Fatty acid metabolic reprogramming promotes C. elegans development

AbstractAcetylcholine signaling has been reported to play essential roles in animal metabolic regulation and disease affected by diets. However, the underlying mechanisms that how diets regulate animal physiology and health are not well understood. Here we found that the acetylcholine receptor gene eat-2 was expressed in most of the pharyngeal muscles, which is in accordance to our previous report that EAT-2 received synaptic signals not only from pharyngeal MC neurons. The expression of fatty acid synthesis genes was significantly increased in both eat-2 and tmc-1 fast-growth mutants on CeMM food environment, compared to the wild-type. Excitingly, dietary fatty acids such as 15-methyl-hexadecanoic acid (C17ISO), palmitic acid (PA, C16:0) and stearic acid (SA, C18:0) supplementation, significantly accelerated wild-type worm development on CeMM, indicating that the fatty acid synthesis reprogramming is an essential strategy for C. elegans to regulate its development and growth on CeMM diet. Furthermore, we found that fatty acid elongase gene elo-6 knock-out significantly attenuated eat-2 mutant’ fast growth, while overexpression of elo-6 could rescue the eat-2; elo-6 double mutant’ slow development, which suggested that elo-6 played a major role in the above metabolic remodeling. Taken together, our report indicates that diets regulate neuromuscular circuit and modulate C. elegans development via fatty acid metabolic reprogramming. As most of the key genes and metabolites found in this study are conserved in both invertebrate and vertebrate animals, we believed that our results might provide essential clues to the molecular mechanisms underlying interactions among animal nutrition sensation, metabolism reprogramming and developmental regulation.Significance StatementDiets and nutritional composition affect animal development and human health, however the underlying mechanisms remain elusive. We demonstrate that the acetylcholine receptor gene eat-2 is expressed in most of pharyngeal muscles, and the expression of fatty acid synthesis genes is significantly increased in both eat-2 and tmc-1 fast-growth mutants on the synthetic chemical defined CeMM food environment. Dietary supplementation of several fatty acids significantly speed up animal development. Furthermore, we demonstrate that the fatty acid elongase gene elo-6 knock-out attenuates eat-2 mutant’ fast growth, and overexpression of wild-type elo-6 promotes the eat-2; elo-6 double mutant’ slow development. Our findings describe that acetylcholine signaling coordinate nutrition sensation and developmental regulation through fatty acid metabolic remodeling.

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Enterococcus faecalisEncodes an Atypical Auxiliary Acyl Carrier Protein Required for Efficient Regulation of Fatty Acid Synthesis by Exogenous Fatty Acids

mBio ◽

10.1128/mbio.00577-19 ◽

2019 ◽

Vol 10 (3) ◽

Cited By ~ 6

Author(s):

Lei Zhu ◽

Qi Zou ◽

Xinyun Cao ◽

John E. Cronan

Keyword(s):

Fatty Acids ◽

Oleic Acid ◽

Fatty Acid ◽

Fatty Acid Synthesis ◽

Type Strain ◽

Wild Type Strain ◽

De Novo ◽

Acid Synthesis ◽

Wild Type ◽

Content Type

ABSTRACTAcyl carrier proteins (ACPs) play essential roles in the synthesis of fatty acids and transfer of long fatty acyl chains into complex lipids. TheEnterococcus faecalisgenome contains two annotatedacpgenes, calledacpAandacpB. AcpA is encoded within the fatty acid synthesis (fab) operon and appears essential. In contrast, AcpB is an atypical ACP, having only 30% residue identity with AcpA, and is not essential. Deletion ofacpBhas no effect onE. faecalisgrowth orde novofatty acid synthesis in media lacking fatty acids. However, unlike the wild-type strain, where growth with oleic acid resulted in almost complete blockage ofde novofatty acid synthesis, theΔacpBstrain largely continuedde novofatty acid synthesis under these conditions. Blockage in the wild-type strain is due to repression offaboperon transcription, leading to levels of fatty acid synthetic proteins (including AcpA) that are insufficient to supportde novosynthesis. Transcription of thefaboperon is regulated by FabT, a repressor protein that binds DNA only when it is bound to an acyl-ACP ligand. Since AcpA is encoded in thefaboperon, its synthesis is blocked when the operon is repressed andacpAthus cannot provide a stable supply of ACP for synthesis of the acyl-ACP ligand required for DNA binding by FabT. In contrast to AcpA,acpBtranscription is unaffected by growth with exogenous fatty acids and thus provides a stable supply of ACP for conversion to the acyl-ACP ligand required for repression by FabT. Indeed,ΔacpBandΔfabTstrains have essentially the samede novofatty acid synthesis phenotype in oleic acid-grown cultures, which argues that neither strain can form the FabT-acyl-ACP repression complex. Finally, acylated derivatives of both AcpB and AcpA were substrates for theE. faecalisenoyl-ACP reductases and forE. faecalisPlsX (acyl-ACP; phosphate acyltransferase).IMPORTANCEAcpB homologs are encoded by many, but not all, lactic acid bacteria (Lactobacillales), including many members of the human microbiome. The mechanisms regulating fatty acid synthesis by exogenous fatty acids play a key role in resistance of these bacteria to those antimicrobials targeted at fatty acid synthesis enzymes. Defective regulation can increase resistance to such inhibitors and also reduce pathogenesis.

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Lipid Metabolism in Development and Progression of Hepatocellular Carcinoma

Cancers ◽

10.3390/cancers12061419 ◽

2020 ◽

Vol 12 (6) ◽

pp. 1419 ◽

Cited By ~ 3

Author(s):

Moris Sangineto ◽

Rosanna Villani ◽

Francesco Cavallone ◽

Antonino Romano ◽

Domenico Loizzi ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Fatty Acid ◽

Lipid Metabolism ◽

Fatty Acid Synthesis ◽

Cell Signalling ◽

Acid Synthesis ◽

Environmental Adaptation ◽

Metabolic Reprogramming ◽

Therapeutic Approaches

Metabolic reprogramming is critically involved in the development and progression of cancer. In particular, lipid metabolism has been investigated as a source of energy, micro-environmental adaptation, and cell signalling in neoplastic cells. However, the specific role of lipid metabolism dysregulation in hepatocellular carcinoma (HCC) has not been widely described yet. Alterations in fatty acid synthesis, β-oxidation, and cellular lipidic composition contribute to initiation and progression of HCC. The aim of this review is to elucidate the mechanisms by which lipid metabolism is involved in hepatocarcinogenesis and tumour adaptation to different conditions, focusing on the transcriptional aberrations with new insights in lipidomics and lipid zonation. This will help detect new putative therapeutic approaches in the second most frequent cause of cancer-related death.

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Suppression of heterocyst differentiation in Anabaena PCC 7120 by a cosmid carrying wild-type genes encoding enzymes for fatty acid synthesis

FEMS Microbiology Letters ◽

10.1111/j.1574-6968.1997.tb10390.x ◽

2006 ◽

Vol 151 (1) ◽

pp. 23-30 ◽

Cited By ~ 49

Author(s):

C.C Bauer ◽

K.S Ramaswamy ◽

S Endley ◽

L.A Scappino ◽

J.W Golden ◽

...

Keyword(s):

Fatty Acid ◽

Fatty Acid Synthesis ◽

Acid Synthesis ◽

Wild Type ◽

Heterocyst Differentiation ◽

Anabaena Pcc 7120 ◽

Genes Encoding ◽

Pcc 7120

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Regulation of the Mitochondrion-Fatty Acid Axis for the Metabolic Reprogramming of Chlamydia trachomatis during Treatment with β-Lactam Antimicrobials

mBio ◽

10.1128/mbio.00023-21 ◽

2021 ◽

Vol 12 (2) ◽

Author(s):

Kensuke Shima ◽

Inga Kaufhold ◽

Thomas Eder ◽

Nadja Käding ◽

Nis Schmidt ◽

...

Keyword(s):

Fatty Acid ◽

Chlamydia Trachomatis ◽

Fatty Acid Synthesis ◽

Tricarboxylic Acid Cycle ◽

Acid Synthesis ◽

Tricarboxylic Acid ◽

Metabolic Reprogramming ◽

Mitochondrial Activity ◽

Content Type ◽

Acid Cycle

ABSTRACT Infection with the obligate intracellular bacterium Chlamydia trachomatis is the most common bacterial sexually transmitted disease worldwide. Since no vaccine is available to date, antimicrobial therapy is the only alternative in C. trachomatis infection. However, changes in chlamydial replicative activity and the occurrence of chlamydial persistence caused by diverse stimuli have been proven to impair treatment effectiveness. Here, we report the mechanism for C. trachomatis regulating host signaling processes and mitochondrial function, which can be used for chlamydial metabolic reprogramming during treatment with β-lactam antimicrobials. Activation of signal transducer and activator of transcription 3 (STAT3) is a well-known host response in various bacterial and viral infections. In C. trachomatis infection, inactivation of STAT3 by host protein tyrosine phosphatases increased mitochondrial respiration in both the absence and presence of β-lactam antimicrobials. However, during treatment with β-lactam antimicrobials, C. trachomatis increased the production of citrate as well as the activity of host ATP-citrate lyase involved in fatty acid synthesis. Concomitantly, chlamydial metabolism switched from the tricarboxylic acid cycle to fatty acid synthesis. This metabolic switch was a unique response in treatment with β-lactam antimicrobials and was not observed in gamma interferon (IFN-γ)-induced persistent infection. Inhibition of fatty acid synthesis was able to attenuate β-lactam-induced chlamydial persistence. Our findings highlight the importance of the mitochondrion-fatty acid interplay for the metabolic reprogramming of C. trachomatis during treatment with β-lactam antimicrobials. IMPORTANCE The mitochondrion generates most of the ATP in eukaryotic cells, and its activity is used for controlling the intracellular growth of Chlamydia trachomatis. Furthermore, mitochondrial activity is tightly connected to host fatty acid synthesis that is indispensable for chlamydial membrane biogenesis. Phospholipids, which are composed of fatty acids, are the central components of the bacterial membrane and play a crucial role in the protection against antimicrobials. Chlamydial persistence that is induced by various stimuli is clinically relevant. While one of the well-recognized inducers, β-lactam antimicrobials, has been used to characterize chlamydial persistence, little is known about the role of mitochondria in persistent infection. Here, we demonstrate how C. trachomatis undergoes metabolic reprogramming to switch from the tricarboxylic acid cycle to fatty acid synthesis with promoted host mitochondrial activity in response to treatment with β-lactam antimicrobials.

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Genetic Evidence that InhA of Mycobacterium smegmatis Is a Target for Triclosan

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.43.3.711 ◽

1999 ◽

Vol 43 (3) ◽

pp. 711-713 ◽

Cited By ~ 109

Author(s):

Laura M. McMurry ◽

Patrick F. McDermott ◽

Stuart B. Levy

Keyword(s):

Escherichia Coli ◽

Fatty Acid ◽

Fatty Acid Synthesis ◽

Mycobacterium Smegmatis ◽

Acid Synthesis ◽

Multicopy Plasmid ◽

Wild Type ◽

Isoniazid Resistance ◽

Enoyl Reductase ◽

Triclosan Resistance

ABSTRACT Three Mycobacterium smegmatis mutants selected for resistance to triclosan each had a different mutation in InhA, an enoyl reductase involved in fatty acid synthesis. Two expressed some isoniazid resistance. A mutation originally selected on isoniazid also mediated triclosan resistance, as did the wild-type inhAgene on a multicopy plasmid. Replacement of the mutant chromosomalinhA genes with wild-type inhA eliminated resistance. These results suggest that M. smegmatis InhA, like its Escherichia coli homolog FabI, is a target for triclosan.

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RAGE-mediated T cell metabolic reprogramming shapes T cell inflammatory response after stroke

Journal of Cerebral Blood Flow & Metabolism ◽

10.1177/0271678x211067133 ◽

2021 ◽

pp. 0271678X2110671

Author(s):

Yueman Zhang ◽

Fengshi Li ◽

Chen Chen ◽

Yan Li ◽

Wanqing Xie ◽

...

Keyword(s):

T Cells ◽

Fatty Acid ◽

T Cell ◽

Fatty Acid Synthesis ◽

Acid Synthesis ◽

Conditional Knockout ◽

Metabolic Reprogramming ◽

Stroke Recovery ◽

Post Stroke ◽

Soluble Rage

The metabolic reprogramming of peripheral CD4+ T cells that occurs after stroke can lead to imbalanced differentiation of CD4+ T cells, including regulation of T cells, and presents a promising target for poststroke immunotherapy. However, the regulatory mechanism underlying the metabolic reprogramming of peripheral CD4+ T cell remains unknown. In this study, using combined transcription and metabolomics analyses, flow cytometry, and conditional knockout mice, we demonstrate that the receptor for advanced glycation end products (RAGE) can relay the ischemic signal to CD4+ T cells, which underwent acetyl coenzyme A carboxylase 1(ACC1)-dependent metabolic reprogramming after stroke. Furthermore, by administering soluble RAGE (sRAGE) after stroke, we demonstrate that neutralization of RAGE reversed the enhanced fatty acid synthesis of CD4+ T cells and the post-stroke imbalance of Treg/Th17. Finally, we found that post-stroke sRAGE treatment protected against infarct volume and ameliorated functional recovery. In conclusion, sRAGE can serve as a novel immunometabolic modulator that ameliorates ischemic stroke recovery by inhibiting fatty acid synthesis and thus favoring CD4+ T cells polarization toward Treg after cerebral ischemia injury. The above findings provide new insights for the treatment of neuroinflammatory responses after ischemia stroke.

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Inactivation of Isocitrate Lyase Leads to Increased Production of Medium-Chain-Length Poly(3-Hydroxyalkanoates) inPseudomonas putida

Applied and Environmental Microbiology ◽

10.1128/aem.66.3.909-913.2000 ◽

2000 ◽

Vol 66 (3) ◽

pp. 909-913 ◽

Cited By ~ 24

Author(s):

Stefan Klinke ◽

Michael Dauner ◽

George Scott ◽

Birgit Kessler ◽

Bernard Witholt

Keyword(s):

Fatty Acid ◽

Chain Length ◽

Fatty Acid Synthesis ◽

Isocitrate Dehydrogenase ◽

Acid Synthesis ◽

Wild Type ◽

Medium Chain ◽

Medium Chain Length ◽

Fatty Acid Synthesis Pathway ◽

The Mean

ABSTRACT Medium-chain-length (mcl) poly(3-hydroxyalkanoates) (PHAs) are storage polymers that are produced from various substrates and accumulate in Pseudomonas strains belonging to rRNA homology group I. In experiments aimed at increasing PHA production inPseudomonas strains, we generated an mcl PHA-overproducing mutant of Pseudomonas putida KT2442 by transposon mutagenesis, in which the aceA gene was knocked out. This mutation inactivated the glyoxylate shunt and reduced the in vitro activity of isocitrate dehydrogenase, a rate-limiting enzyme of the citric acid cycle. The genotype of the mutant was confirmed by DNA sequencing, and the phenotype was confirmed by biochemical experiments. The aceA mutant was not able to grow on acetate as a sole carbon source due to disruption of the glyoxylate bypass and exhibited two- to fivefold lower isocitrate dehydrogenase activity than the wild type. During growth on gluconate, the difference between the mean PHA accumulation in the mutant and the mean PHA accumulation in the wild-type strain was 52%, which resulted in a significant increase in the amount of mcl PHA at the end of the exponential phase in the mutantP. putida KT217. On the basis of a stoichiometric flux analysis we predicted that knockout of the glyoxylate pathway in addition to reduced flux through isocitrate dehydrogenase should lead to increased flux into the fatty acid synthesis pathway. Therefore, enhanced carbon flow towards the fatty acid synthesis pathway increased the amount of mcl PHA that could be accumulated by the mutant.

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