Enzyme In Fatty Acid Biosynthesis Research Articles

Disruption of polyunsaturated fatty acid biosynthesis drives STING-dependent acute myeloid leukemia cell maturation and death

The role of polyunsaturated fatty acid (PUFA) biosynthesis in acute myeloid leukemia (AML) remains largely undefined. A comparative expression analysis of 35 genes encoding fatty acid biosynthesis enzymes showed that fatty acid desaturase 1 (FADS1) was highly expressed across multiple AML subtypes relative to healthy controls and that elevated FADS1 expression correlates with worse overall AML patient survival. Functionally, shRNA-mediated inhibition of FADS1 reduced AML cell growth invitro and significantly delayed leukemia onset in an AML mouse model. AML cell lines depleted of FADS1 arrested in the G1/S-phase of the cell cycle, acquired characteristics of myeloid maturation and subsequently died. To understand the molecular consequences of FADS1 inhibition, a combination of mass spectrometry-based analysis of complex lipids and gene expression analysis (RNA-seq) was performed. FADS1 inhibition caused AML cells to exhibit significant lipidomic remodeling, including depletion of PUFAs from the phospholipids, phosphatidylserine, and phosphatidylethanolamine. These lipidomic alterations were accompanied by an increase induction of inflammatory and stimulator of interferon genes (STING)-mediated type-1 interferon signaling. Remarkably, genetic deletion of STING largely prevented the AML cell maturation and death phenotypes mediated by FADS1 inhibition. Highlighting the therapeutic implications of these findings, pharmacological blockade of PUFA biosynthesis reduced patient-derived AML cell numbers exvivo but not that of healthy donor cells. Similarly, STING agonism attenuated patient-derived-AML survival; however, STING activation also reduced healthy granulocyte numbers. Collectively, these data unveil a previously unrecognized importance of PUFA biosynthesis in leukemogenesis and that imbalances in PUFA metabolism can drive STING-mediated AML maturation and death.

Stearoyl-CoA desaturase 1 inhibition impairs triacylglycerol accumulation and lipid droplet formation in colorectal cancer cells.

Increases in fatty acid (FA) biosynthesis meet the higher lipid demand by intensely proliferating cancer cells and promoting their progression. Stearoyl-CoA desaturase 1 (SCD1) is the key enzyme in FA biosynthesis, converting saturated FA (SFA) into monounsaturated FA (MUFA). Increases in the MUFA/SFA ratio and SCD1 expression have been observed in cancers of various origins and correlate with their aggressiveness. However, much is still unknown about the SCD1-dependent molecular mechanisms that promote specific changes in metabolic pathways of cancer cells. The present study investigated the involvement of SCD1 in shaping glucose and lipid metabolism in colorectal cancer (CRC) cells. Excess FAs that derive from de novo lipogenesis are stored in organelles, called lipid droplets (LDs), mainly in the form of triacylglycerol (TAG) and cholesteryl esters. LD accumulation is associated with key features of cancer development and progression. Consistent with our findings, the pharmacological inhibition of SCD1 activity affects CRC cell viability and impairs TAG accumulation and LD formation in these cells through the activation of lipolytic and lipophagic pathways. We showed that SCD1 suppression affects crucial lipogenic processes that promote lipid accumulation in CRC cells but in a sterol regulatory element-binding protein 1-independent manner. We propose that adenosine monophosphate-activated protein kinase contributes to these changes through the activation of lipolysis and inhibition of TAG synthesis. We also provide evidence of the involvement of SCD1 in the regulation of glucose uptake and utilization in CRC cells. These findings underscore the importance of SCD1 in regulating cellular processes that promote cancer development and progression.

Effect of Green and Red Thai Kratom (Mitragyna speciosa) on pancreatic digestive enzymes (alpha-glucosidase and lipase) and acetyl-carboxylase 1 activity: A possible therapeutic target for obesity prevention.

Regular use of Thai kratom has been linked to reduced blood triglyceride levels and body mass index (BMI) in healthy individuals. We analyzed Green Thai Kratom (GTK) and Red Thai Kratom (RTK) to investigate their effects on pancreatic digestive enzymes. The ethanol extracts of GTK and RTK inhibited lipase activity more strongly than alpha-glucosidase activity, suggesting the presence of lipase inhibitors. Mitragynine, the major compound in GTK, showed potent lipase inhibition and moderate alpha-glucosidase inhibition. Quercetin, found in both extracts, strongly inhibited alpha-glucosidase but had limited effects on lipase. These findings suggest that mitragynine and quercetin may hinder triglyceride and starch digestion. Combination inhibition studies revealed synergistic effects between mitragynine and quercetin on alpha-glucosidase activity. Additionally, both GTK and RTK extracts reduced fat accumulation in 3T3-L1 adipocyte cells, with quercetin specifically inhibiting Acetyl-CoA carboxylase 1 (ACC1), a key enzyme in fatty acid biosynthesis. Thus, GTK and RTK extracts, particularly mitragynine and quercetin, exhibit potential anti-obesity effects. We report the novel finding that Thai kratom inhibits de novo fatty acid synthesis by targeting ACC1, resulting in decreased fat accumulation in adipocytes. Regular use of Thai kratom in specific populations may improve blood triglyceride levels and reduce BMI by inhibiting lipase, alpha-glucosidase, and ACC1 activity. Further clinical trials are needed to determine optimal dosage, duration, toxicity levels, and potential side effects of Kratom use.

Multiple phases of yttrium-doped molybdenum trioxide nanorods as efficient dye degrader and bactericidal agents with molecular docking analysis

Contaminants removal is usually becoming an exciting subject of research from water considering their environmental and ecological effects. This work provides pathways to remove organic pollutants from water via nanomaterials and is used as an antibiotic against bacteria like Escherichia coli (E. coli). In this study, molybdenum trioxide (MoO3) and yttrium (Y) doped (2 and 4%) MoO3 nanorods were synthesized by co-precipitation method. Advanced characterization techniques have been introduced to study textural structures, morphological developments, and optical characteristics of produced products. X-ray diffraction studied multiple crystalline structures of prepared samples as hexagonal, orthorhombic, and monoclinic of pure MoO3 with decrease in crystallinity and crystallite size upon Y doping. UV–visible spectroscopy unveiled a redshift (bathochromic effect) in absorption pattern attributed to band gap energy (Eg) decreases. Photoluminescence spectra examined the recombination rate of electrons (e−) and holes (h+) as charge carriers. A sufficient catalytic activity (CA) was observed against methylene blue (MB) dye in an acidic medium (99.74%) and efficient bactericidal action was studied against (E. coli) with zone of inhibition (5.20 mm) for 4% Y-doped MoO3. In addition, in silico docking demonstrated potential inhibitory effect of produced nanomaterials on FabH and FabI enzymes of fatty acid biosynthesis.

Dye degradation, antimicrobial activity, and molecular docking analysis of carbon sphere and graphene oxide–doped aluminum oxide

In this research work, pristine and various concentrations (2.4 wt%) of graphene oxide (GO)/carbon sphere (CS)–doped Al2O3 nanostructures (NSs) were synthesized with the chemical sol–gel method. Aluminum oxide (Al2O3) exhibits quick recombination of electrons and holes with a low specific surface to limit catalytic and antibacterial activities. Al2O3 doped with CS is good in wastewater treatment and reduces the size of NSs. The incorporation of graphene oxide (GO) into Al2O3 at different concentrations (2 and 4 wt%) enhances both the structural and chemical stabilities of the resulting material while concurrently decreasing the number of charge carriers and reducing the band gap energy. This modified Al2O3-GO composite exhibits promising potential for utilization in dye degradation and antibacterial activity. A series of characterizations were performed to investigate the structural, morphological, and optical properties. The NSs exhibited excellent catalytic activity (CA) against rhodamine B (RhB) dye in acidic, basic, and neutral media. The antimicrobial activity was tested against Escherichia coli. Pairs of electrons and holes are the primary building blocks for the production of reactive oxygen species (ROS), which causes bacteria to die. The significant inhibition zones against E. coli were calculated to be approximately 5.65 mm when compared to ciprofloxacin. Moreover, in silico investigations have revealed the possible inhibitory impact of produced nanomaterials (GO/CS-doped Al2O3) on DNA gyrase and FabI enzymes of fatty acid biosynthesis.

Structures of an unusual 3-hydroxyacyl dehydratase (FabZ) from a ladderane-producing organism with an unexpected substrate preference

The genomes of anaerobic ammonium-oxidizing (anammox) bacteria contain a gene cluster comprising genes of unusual fatty acid biosynthesis enzymes that were suggested to be involved in the synthesis of the unique "ladderane" lipids produced by these organisms. This cluster encodes an acyl carrier protein (denoted as "amxACP") and a variant of FabZ, an ACP-3-hydroxyacyl dehydratase. In this study, we characterize this enzyme, which we call anammox-specific FabZ ("amxFabZ"), to investigate the unresolved biosynthetic pathway of ladderane lipids. We find that amxFabZ displays distinct sequence differences to "canonical" FabZ, such as a bulky, apolar residue on the inside of the substrate binding tunnel, where the canonical enzyme has a glycine. Additionally, substrate screens suggest that amxFabZ efficiently converts substrates with acyl chain lengths of up to eight carbons, whereas longer substrates are converted much more slowly under the conditions used. We also present crystal structures of amxFabZs, mutational studies and the structure of a complex between amxFabZ and amxACP, which show that the structures alone cannot explain the apparent differences from canonical FabZ. Moreover, we find that while amxFabZ does dehydrate substrates bound to amxACP, it does not convert substrates bound to canonical ACP of the same anammox organism. We discuss the possible functional relevance of these observations in the light of proposals for the mechanism for ladderane biosynthesis.

A Review of Fatty Acid Biosynthesis Enzyme Inhibitors as Promising Antimicrobial Drugs.

Resistance to antimicrobial drugs is currently a serious threat to human health. Consequently, we are facing an urgent need for new antimicrobial drugs acting with original modes of action. The ubiquitous and widely conserved microbial fatty acid biosynthesis pathway, called FAS-II system, represents a potential target to tackle antimicrobial resistance. This pathway has been extensively studied, and eleven proteins have been described. FabI (or InhA, its homologue in mycobacteria) was considered as a prime target by many teams and is currently the only enzyme with commercial inhibitor drugs: triclosan and isoniazid. Furthermore, afabicin and CG400549, two promising compounds which also target FabI, are in clinical assays to treat Staphylococcus aureus. However, most of the other enzymes are still underexploited targets. This review, after presenting the FAS-II system and its enzymes in Escherichia coli, highlights the reported inhibitors of the system. Their biological activities, main interactions formed with their targets and structure-activity relationships are presented as far as possible.

Anomalous catalytic and antibacterial activity confirmed by molecular docking analysis of silver and polyacrylic acid doped CeO2 nanostructures.

This research presents the novel synthesis of CeO2 nanostructures (NSs) doped with a fixed amount of capping agent (polyacrylic acid-PAA) and different concentrations (0.01 and 0.03) of silver (Ag). This work aimed to examine the catalytic and antibacterial efficacy with evidential molecular docking analysis of Ag/PAA doped CeO2. Systematic characterization was used to analyze the effect of Ag and a capping agent on crystal structure, morphology, absorbance wavelength, and the exciton recombination rate of CeO2. The silver metal and capping agent (PAA) were added into CeO2 to reduce the size of NSs, enhancing the catalytic efficacy. These binary dopants (Ag-PAA) based CeO2 revealed remarkable results for catalytic de-colorization of rhodamine B dye and antimicrobial potential as the dopants provide more active sites. Notably, (0.03) Ag/PAA doped CeO2 NSs exhibited a substantial catalytic reduction (98.9%) of rhodamine B dye in an acidic medium. The higher doped CeO2 revealed a significant inhibition zone (3.75 mm) against Escherichia coli at maximal concentration. Furthermore, in silico docking showed the possible inhibitory impact of produced nanomaterials on the fatty acid biosynthesis enzymes FabI and FabH.

Dietary Salvia hispanica L. Seed Counteracted Kidney Failure in Experimental Metabolic Syndrome

Metabolic Syndrome (MS) has become a major health hazard in the current world by triggering cardiovascular and renal pathologies. Chia seed is a rich source of bioactive food components (n-3 fatty acids, antioxidants and fiber, among others) with several benefits on cardiovascular health. Therefore, we hypothesized that the intake of chia seed could counteract kidney failure of MS by protecting against lipid accretion, oxidative stress and fibrosis in this tissue. An experimental model of MS was induced by feeding male Wistar rats for 3 months with a sucrose-rich diet (SRD) containing corn oil as a source of fat. During the next 3 months, half of the animals continued with SRD. The other half received the SRD in which corn oil was replaced by Salvia hispanica L. seeds (chia) (SRD+C). The control group received a reference diet (RD). In experimental MS, dietary administration of chia seed significantly decreased albumin and glucose urine levels (p<0.05). Chia reverted fibrosis (SiriusRed-collagen staining), morphological anomalies and the altered markers (PEPCK and FBPase) of renal glucose metabolism (p<0.05). These effects were accompanied by a decrease in the accumulation of triglycerides and oxidative stress biomarkers (ROS and lipid peroxides) in kidney (p<0.05). The mechanisms included down-regulation of key enzymes of fatty acid biosynthesis (ACC, FAS and G6PDH) and up-regulation of antioxidant defenses (GSH, GR and GPx activities). Dietary chia seed counteracted renal failure in an experimental model of MS, indicating that it could be an exceptional food for the clinical management of this disorder.

Transcriptome analysis of mangrove-isolated Chlorella vulgaris UMT-M1 reveals insights for vigorous growth and lipid accumulation through reduced salinity

Salinity effectively triggers lipid accumulation in microalgae culture but adversely affects its growth parameters. In a previous study, mangrove-isolated Chlorella vulgaris UMT-M1 exhibited physiological evidence of high oil accumulation occurring together with uncompromised growth parameters at various salinity levels. At present, the genetic basis for successful mangrove-acclimated species is lesser studied. Hence, this study conducted transcriptome analysis on C. vulgaris UMT-M1 samples where unperturbed growth coincided with highest oil accumulation (15 ppt). De novo assembly furnished 77,727 transcripts while subsequent differential expression analysis identified a total of 9231 differentially expressed genes (DEGs). Functional enrichment under gene ontology (GO) and KEGG pathways analysis identified 51 terms and 14 significantly affected pathways respectively. Notably, transcripts involved in photosynthesis and carotenoid biosynthesis were crucial for salinity acclimation . Furthermore, enhancement of glycolysis , utilization of PDH bypass pathways, in addition to upregulation of intracellular energy routes and downregulation of β-oxidation represent an increased preference for fatty acid precursor accumulation in the cell. Key enzymes in fatty acid biosynthesis together with membrane-forming peroxygenase further supports the narrative that fatty acid precursors may be directed towards lipid droplet formation. The results thus highlight key genetic routes for successful growth and lipid accumulation in mangrove-isolated C. vulgaris UMT-M1. • Uncompromised growth and increased oil accumulation at 15 ppt salinity. • Transcripts of photosynthetic apparatus supported salinity acclimatization. • Lipid precursor pathways such as PDH bypass and glycolysis were upregulated. • Upregulation of membrane-forming peroxygenase in line with lipid droplet formation.

O-GlcNAc stimulation is beneficial in septic shock in the young rat without affecting gene expression

O-GlcNAcylation, a post-translational modification, has been associated with an improvement of the cell survival and the stress response through a modulation of gene expression. We have previously demonstrated that O-GlcNAc stimulation in different models of sepsis is associated with a reduction in mortality and an improvement of different biological markers. Evaluate how O-GlcNAcylation stimulation improves sepsis outcomes in young rats. Endotoxemic shock was induced in 28 days old rats by lipopolysaccharides injection (O111:B4, 20 mg.kg −1 ) and compared to control rats (NaCl 0.9%). One hour after lipopolysaccharides injection, rats were randomly assigned to no therapy (LPS), fluidotherapy (NaCl 0.9%, 10 mg.kg −1 -LPS + R) ± NButGT (10 mg.kg −1 ) to increase O-GlcNAc levels. Physiological functions were evaluated 2 hours later, as well as mortality over 36 hours. Cardiac O-GlcNAcylated proteins were mapped by untargeted mass spectrometry and compared to genes transcription via 3′ SRP analysis. The impact of O-GlcNAc has been evaluated on cardiac tissue and HL1 cells (Thiamet G (O-GlcNAc stimulator): 10-8 to 10-5 M). LPS induced a shock with a decrease in mean arterial pressure ( P < 0.05). LPS + R had no beneficial effect while NButGT improves mean arterial pressure and median time of survival ( P < 0.05). The mRNA expression was not impacted 2 hours after treatment in LPS + R and NButGT group. However, 33 proteins are differentially O-GlcNAcylated in all groups. Among them, 60% are involved in metabolism and metabolic pathways. ATP-citrate lyase (ACLY) a key enzyme in fatty acid biosynthesis, is the only protein less O-GlcNAcylated in the NButGT group. O-GlcNAc stimulation on HL1 cells increases expression of tetrameric form of ACLY ( P < 0.05). Acute O-GlcNAc stimulation improves outcome in young septic rat. Stimulate the O-GlcNAcylation increased cardiac O-GlcNAcylated proteins notably those involved in metabolic pathways. Surprisingly, the transcription is not impacted by the O-GlcNAc stimulation. Study the impact of the O-GlcNAcylation on the activity or the interactome of ACLY is one issue to decipher the involvment of the O-GlcNAcylation during sepsis.

DGAT1 activity synchronises with mitophagy to protect cells from metabolic rewiring by iron depletion.

Mitophagy removes defective mitochondria via lysosomal elimination. Increased mitophagy coincides with metabolic reprogramming, yet it remains unknown whether mitophagy is a cause or consequence of such state changes. The signalling pathways that integrate with mitophagy to sustain cell and tissue integrity also remain poorly defined. We performed temporal metabolomics on mammalian cells treated with deferiprone, a therapeutic iron chelator that stimulates PINK1/PARKIN‐independent mitophagy. Iron depletion profoundly rewired the metabolome, hallmarked by remodelling of lipid metabolism within minutes of treatment. DGAT1‐dependent lipid droplet biosynthesis occurred several hours before mitochondrial clearance, with lipid droplets bordering mitochondria upon iron chelation. We demonstrate that DGAT1 inhibition restricts mitophagy in vitro, with impaired lysosomal homeostasis and cell viability. Importantly, genetic depletion of DGAT1 in vivo significantly impaired neuronal mitophagy and locomotor function in Drosophila. Our data define iron depletion as a potent signal that rapidly reshapes metabolism and establishes an unexpected synergy between lipid homeostasis and mitophagy that safeguards cell and tissue integrity.

Adhesion behavior of silica nanoparticles with bacteria: Spectroscopy measurements based on kinetics, and molecular docking

Nanoparticles are intriguing researchers due to their unique properties. In this study, the Stöber method was used to obtain white particles. Through scanning electron microscopy (SEM), X-ray diffraction (XRD) and Fourier transform infrared (FTIR) analysis, the spherical nano-scale particles were confirmed to be nano-silica. Bacteria adsorption experiment displayed that nano-silica could be accumulated on the surface of bacteria. The ultraviolet and fluorescence spectroscopy were used to explain the interaction between silica nanoparticles and recombinant protein A (S. aureus membrane protein) under simulated physiological conditions. The results of UV–vis and fluorescence experiments showed that the quenching mechanism between silica nanoparticles and recombinant protein A was static quenching. The key enzymes in bacterial cell wall synthesis (β-lactamase) and fatty acid biosynthesis (FabI and FabH) pathways were selected, and the molecular docking results explained that silica nanoparticles adhered to the surface of E. coli and S. aureus through forming hydrogen bond with amino acid residue.

Impact of Target Turnover on the Translation of Drug-Target Residence Time to Time-Dependent Antibacterial Activity.

The translation of time-dependent drug-target occupancy to extended pharmacological activity at low drug concentration depends on factors such as target vulnerability and the rate of target turnover. Previously, we demonstrated that the postantibiotic effect (PAE) caused by inhibitors of bacterial drug targets could be used to assess target vulnerability, and that high levels of target vulnerability coupled with relatively low rates of target resynthesis resulted in a strong correlation between drug-target residence time and the PAE following compound washout. Although the residence time of inhibitors on UDP-3-O-acyl-N-acetylglucosamine deacetylase (LpxC) in Pseudomonas aeruginosa (paLpxC) results in significant PAE, inhibitors of the equivalent enzyme in Escherichia coli (ecLpxC) do not cause a PAE. Hyperactivity of the fatty acid biosynthesis enzyme FabZ or the inclusion of sub-MIC levels of azithromycin lead to the observation of a PAE for three inhibitors of ecLpxC. FabZ hyperactivity has been shown to stabilize ecLpxC, and using mass spectrometry, we demonstrate that the appearance of a PAE can be directly linked to a 3-fold increase in the stability of ecLpxC. These studies substantiate the importance of target turnover in time-dependent drug activity.

Screening the rate-limiting genes in the ω6 polyunsaturated fatty acid biosynthesis pathway in Nannochloropsis oceanica

The enrichment of polyunsaturated fatty acids has made Nannochloropsis sp. a promising candidate for the production of polyunsaturated fatty acids. Although most of the genes involved in polyunsaturated fatty acid biosynthesis have been cloned, the regulatory mechanism at the molecular level has not been elucidated. To target the rate-limiting genes in the ω6 polyunsaturated fatty acid biosynthesis pathway in Nannochloropsis oceanica, we performed the following experiments. The function of the Δ9 fatty acid desaturase gene of N. oceanica was verified in Saccharomyces cerevisiae with a substrate preference for stearic acid. With gas chromatography–mass spectrometry (GC–MS) analysis, the fatty acid profiles in N. oceanica under different stress conditions (high nitrogen, low nitrogen, high temperature, and low temperature) were measured. The results showed that high nitrogen and low temperature stresses played significant roles in promoting polyunsaturated fatty acid biosynthesis. In contrast, low nitrogen and high temperature stresses were beneficial for the accumulation of monounsaturated fatty acids. We further measured the transcriptional abundances of all six genes in the ω6 polyunsaturated fatty acid biosynthesis pathway in N. oceanica and found that the Δ6 fatty acid elongase and the Δ12, Δ5, and Δ17 fatty acid desaturase genes were more sensitive to the stresses set in this study. Pearson correlation analysis showed that the Δ9 fatty acid desaturase was significantly associated with monounsaturated fatty acid biosynthesis, while Δ12, Δ5, and Δ17 fatty acid desaturases were proposed to be the rate-limiting enzymes in polyunsaturated fatty acid biosynthesis. This study helps to thoroughly elucidate the responses of N. oceanica to nitrogen and temperature stresses and optimize cultivation for high yield and quality of polyunsaturated fatty acids. More importantly, the selected rate-limiting genes may benefit further genetic engineering in N. oceanica.

Synthesis, in vitro bioassays, and computational study of heteroaryl nitazoxanide analogs.

Antiprotozoal drug nitazoxanide (NTZ) has shown diverse pharmacological properties and has appeared in several clinical trials. Herein we present the synthesis, characterization, in vitro biological investigation, and in silico study of four hetero aryl amide analogs of NTZ. Among the synthesized molecules, compound 2 and compound 4 exhibited promising antibacterial activity against Escherichia coli (E. coli), superior to that displayed by the parent drug nitazoxanide as revealed from the in vitro antibacterial assay. Compound 2 displayed zone of inhibition of 20 mm, twice as large as the parent drug NTZ (10 mm) in their least concentration (12.5 µg/ml). Compound 1 also showed antibacterial effect similar to that of nitazoxanide. The analogs were also tested for in vitro cytotoxic activity by employing cell counting kit‐8 (CCK‐8) assay technique in HeLa cell line, and compound 2 was identified as a potential anticancer agent having IC50 value of 172 µg which proves it to be more potent than nitazoxanide (IC50 = 428 µg). Furthermore, the compounds were subjected to molecular docking study against various bacterial and cancer signaling proteins. The in vitro test results corroborated with the in silico docking study as compound 2 and compound 4 had comparatively stronger binding affinity against the proteins and showed a higher docking score than nitazoxanide toward human mitogen‐activated protein kinase (MAPK9) and fatty acid biosynthesis enzyme (FabH) of E. coli. Moreover, the docking study demonstrated dihydrofolate reductase (DHFR) and thymidylate synthase (TS) as probable new targets for nitazoxanide and its synthetic analogs. Overall, the study suggests that nitazoxanide and its analogs can be a potential lead compound in the drug development.

Effect of fat diet on essential fatty acid metabolism of neutral lipids in rat blood serum

Aim. To determine the effect of dietary fats on the content and metabolism of polyunsaturated fatty acids (PUFA) in the fraction of neutral lipids blood serum.Methods. The effect of sunflower, high oleic sunflower (HOSO) and palm oils was studied when feeding rats with diets with 5 % fat for 30 days. Rats fed a fat-free diet (FFD) served as a control. The fatty acid composition of neutral blood serum lipids was determined by gas chromatography. The “activity” of fatty acid biosynthesis enzymes: elongase and desaturases was calculated from the ratio of the content of fatty acids.Results. A high content of PUFA was found in rats treated with FFD. Feeding rats with a diet with 5 % sunflower oil increased the total content of PUFAs with a slight decrease in the level of ω-3 PUFAs. Feeding rats with diets containing 5 % palm oil or HOSO did not affect the total content of PUFA, but increased the content of ω-3 PUFA. A very high "activity" of stearyl-CoA desaturase was found in rats fed FFD and fat diets. The consumption of HOSO inhibits the formation of arachidonic acid, while the consumption of palm oil enhances it.Conclusions. A high level of PUFA in neutral lipids in the blood serum of rats may indicate the presence of endogenous sources of PUFA. The optimal (for rats) consumption of dietary fats has a small effect on the content and metabolism of PUFA, with the exception of sunflower oil, the consumption of which significantly increases the ω-6/ω-3 PUFA ratio.

Serum fatty acid synthase levels and n-3 fatty acid intake in patients with breast cancer.

Fatty acid synthase (FASN) is a key enzyme in fatty acid biosynthesis that is usually over-expressed in patients with breast cancer, but its relationship with the patient's dietary habit is not clear. A higher intake of n-3 polyunsaturated fatty acids is related to reduced breast carcinogenesis invitro and invivo. The aim of this study was to clinically investigate the association between serum FASN levels and fatty acid intake in women newly diagnosed with breast cancer. In a case-control cross-sectional study, with 18 breast cancer patients and 29 controls, we evaluated nutritional status, dietary intake, and serum FASN levels. Statistical analyses were carried out with parametric and non-parametric tests, according to the sample's normality distribution. The mean age of breast cancer group (n=18) and control group (n=29) was 46.8±9.7y and 44.4.±8.6y, respectively. Mean serum concentration of FASN in breast cancer group was significantly higher (132.51±95.05ng/mL) than in control group (36.88±20.87ng/mL) (p<0.0001). Among breast cancer group, serum FASN levels of premenopausal women were significantly higher than those of postmenopausal women (p=0.026). There was no significant difference between the early and late disease stages in regard to serum FASN levels in breast cancer group. Mean nutrient intake was similar and n-3 docosahexaenoic acid intake was low in both groups. We observed no association regarding fatty acid intake and serum FASN levels. These data suggest that dietary n-3 fatty acid has no association with serum FASN levels among newly diagnosed breast cancer patients.

(p)ppGpp/GTP and Malonyl-CoA Modulate Staphylococcus aureus Adaptation to FASII Antibiotics and Provide a Basis for Synergistic Bi-Therapy.

Fatty acid biosynthesis (FASII) enzymes are considered valid targets for antimicrobial drug development against the human pathogen Staphylococcus aureus However, incorporation of host fatty acids confers FASII antibiotic adaptation that compromises prospective treatments. S. aureus adapts to FASII inhibitors by first entering a nonreplicative latency period, followed by outgrowth. Here, we used transcriptional fusions and direct metabolite measurements to investigate the factors that dictate the duration of latency prior to outgrowth. We show that stringent response induction leads to repression of FASII and phospholipid synthesis genes. (p)ppGpp induction inhibits synthesis of malonyl-CoA, a molecule that derepresses FapR, a key regulator of FASII and phospholipid synthesis. Anti-FASII treatment also triggers transient expression of (p)ppGpp-regulated genes during the anti-FASII latency phase, with concomitant repression of FapR regulon expression. These effects are reversed upon outgrowth. GTP depletion, a known consequence of the stringent response, also occurs during FASII latency, and is proposed as the common signal linking these responses. We next showed that anti-FASII treatment shifts malonyl-CoA distribution between its interactants FapR and FabD, toward FapR, increasing expression of the phospholipid synthesis genes plsX and plsC during outgrowth. We conclude that components of the stringent response dictate malonyl-CoA availability in S. aureus FASII regulation, and contribute to latency prior to anti-FASII-adapted outgrowth. A combinatory approach, coupling a (p)ppGpp inducer and an anti-FASII, blocks S. aureus outgrowth, opening perspectives for bi-therapy treatment.IMPORTANCEStaphylococcus aureus is a major human bacterial pathogen for which new inhibitors are urgently needed. Antibiotic development has centered on the fatty acid synthesis (FASII) pathway, which provides the building blocks for bacterial membrane phospholipids. However, S. aureus overcomes FASII inhibition and adapts to anti-FASII by using exogenous fatty acids that are abundant in host environments. This adaptation mechanism comprises a transient latency period followed by bacterial outgrowth. Here, we use metabolite sensors and promoter reporters to show that responses to stringent conditions and to FASII inhibition intersect, in that both involve GTP and malonyl-CoA. These two signaling molecules contribute to modulating the duration of latency prior to S. aureus adaptation outgrowth. We exploit these novel findings to propose a bi-therapy treatment against staphylococcal infections.

PQM-1 controls hypoxic survival via regulation of lipid metabolism

Animals have evolved responses to low oxygen conditions to ensure their survival. Here, we have identified the C. elegans zinc finger transcription factor PQM-1 as a regulator of the hypoxic stress response. PQM-1 is required for the longevity of insulin signaling mutants, but surprisingly, loss of PQM-1 increases survival under hypoxic conditions. PQM-1 functions as a metabolic regulator by controlling oxygen consumption rates, suppressing hypoxic glycogen levels, and inhibiting the expression of the sorbitol dehydrogenase-1 SODH-1, a crucial sugar metabolism enzyme. PQM-1 promotes hypoxic fat metabolism by maintaining the expression of the stearoyl-CoA desaturase FAT-7, an oxygen consuming, rate-limiting enzyme in fatty acid biosynthesis. PQM-1 activity positively regulates fat transport to developing oocytes through vitellogenins under hypoxic conditions, thereby increasing survival rates of arrested progeny during hypoxia. Thus, while pqm-1 mutants increase survival of mothers, ultimately this loss is detrimental to progeny survival. Our data support a model in which PQM-1 controls a trade-off between lipid metabolic activity in the mother and her progeny to promote the survival of the species under hypoxic conditions.