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

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.

scholarly journals Fatty acid oxidation participates of the survival to starvation, cell cycle progression and differentiation in the insect stages of Trypanosoma cruzi

2021 ◽  
Author(s):  
Rodolpho Ornitz Oliveira Souza ◽  
Flávia Silva Damasceno ◽  
Sabrina Marsiccobetre ◽  
Marc Biran ◽  
Gilson Murata ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Fatty Acid ◽  
Trypanosoma Cruzi ◽  
Cell Cycle Progression ◽  
De Novo ◽  
Tricarboxylic Acid Cycle ◽  
Complex Life Cycle ◽  
Acid Oxidation ◽  
Beta Oxidation ◽  
Cycle Progression

During its complex life cycle, Trypanosoma cruzi colonizes different niches in its insect and mammalian hosts. This characteristic determined the types of parasites that adapted to face challenging environmental cues. The primary environmental challenge, particularly in the insect stages, is poor nutrient availability. These T. cruzi stages could be exposed to fatty acids originating from the degradation of the perimicrovillar membrane. 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- 14 C]-palmitate can be taken up from the medium, leading to CO 2 production via beta-oxidation. Lastly, we also show that fatty acids are degraded through beta-oxidation. Additionally, through beta-oxidation, electrons are fed directly to oxidative phosphorylation, and acetyl-CoA is supplied to the tricarboxylic acid cycle, which can be used to feed other anabolic pathways such as the de novo biosynthesis of fatty acids.

scholarly journals Isomeric lipid signatures reveal compartmentalised fatty acid metabolism in cancer

2021 ◽  
Author(s):  
Reuben S. E. Young ◽  
Andrew P Bowman ◽  
Kaylyn Davis Tousignant ◽  
Berwyck L.J. Poad ◽  
Jennifer H Gunter ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Structural Changes ◽  
Acid Metabolism ◽  
De Novo ◽  
Net Energy ◽  
Glycerol Backbone ◽  
De Novo Synthesis ◽  
Metabolic Fate ◽  
Complex Dynamic ◽  
Cellular Energy

Cellular energy and biomass demands of cancer drive a complex dynamic between uptake of extracellular fatty acids (FA) and de novo synthesis. Given that oxidation of de novo synthesised FAs for energy would result in net-energy loss, there is an implication that FAs from these two sources must have distinct metabolic fates - however hitherto FAs were considered part of a common pool. To probe FA metabolic partitioning, cancer cells were supplemented with stable-isotope labelled FAs. Structural analysis of the resulting glycerophospholipids revealed that labelled FAs from uptake were largely incorporated to canonical (sn-)positions on the glycerol backbone. Surprisingly, labelled FA uptake disrupted canonical isomer patterns of the unlabelled lipidome and induced repartitioning of n-3 and n-6 polyunsaturated-FAs into glycerophospholipid classes. These structural changes evidence differences in the metabolic fate of FAs derived from uptake or de novo sources and demonstrate unique signalling and remodelling behaviours usually hidden to conventional lipidomics. 

Effect of metformin chemoprevention on metabolomics profiles in Li-Fraumeni Syndrome (LFS).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 1556-1556 ◽  
Author(s):  
Farzana L. Walcott ◽  
Christina M. Annunziata ◽  
Eduardo M. Sotomayor ◽  
Antonio Tito Fojo
Keyword(s):  
Fatty Acids ◽  
Fatty Acid ◽  
Tca Cycle ◽  
Cellular Transformation ◽  
Acid Oxidation ◽  
Metformin Treatment ◽  
Beta Oxidation ◽  
Serum Samples ◽  
Li Fraumeni Syndrome ◽  
Tca Cycle Intermediates

1556 Background: LFS is a highly-penetrant, autosomal dominant, cancer predisposition disorder characterized by early onset cancer; germline mutations in TP53are present in 70% of LFS. We previously observed metformin inhibition on mitochondrial function in LFS patients. Metformin may reduce TCA cycle and glycolytic intermediates during cellular transformation, indicating inhibition of complex I of the mitochondria. To further explore this, we performed untargeted metabolomics profiling on stored serum of study participants. To our knowledge, there are no previous studies of metabolomics profiling in LFS patients treated with metformin. Methods: Adult LFS patients (≥18 years old) were enrolled for 20 weeks. Metformin was initiated at 500 mg per day and increased in 500 mg dose increments every two weeks to a maintenance dose of 2000 mg of metformin. Patients were taken off metformin for the last six weeks of the study (week 20). Global biochemical profiles were determined in human serum samples collected in 21 patients, each providing one sample at baseline, week 14 (on 2000 mg metformin) and week 20 (off metformin). Metabolomics analyses were performed by Metabolon, Inc. Results: Treatment with metformin induced a strong metabolic signature of increased fatty acid beta-oxidation in LFS patients. Acylcarnitines, long chain fatty acids, and 3-hydroxy fatty acids were significantly elevated following metformin treatment. TCA cycle intermediates, aconitate, malate, and fumarate were also increased as were levels of ketone body 3-hydroxybutyrate (BHBA)indicating robust β-oxidation, presumably to support increased energy production via the TCA cycle. Clearance of metformin results in normalization of levels to comparable baseline values, indicating a causal role of metformin in these changes. Conclusions: Global metabolomics profiling suggests an increase in TCA cycle intermediates and a strong signature of fatty acid oxidation with metformin treatment in LFS, suggesting metformin effect on the mitochondria and TCA cycle is more dynamic than previously shown. LFS patients may have distinct metabolic profiles which may be altered by treatment with metformin. Funding: ASCO Young Investigator’s Award 2016. Clinical trial information: NCT01981525.

scholarly journals Lack of mitochondria-generated acetyl-CoA by pyruvate dehydrogenase complex downregulates gene expression in the hepatic de novo lipogenic pathway

2016 ◽  
Vol 311 (1) ◽  
pp. E117-E127 ◽  
Author(s):  
Saleh Mahmood ◽  
Barbara Birkaya ◽  
Todd C. Rideout ◽  
Mulchand S. Patel
Keyword(s):  
Gene Expression ◽  
Fatty Acids ◽  
Fatty Acid ◽  
Pyruvate Dehydrogenase ◽  
De Novo ◽  
Pyruvate Dehydrogenase Complex ◽  
Acid Oxidation ◽  
Acetyl Coa ◽  
Key Genes ◽  
Dehydrogenase Complex

During the absorptive state, the liver stores excess glucose as glycogen and synthesizes fatty acids for triglyceride synthesis for export as very low density lipoproteins. For de novo synthesis of fatty acids from glucose, the mitochondrial pyruvate dehydrogenase complex (PDC) is the gatekeeper for the generation of acetyl-CoA from glucose-derived pyruvate. Here, we tested the hypothesis that limiting the supply of PDC-generated acetyl-CoA from glucose would have an impact on expression of key genes in the lipogenic pathway. In the present study, although the postnatal growth of liver-specific PDC-deficient (L-PDCKO) male mice was largely unaltered, the mice developed hyperinsulinemia with lower blood glucose levels in the fed state. Serum and liver lipid triglyceride and cholesterol levels remained unaltered in L-PDCKO mice. Expression of several key genes ( ACL, ACC1) in the lipogenic pathway and their upstream regulators ( LXR, SREBP1, ChREBP) as well as several genes in glucose metabolism ( Pklr, G6pd2, Pck1) and fatty acid oxidation ( FAT, Cpt1a) was downregulated in livers from L-PDCKO mice. Interestingly, there was concomitant upregulation of lipogenic genes in adipose tissue from L-PDCKO mice. Although, the total hepatic acetyl-CoA content remained unaltered in L-PDCKO mice, modified acetylation profiles of proteins in the nuclear compartment suggested an important role for PDC-generated acetyl-CoA in gene expression in de novo fatty acid synthesis in the liver. This finding has important implications for the regulation of hepatic lipid synthesis in pathological states.

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 Vitamin B12 Induces Hepatic Fatty Infiltration through Altered Fatty Acid Metabolism

2021 ◽  
Vol 55 (3) ◽  
pp. 241-255
Keyword(s):  
Fatty Acids ◽  
Fatty Acid ◽  
Vitamin B12 ◽  
Fatty Acid Oxidation ◽  
Lipid Droplets ◽  
De Novo ◽  
Quantitative Polymerase Chain Reaction ◽  
Saturated Fatty Acids ◽  
Fatty Infiltration ◽  
Acid Oxidation

Background/Aims: Rise in global incidence of obesity impacts metabolic health. Evidence from human and animal models show association of vitamin B12 (B12) deficiency with elevated BMI and lipids. Human adipocytes demonstrated dysregulation of lipogenesis by low B12 via hypomethylation and altered microRNAs. It is known de novo hepatic lipogenesis plays a key role towards dyslipidaemia, however, whether low B12 affects hepatic metabolism of lipids is not explored. Methods: HepG2 was cultured in B12-deficient EMEM medium and seeded in different B12 media: 500nM(control), 1000pM(1nM), 100pM and 25pM(low) B12. Lipid droplets were examined by Oil Red O (ORO) staining using microscopy and then quantified by elution assay. Gene expression were assessed with real-time quantitative polymerase chain reaction (qRT-PCR) and intracellular triglycerides were quantified using commercial kit (Abcam, UK) and radiochemical assay. Fatty acid composition was measured by gas chromatography and mitochondrial function by seahorse XF24 flux assay. Results: HepG2 cells in low B12 had more lipid droplets that were intensely stained with ORO compared with control. The total intracellular triglyceride and incorporation of radio-labelled-fatty acid in triglyceride synthesis were increased. Expression of genes regulating fatty acid, triglyceride and cholesterol biosynthesis were upregulated. Absolute concentrations of total fatty acids, saturated fatty acids (SFAs), monounsaturated fatty acids (MUFAs), trans-fatty acids and individual even-chain and odd-chain fatty acids were significantly increased. Also, low B12 impaired fatty acid oxidation and mitochondrial functional integrity in HepG2 compared with control. Conclusion: Our data provide novel evidence that low B12 increases fatty acid synthesis and levels of individual fatty acids, and decreases fatty acid oxidation and mitochondrial respiration, thus resulting in dysregulation of lipid metabolism in HepG2. This highlights the potential significance of de novo lipogenesis and warrants possible epigenetic mechanisms of low B12.

scholarly journals Mogroside V Protects against Hepatic Steatosis in Mice on a High-Fat Diet and LO2 Cells Treated with Free Fatty Acids via AMPK Activation

2020 ◽  
Vol 2020 ◽  
pp. 1-11
Author(s):  
Linghuan Li ◽  
Wanfang Zheng ◽  
Can Wang ◽  
Jiameng Qi ◽  
Hanbing Li
Keyword(s):  
Fatty Acids ◽  
Fatty Acid ◽  
Lipid Metabolism ◽  
Free Fatty Acids ◽  
Mrna Expression ◽  
Hepatic Steatosis ◽  
High Fat Diet ◽  
De Novo ◽  
Acid Oxidation ◽  
High Fat

Previous studies presented various beneficial effects of mogrosides extract from Siraitia grosvenorii, which has been included in the list of Medicine Food Homology Species in China. Mogroside V (MV) is one of the main ingredients in mogrosides extract; however, whether and how MV improves impaired lipid metabolism in the liver remains to be elucidated. Herein, we investigated the therapeutic effects of mogroside V upon hepatic steatosis in vivo and in vitro and explored the underlying mechanisms. The results showed that MV significantly ameliorated hepatic steatosis in high-fat diet- (HFD-) fed mice. Furthermore, the increased protein expression of PPAR-γ, SREBP-1, and FASN and mRNA expression of pparg, srebp1, scd1, and fasn in the liver in HFD-fed mice, which contribute to de novo lipogenesis, were dose-dependently reversed by MV treatment. Meanwhile, MV counteracted the suppressed expression of PPAR-α and CPT-1A and mRNA expression of atgl, hsl, ppara, and cpt1a, thus increasing lipolysis and fatty acid oxidation. In addition, in free fatty acids- (FFAs-) incubated LO2 cells MV downregulated de novo lipogenesis and upregulated lipolysis and fatty acid oxidation, thereby attenuating lipid accumulation, which was significantly abrogated by treatment with Compound C, an inhibitor of AMP-activated protein kinase (AMPK). Taken together, these results suggested that MV exerted a pronounced effect upon improving hepatic steatosis through regulating the disequilibrium of lipid metabolism in the liver via an AMPK-dependent pathway, providing a potential lead compound candidate for preventing nonalcoholic fatty liver disease.

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

2020 ◽  
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.

scholarly journals Effects of insulin treatment of diabetic rats on hepatic partitioning of fatty acids between oxidation and esterification, phospholipid and acylglycerol synthesis, and on the fractional rate of secretion of triacylglycerol in vivo

1994 ◽  
Vol 304 (1) ◽  
pp. 177-182 ◽  
Author(s):  
A M B Moir ◽  
V A Zammit
Keyword(s):  
Fatty Acids ◽  
Fatty Acid ◽  
Fatty Acid Metabolism ◽  
Insulin Treatment ◽  
Acid Metabolism ◽  
Diabetic Rats ◽  
Acid Oxidation ◽  
Phospholipid Synthesis ◽  
Fractional Rate

1. The hypothesis that insulin treatment of streptozotocin-diabetic rats does not alter acutely the ability of acylcarnitine synthesis to compete successfully for cytosolic long-chain acyl-CoA [Grantham and Zammit (1988) Biochem. J. 249, 409-414], was tested in vivo by using the technique of selective labelling of hepatic fatty acids in awake unrestrained rats. In the same animals, the partitioning of hepatic fatty acids between acylglycerol and phospholipid synthesis, and of newly labelled triacylglycerol between secretion into the plasma and retention in the liver, was also studied. 2. In untreated diabetic animals, the ratio of fatty acid oxidation to esterification was double that found in normal fed animals, whereas there were no differences in the values of the above-mentioned parameters of glycerolipid metabolism. Thus the insulin status of the rats only has chronic effects on specific aspects of fatty acid metabolism in the liver. 3. Treatment of diabetic rats with insulin resulted in no change in the oxidation/esterification ratio for the first 5 h after the start of insulin administration. Thereafter, there were reciprocal changes in the 14CO2 expired (an index of oxidation) and 14C label recovered in hepatic and plasma glycerolipids. However, the pattern of partitioning observed in normal fed rats was still not re-established after 8 h of insulin treatment. 4. There was a small and transient decrease in the fractional rate of triacylglycerol secretion by the liver at the start of insulin treatment and an increase in the proportion of labelled fatty acid that was utilized for phospholipid synthesis such that phospholipid labelling as a proportion of that of total glycerolipids was doubled after 8 h of insulin treatment. 5. The data are discussed in relation to the roles of insulin in mediating acute changes in hepatic fatty acid metabolism and very-low-density-lipoprotein triacylglycerol secretion by the liver.

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