 ◽

Vol 258 (2) ◽

pp. E382-E389 ◽

Cited By ~ 56

Author(s):

R. R. Wolfe ◽

S. Klein ◽

F. Carraro ◽

J. M. Weber

Keyword(s):

Fatty Acids ◽

Fatty Acid ◽

Acid Metabolism ◽

Fat Oxidation ◽

Triglyceride Fatty Acid ◽

A Value ◽

Net Flux ◽

Total Fat ◽

Response To Exercise

We have investigated the role of triglyceride-fatty acid cycling in amplifying control of the net flux of fatty acids in response to exercise and in recovery from exercise. Five normal volunteers were infused with [1-13C]palmitate and D-5-glycerol throughout rest, 4 h of treadmill exercise at 40% maximum O2 consumption, and 2 h of recovery. Total fat oxidation was quantified by indirect calorimetry. Lipolysis (rate of appearance of glycerol) increased from 2.1 +/- 0.3 to 6.0 +/- 1.2 mumol.kg-1.min-1 after 30 min of exercise and progressively increased thereafter to a value of 10.5 +/- 0.8 mumol.kg-1.min-1 after 4 h. Lipolysis decreased rapidly during the first 20 min of recovery, but it was still significantly elevated after 2 h of recovery. The rate of appearance of free fatty acids followed the same pattern of response. Seventy percent of released fatty acids were reesterified at rest, and this value decreased to 25% within the first 30 min of exercise. Reesterification remained less than 35% of lipolysis until the start of recovery, at which time the value rose to 90%. In exercise, more than one-half the increase in fat oxidation could be attributed to the reduction in the percent reesterification. Most of the change in percent reesterification during exercise and recovery was caused by changes in extracellular cycling of fatty acids released into plasma. We conclude that triglyceride-fatty acid cycling plays an important role in enabling a rapid response of fatty acid metabolism to major changes in energy metabolism.

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Impact of Environmental Stressors on the Metabolic Functioning of a Temperate Cnidarian-Dinoflagellate Symbiosis

10.26686/wgtn.17019161 ◽

2021 ◽

Author(s):

◽

Oliver Bone

Keyword(s):

Amino Acids ◽

Fatty Acids ◽

Fatty Acid ◽

Amino Acid ◽

Metabolic Pathways ◽

Metabolic Processes ◽

Pathway Activity ◽

Wide Range ◽

Winter Cold

<p>Cnidarian-dinoflagellate symbioses occur across a wide latitudinal range, from temperate to tropical locations in both hemispheres. In the tropics, this association provides the foundation for the development of highly diverse coral reef ecosystems. Tropical associations are particularly sensitive to thermal variability, however, leading to dysfunction of the relationship and eventual expulsion of the symbiont, known as ‘coral bleaching’. In contrast, temperate associations maintain stable symbiotic relationships in highly fluctuating thermal environments. The reason behind the relative thermal tolerance of temperate associations is still unclear, though the ability to maintain cellular homeostasis through adjustments to metabolic processes is likely a core feature of their resilience. Both a field study and laboratory experiment were conducted to determine the metabolic responses to thermal change of the symbiosis between the temperate anemone Anthopleura aureoradiata and the dinoflagellate Symbiodinium. For the field component, A. aureoradiata were collected from Point Halswell in Wellington Harbour in both summer and winter. For the laboratory experiment, specimens collected at Pautahanui inlet were thermally acclimated in the laboratory, after which temperatures were altered over the course of one week to either 8°C (cold) or 28°C (hot) and maintained at these temperatures for six weeks. Gas chromatography coupled to mass spectrometry was then employed to determine the identity and relative quantity of a wide range of metabolites involved in primary metabolism including organic acids, fatty acids, amino acids and sugars. Based on these data, pathway activity profiling was used to determine the activity of different metabolic pathways both between seasons and in response to cold and heat treatment. A wide range of changes to metabolic processes were observed in both host and symbiont. Photosynthetic capacity was reduced in the symbionts at low temperatures and increased at high temperatures. The only organic acid to be significantly impacted was propanedioic acid, which increased in the host in response to cold treatment, potentially related to increased translocation from the symbiont. Altered fatty acid content in both host and symbiont was related to the role of fatty acids as energy sources and storage compounds and in cell signalling processes. Changes in fatty acid-associated metabolic pathways were exemplified by arachidonic acid and linoleic acid metabolism. Alterations to free amino acids and amino acid related pathways in both host and symbiont were associated with their role as antioxidants and osmoprotectants and the catabolism of amino acids for the production of energy. In symbionts only, altered amino acid content was associated with the role of amino acids in the production of alkaloids. Changes in a number of sugar derivatives in both host and symbiont were associated with their role as antioxidants and osmoprotectants. Altered sugar metabolism in the symbiont clearly indicated an increase in the production of energy rich sugar molecules and production of cellular energy in summer/hot conditions and a decrease in winter/cold conditions. Notably impacted pathways included the Calvin cycle, glycolysis, the pentose phosphate pathway and oxidative phosphorylation. Patterns of sugar related pathway activity in the host were generally opposite to that observed in the symbiont. Overall, prominent but opposing changes in the host and symbiont were detected in the central carbohydrate and energy metabolic pathways. In general, the activity of these pathways increased in the host in winter/cold conditions and decreased in summer/hot conditions, while in the symbiont the pattern was the opposite. These findings highlight the role of metabolic processes in enabling the persistence of a temperate cnidarian-dinoflagellate symbiosis in the face of large temperature fluctuations. This work provides a foundation upon which a deeper understanding of metabolic functioning in the cnidarian-dinoflagellate symbiosis can be built and provides a comparative platform for studies of the more thermally sensitive tropical associations.</p>

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Impact of Environmental Stressors on the Metabolic Functioning of a Temperate Cnidarian-Dinoflagellate Symbiosis

10.26686/wgtn.17019161.v1 ◽

2021 ◽

Author(s):

◽

Oliver Bone

Keyword(s):

Amino Acids ◽

Fatty Acids ◽

Fatty Acid ◽

Amino Acid ◽

Metabolic Pathways ◽

Metabolic Processes ◽

Pathway Activity ◽

Wide Range ◽

Winter Cold

<p>Cnidarian-dinoflagellate symbioses occur across a wide latitudinal range, from temperate to tropical locations in both hemispheres. In the tropics, this association provides the foundation for the development of highly diverse coral reef ecosystems. Tropical associations are particularly sensitive to thermal variability, however, leading to dysfunction of the relationship and eventual expulsion of the symbiont, known as ‘coral bleaching’. In contrast, temperate associations maintain stable symbiotic relationships in highly fluctuating thermal environments. The reason behind the relative thermal tolerance of temperate associations is still unclear, though the ability to maintain cellular homeostasis through adjustments to metabolic processes is likely a core feature of their resilience. Both a field study and laboratory experiment were conducted to determine the metabolic responses to thermal change of the symbiosis between the temperate anemone Anthopleura aureoradiata and the dinoflagellate Symbiodinium. For the field component, A. aureoradiata were collected from Point Halswell in Wellington Harbour in both summer and winter. For the laboratory experiment, specimens collected at Pautahanui inlet were thermally acclimated in the laboratory, after which temperatures were altered over the course of one week to either 8°C (cold) or 28°C (hot) and maintained at these temperatures for six weeks. Gas chromatography coupled to mass spectrometry was then employed to determine the identity and relative quantity of a wide range of metabolites involved in primary metabolism including organic acids, fatty acids, amino acids and sugars. Based on these data, pathway activity profiling was used to determine the activity of different metabolic pathways both between seasons and in response to cold and heat treatment. A wide range of changes to metabolic processes were observed in both host and symbiont. Photosynthetic capacity was reduced in the symbionts at low temperatures and increased at high temperatures. The only organic acid to be significantly impacted was propanedioic acid, which increased in the host in response to cold treatment, potentially related to increased translocation from the symbiont. Altered fatty acid content in both host and symbiont was related to the role of fatty acids as energy sources and storage compounds and in cell signalling processes. Changes in fatty acid-associated metabolic pathways were exemplified by arachidonic acid and linoleic acid metabolism. Alterations to free amino acids and amino acid related pathways in both host and symbiont were associated with their role as antioxidants and osmoprotectants and the catabolism of amino acids for the production of energy. In symbionts only, altered amino acid content was associated with the role of amino acids in the production of alkaloids. Changes in a number of sugar derivatives in both host and symbiont were associated with their role as antioxidants and osmoprotectants. Altered sugar metabolism in the symbiont clearly indicated an increase in the production of energy rich sugar molecules and production of cellular energy in summer/hot conditions and a decrease in winter/cold conditions. Notably impacted pathways included the Calvin cycle, glycolysis, the pentose phosphate pathway and oxidative phosphorylation. Patterns of sugar related pathway activity in the host were generally opposite to that observed in the symbiont. Overall, prominent but opposing changes in the host and symbiont were detected in the central carbohydrate and energy metabolic pathways. In general, the activity of these pathways increased in the host in winter/cold conditions and decreased in summer/hot conditions, while in the symbiont the pattern was the opposite. These findings highlight the role of metabolic processes in enabling the persistence of a temperate cnidarian-dinoflagellate symbiosis in the face of large temperature fluctuations. This work provides a foundation upon which a deeper understanding of metabolic functioning in the cnidarian-dinoflagellate symbiosis can be built and provides a comparative platform for studies of the more thermally sensitive tropical associations.</p>

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