Long-chain acyl-CoA Synthetase Research Articles

Lipid metabolism in dopaminergic neurons influences light entrainment.

Dietary lipids, particularly omega-3 polyunsaturated fatty acids, are speculated to impact behaviors linked to the dopaminergic system, such as movement and control of circadian rhythms. However, the ability to draw a direct link between dopaminergic omega-3 fatty acid metabolism and behavioral outcomes has been limited to the use of diet-based approaches, which are confounded by systemic effects. Here, neuronal lipid metabolism was targeted in a diet-independent manner by manipulation of long-chain acyl-CoA synthetase 6 (ACSL6) expression. ACSL6 performs the initial reaction for cellular fatty acid metabolism and prefers the omega-3 polyunsaturated fatty acid, docosahexaenoic acid (DHA). The loss of Acsl6 in mice (Acsl6-/- ) depletes neuronal membranes of DHA content and results in phenotypes linked to dopaminergic control, such as hyperlocomotion, impaired short-term spatial memory, and imbalances in dopamine neurochemistry. To investigate the role of dopaminergic ACSL6 on these outcomes, a dopaminergic neuron-specific ACSL6 knockout mouse was generated (Acsl6DA-/- ). Acsl6DA-/- mice demonstrated hyperlocomotion and imbalances in striatal dopamine neurochemistry. Circadian rhythms of both the Acsl6-/- and the Acsl6DA-/- mice were similar to control mice under basal conditions. However, upon light entrainment, a mimetic of jet lag, both the complete knockout of ACSL6 and the dopaminergic-neuron-specific loss of ACSL6 resulted in a longer recovery to entrainment compared to control mice. In conclusion, these data demonstrate that ACSL6 in dopaminergic neurons alters dopamine metabolism and regulation of light entrainment suggesting that DHA metabolism mediated by ACSL6 plays a role in dopamine neuron biology.

1,25-Dihydroxyvitamin D3 alleviates hyperandrogen-induced ferroptosis in KGN cells

PurposeHyperandrogenism, one of the most frequent causes of anovulation in women, increases the risk of metabolic disorders in patients with polycystic ovary syndrome (PCOS). Ferroptosis, characterized by iron-dependent lipid peroxidation, has provided new insight into the progression of PCOS. 1,25-dihydroxyvitamin D3 (1,25D3) may play a role in reproduction because its receptor, VDR, which contributes to the inhibition of oxidative stress, is primarily located in the nuclei of granulosa cells. This study has therefore investigated whether 1,25D3 and hyperandrogenism affect granulosa-like tumor cells (KGN cells) through ferroptosis.MethodsKGN cells were treated with dehydroepiandrosterone (DHEA) or pretreated with 1,25D3. Cell viability was evaluated with the cell counting kit-8 (CCK-8) assay. The mRNA and protein expression levels of ferroptosis-related molecules, including glutathione peroxidase 4 (GPX4), solute carrier family 7 member (SLC7A11), and long-chain acyl-CoA synthetase 4 (ACSL4), were assessed via qRT–PCR and western blot. The concentration of malondialdehyde (MDA) was measured by ELISA. The rates of reactive oxygen species (ROS) production and lipid peroxidation were assessed via photometric methods.ResultsDecreased cell viability, suppression of GPX4 and SLC7A11 expression, increased expression of ACSL4, elevated levels of MDA, accumulation of ROS, and increased lipid peroxidation, which are changes representative of ferroptosis, were observed in KGN cells after treatment with DHEA. Pretreatment with 1,25D3 in KGN cells significantly prevented these changes.ConclusionsOur findings demonstrate that 1,25D3 attenuates hyperandrogen-induced ferroptosis of KGN cells. This finding might lead to new insights into the pathophysiology and therapy of PCOS and provides new evidence for the treatment of PCOS with 1,25D3.

Heterologous Production of Calendic Acid Naturally Found in Calendula officinalis by Recombinant Fission Yeast.

Calendic acid (CA) is a conjugated fatty acid with anti-cancer properties that is widely present in seed oil of Calendula officinalis. Using the co-expression of C. officinalis fatty acid conjugases (CoFADX-1 or CoFADX-2) and Punica granatum fatty acid desaturase (PgFAD2), we metabolically engineered the synthesis of CA in the yeast Schizosaccharomyces pombe without the need for linoleic acid (LA) supplementation. The highest CA titer and achieved accumulation were 4.4 mg/L and 3.7 mg/g of DCW in PgFAD2 + CoFADX-2 recombinant strain cultivated at 16 °C for 72 h, respectively. Further analyses revealed the accumulation of CA in free fatty acids (FFA) and downregulation of the lcf1 gene encoding long-chain fatty acyl-CoA synthetase. The developed recombinant yeast system represents an important tool for the future identification of the essential components of the channeling machinery to produce CA as a high-value conjugated fatty acid at an industrial level.

Prognostic Role of Long-Chain Acyl-Coenzyme A Synthetase Family Genes in Patients with Clear Cell Renal Cell Carcinoma: A Comprehensive Bioinformatics Analysis Confirmed with External Validation Cohorts

We aimed to determine the prognostic role of long-chain acyl-CoA synthetases (ACSLs) as a disease marker for kidney clear cell carcinoma (KIRC). The Cancer Genome Atlas (TCGA) data were accessed via open access LinkedOmics database for KIRC. Provisional datasets were used for analysis as previously described and gene expression quantification data were downloaded. The corresponding clinical information of patients also were obtained from the database. Five ACSL family members, ACSL1, ACSL3, ACSL4, ACSL5, and ACSL6, were investigated in the TCGA-KIRC cohort. Xena browser, cBioPortal and UALCAN, and Cancer Cell Line Encyclopedia (CCLE) databases were also used to confirm the results. External validation was performed using patient cohorts from the Gene Expression Omnibus (GEO-NCBI) database. Finally, the protein-protein interaction (PPI) was constructed based on the Search Tool for the Retrieval of Interacting Genes (STRING) database and visualized using Cytoscape software. Pathological T3-T4 stage tumors had significantly lower ACSL1 mRNA expression (P=.009). Patients with pathologically confirmed metastasis exhibited significantly lower expression, as well (P=.02). ACSL1 mRNA expression was associated with overall survival (OS) and negatively correlated with OS time. Univariate and multivariate analyses showed that lower ACSL1 mRNA expression level was associated with mortality. Moreover, ACSL1 mRNA expression was exhibited significant difference in some VHL gene region mutations and PBRM1_p.R1010 mutation, and negatively correlated with HIF1-alpha mRNA expression (P < .001). Confirmatory analyses and external validation also revealed similar findings. Lowered ACSL1 mRNA expression is associated with worse tumor histopathology and poor overall survival in KIRC. It may be used for prognostic marker for KIRC.

Cyclic stretch promotes vascular homing of endothelial progenitor cells via Acsl1 regulation of mitochondrial fatty acid oxidation

Endothelial progenitor cells (EPCs) play an important role in vascular repair and re-endothelialization after vessel injury. EPCs in blood vessels are subjected to cyclic stretch (CS) due to the pulsatile pressure, but the role of CS in metabolic reprogramming of EPC, particularly its vascular homing and repair, is largely unknown. In the current study, physiological CS applied to EPCs at a magnitude of 10% and a frequency of 1 Hz significantly promoted their vascular adhesion and endothelial differentiation. CS enhanced mitochondrial elongation and oxidative phosphorylation (OXPHOS), as well as adenosine triphosphateproduction. Metabolomic study and Ultra-high performance liquid chromatography-mass spectrometry assay revealed that CS significantly decreased the content of long-chain fatty acids (LCFAs) and markedly induced long-chain fatty acyl-CoA synthetase 1 (Acsl1), which in turn facilitated the catabolism of LCFAs in mitochondria via fatty acid β-oxidation and OXPHOS. In a rat carotid artery injury model, transplantation of EPCs overexpressing Acsl1 enhanced the adhesion and re-endothelialization of EPCs invivo. MRI and vascular morphology staining showed that Acsl1 overexpression in EPCs improved vascular repair and inhibited vascular stenosis. This study reveals a mechanotransduction mechanism by which physiological CS enhances endothelial repair via EPC patency.

Metabolomics and Transcriptomics Provide Insights into Lipid Biosynthesis in the Embryos of Walnut (Juglans regia L.).

Walnut (Juglans regia L.) is an important woody oilseed tree species due to its commercial value. However, the regulation mechanism of walnut oil accumulation is still poorly understood, which restricted the breeding and genetic improvement of high-quality oil-bearing walnuts. In order to explore the metabolic mechanism that regulates the synthesis of walnut oil, we used transcriptome sequencing technology and metabolome technology to comprehensively analyze the key genes and metabolites involved in oil synthesis of the walnut embryo at 60, 90, and 120 days after pollination (DAP). The results showed that the oil and protein contents increased gradually during fruit development, comprising 69.61% and 18.32% of the fruit, respectively, during ripening. Conversely, the contents of soluble sugar and starch decreased gradually during fruit development, comprising 2.14% and 0.84%, respectively, during ripening. Transcriptome sequencing generated 40,631 unigenes across 9 cDNA libraries. We identified 51 and 25 candidate unigenes related to the biosynthesis of fatty acid and the biosynthesis of triacylglycerol (TAG), respectively. The expression levels of the genes encoding Acetyl-CoA carboxylase (ACCase), long-chain acyl-CoA synthetases (LACS), 3-oxoacyl-ACP synthase II (KASII), and glycerol-3-phosphate acyl transfer (GPAT) were upregulated at 60 DAP relative to the levels at 90 and 120 DAP, while the stearoyl-ACP-desaturase (SAD) and fatty acid desaturase 2 (FAD2) genes were highly abundantly expressed during all walnut developmental periods. We found that ABSCISIC ACID INSENSEITIVE3 (ABI3), WRINKLEDl (WRI1), LEAFY COTYLEDON1 (LEC1), and FUSCA3 (FUS3) may be key transcription factors involved in lipid synthesis. Additionally, the metabolomics analysis detected 706 metabolites derived from 18 samples, among which, 4 are implicated in the TAG synthesis, 2 in the glycolysis pathway, and 5 in the tricarboxylic acid cycle (TCA cycle) pathway. The combined analysis of the related genes and metabolites in TAG synthesis showed that phospholipid:diacylglycerol acyltransferase (PDAT) genes were highly abundantly expressed across walnut fruit developmental periods, and their downstream metabolite TAG gradually accumulated with the progression of fruit development. The FAD2 gene showed consistently higher expression during fruit development, and its downstream metabolites 18:2-PC and 18:3-PC gradually accumulated. The ACCase, LACS, SAD, FAD2, and PDAT genes may be crucial genes required for walnut oil synthesis. Our data will enrich public databases and provide new insights into functional genes related to lipid metabolism in walnut.

The Pathogenetic Basis of the Action of Bempedoic Acid

The modern cardiology has a wide range of medications which affect various pathogenetic links of atherosclerosis, but even the best of them still obtain disadvantages causing intolerance and medicine discontinuation. The development of new hypolipidemic medications will allow not only to introduce alternative therapies into the cardiology practice, but also to completely execute the strategy of residual risk reduction by utilizing rational combinations of medications. One of such alternatives could be bempedoic acid, which can have a positive effect on a number of endpoints as the results of third phase trials have shown. These effects are also confirmed in Mendelian randomization studies. The mechanism of action of bempedoic acid is presumably associated with inhibition of the activity of ATP citrate lyase – the enzyme responsible for the breakdown of citrate into acetyl-CoA and oxaloacetate. Acetyl-CoA, in turn, is used by the cell to synthesize cholesterol and fatty acids. Thus, bempedoic acid affects in the same metabolic pathway as statins, but at an earlier stage. According to this, it is possible that medications of these classes will have similar side effects and pleiotropic effects associated with modulation of the mevalonic pathway, such as prenylation regulatory proteins (small GTPases) or reduction of coenzyme Q synthesis. However, there are also some specific features of the pharmacodynamics and pharmacokinetics of bempedoic acid to be considered. In particular, once entered the body, it must be activated via esterification by very long-chain acyl-CoA synthetase-1. The enzyme isoform required for this process is expressed in a tissue-specific manner and, for example, is absent in skeletal myocytes. In addition, citrate, oxaloacetate, and acetyl-CoA are important regulators of many intracellular processes: metabolism, growth and proliferation, mechanotransduction, posttranslational modifications of histones and other proteins. The levels of all three substances are altered by bempedoic acid, although no firm conclusions about the effects of these changes can be drawn at this time. The mentioned features probably have a significant impact on the clinical profile of bempedoic acid and underlie the differences from statins already observed in third phase trials, including, for example, a reduced risk of the onset or worsening of diabetes mellitus while taking bempedoic acid.

Overexpression the BnLACS9 could increase the chlorophyll and oil content in Brassica napus

BackgroundChlorophyll is a very important pigment involved in photosynthesis, while plant acyl-CoA biosynthesis is derived from plastid-localized fatty acids (FAs). Until now, the regulation of the acyl-CoA pathway for chlorophyll biosynthesis is still unknown.ResultsHere, we identified a long-chain acyl-CoA synthetase (LACS) gene BnLACS9 from Brassica napus. BnLACS9 complemented a LACS-deficient yeast strain YB525, which indicated that BnLACS9 has the LACS function. BnLACS9 was localized in the chloroplast envelope membrane, while mainly expressed in young leaves and flowers. Overexpression of BnLACS9 in Nicotiana benthamiana resulted in an increase in total CoA and MGDG content. In B. napus with overexpression of BnLACS9, the number of chloroplast grana lamellae and the chlorophyll content, as well as the MGDG and DGDG contents, increased compared to wild type. The net photosynthetic rate, dry weight of the entire plant and oil content of seeds increased significantly, accompanied by an increase in chlorophyll content. Transcriptome analysis revealed that overexpression of BnLACS9 improved the pathway of acyl-CoA biosynthesis and further improved the enzymes in the glycolipid synthesis pathway, while acyl-CoA was the substrate for glycolipid synthesis. The increased glycolipids, especially MGDG and DGDG, accelerated the formation of the chloroplast grana lamellae, which increased the number of chloroplast thylakoid grana lamella and further lead to increased chlorophyll content.ConclusionsIn the present study, we demonstrated that BnLACS9 played a crucial role in glycolipids and chlorophyll biosynthesis in B. napus. The results also provide a new direction and theoretical basis for the improvement of the agronomic traits of plants.

ACSL3 and ACSL4, Distinct Roles in Ferroptosis and Cancers

The long-chain fatty acyl CoA synthetase (ACSLs) family of enzymes contributes significantly to lipid metabolism and produces acyl-coenzyme A by catalyzing fatty acid oxidation. The dysregulation of ACSL3 and ACSL4, which belong to the five isoforms of ACSLs, plays a key role in cancer initiation, development, metastasis, and tumor immunity and may provide several possible therapeutic strategies. Moreover, ACSL3 and ACSL4 are crucial for ferroptosis, a non-apoptotic cell death triggered by the accumulation of membrane lipid peroxides due to iron overload. Here, we present a summary of the current knowledge on ACSL3 and ACSL4 and their functions in various cancers. Research on the molecular mechanisms involved in the regulation of ferroptosis is critical to developing targeted therapies for cancer.

Beneficial effects of bempedoic acid treatment in polycystic kidney disease cells and mice.

ADPKD has few therapeutic options. Tolvaptan slows disease but has side effects limiting its tolerability. Bempedoic acid (BA), an ATP citrate-lyase (ACLY) inhibitor FDA-approved for hypercholesterolemia, catalyzes a key step in fatty acid/sterol synthesis important for cell proliferation. BA is activated by very long-chain acyl-CoA synthetase (FATP2) expressed primarily in kidney and liver. BA also activates AMPK. We hypothesized that BA could be a novel ADPKD therapy by inhibiting cyst growth, proliferation, injury, and metabolic dysregulation via ACLY inhibition and AMPK activation. Pkd1-null kidney cell lines derived from mouse proximal tubule (PT) and collecting duct (IMCD) were grown in 2D or 3D Matrigel cultures and treated ± BA, ± SB-204990 (another ACLY inhibitor) or with Acly shRNA before cyst analysis, immunoblotting or mitochondrial assays using MitoSox and MitoTracker staining. Pkd1 fl/fl ; Pax8-rtTA; Tet-O-Cre C57BL/6J mice were induced with doxycycline injection on postnatal days 10 and 11 (P10-P11) and then treated ± BA (30mg/kg/d) ± tolvaptan (30-100mg/kg/d) by gavage from P12-21. Disease severity was determined by % total-kidney-weight-to-bodyweight (%TKW/BW) and BUN levels at euthanasia (P22). Kidney and liver homogenates were immunoblotted for expression of key biomarkers. ACLY expression and activity were upregulated in Pkd1-null PT and IMCD-derived cells vs. controls. Relative to controls, both BA and SB-204990 inhibited cystic growth in Pkd1-null kidney cells, as did Acly knockdown. BA inhibited mitochondrial superoxide production and promoted mitochondrial elongation, suggesting improved mitochondrial function. In ADPKD mice, BA reduced %TKW/BW and BUN to a similar extent as tolvaptan vs. untreated controls. Addition of BA to tolvaptan caused a further reduction in %TKW/BW and BUN vs. tolvaptan alone. BA generally reduced ACLY and stimulated AMPK activity in kidneys and livers vs. controls. BA also inhibited mTOR and ERK signaling and reduced kidney injury markers. In liver, BA treatment, both alone and together with tolvaptan, increased mitochondrial biogenesis while inhibiting apoptosis. We conclude that BA and ACLY inhibition inhibited cyst growth in vitro, and BA decreased ADPKD severity in vivo. Combining BA with tolvaptan further improved various ADPKD disease parameters. Repurposing BA may be a promising new ADPKD therapy, having beneficial effects alone and along with tolvaptan.

Transcript variants of long-chain acyl-CoA synthase 1 have distinct roles in sheep lipid metabolism.

Mutton has recently been identified to be a consumer favorite, and intermuscular fat is the key factor in determining meat tenderness. Long-chain acyl-CoA synthetase 1 (ACSL1) is a vital subtype of the ACSL family that is involved in the synthesis of lipids from acyl-CoA and the oxidation of fatty acids. The amplification of the ACSL1 gene using rapid amplification of cDNA ends revealed that the alternative polyadenylation (APA) results in two transcripts of the ACSL1 gene. Exon 18 had premature termination, resulting in a shorter CDS region. In this study, the existence of two transcripts of varying lengths translated normally and designated ACSL1-a and ACSL1-b was confirmed. Overexpression of ACSL1-a can promote the synthesis of an intracellular diglyceride, while ACSL1-b can promote triglyceride synthesis. The transfection of ACSL1 shRNA knocks down both the transcripts, the triglyceride content was significantly reduced after differentiation and induction; and lipidome sequencing results exhibited a significant decrease in 14-22 carbon triglyceride metabolites. The results of the present study indicated that the ACSL1 gene played a crucial role in the synthesis of triglycerides. Furthermore, the two transcripts involved in various interactions in the triglyceride synthesis process may be the topic of interest for future research and provide a more theoretical basis for sheep breeding.

Loss of long-chain acyl-CoA synthetase 1 promotes hepatocyte death in alcohol-induced steatohepatitis

BackgroundAlcohol consumption has been shown to disrupt hepatic lipid homeostasis. Long-chain acyl-CoA synthetase 1 (ACSL1) critically regulates hepatic fatty acid metabolism and lipid homeostasis by channeling fatty acids to lipid metabolic pathways. However, it remains unclear how ACSL1 contributes to the development of alcohol-associated liver disease (ALD). MethodsWe performed chronic alcohol feeding animal studies with hepatocyte-specific ACSL1 knockout (ACSL1Δhep) mice, hepatocyte-specific STAT5 knockout (STAT5Δhep) mice, and ACSL1Δhep based-STAT5B overexpression (Stat5b-OE) mice. Cell studies were conducted to define the causal role of ACSL1 deficiency in the pathogenesis of alcohol-induced liver injury. The clinical relevance of the STAT5-ACSL1 pathway was examined using liver tissues from patients with alcoholic hepatitis (AH) and normal subjects (Normal). ResultsWe found that chronic alcohol consumption reduced hepatic ACSL1 expression in AH patients and ALD mice. Hepatocyte-specific ACSL1 deletion exacerbated alcohol-induced liver injury by increasing free fatty acids (FFA) accumulation and cell death. Cell studies revealed that FFA elicited the translocation of BAX and p-MLKL to the lysosomal membrane, resulting in lysosomal membrane permeabilization (LMP) and thereby initiating lysosomal-mediated cell death pathway. Furthermore, we identified that the signal transducer and activator of transcription 5 (STAT5) is a novel transcriptional regulator of ACSL1. Deletion of STAT5 exacerbated alcohol-induced liver injury in association with downregulation of ACSL1, and reactivation of ACSL1 by STAT5 overexpression effectively ameliorated alcohol-induced liver injury. In addition, ACSL1 expression was positively correlated with STAT5 and negatively correlated with cell death was also validated in the liver of AH patients. ConclusionsACSL1 deficiency due to STAT5 inactivation critically mediates alcohol-induced lipotoxicity and cell death in the development of ALD. These findings provide insights into alcohol-induced liver injury.

ACSL1 promotes imatinib-induced chronic myeloid leukemia cell senescence by regulating SIRT1/p53/p21 pathway

Although tyrosine kinase inhibitors (TKIs) improve the prognosis of chronic myeloid leukemia (CML) patients, resistance to TKIs and residual leukemia stem cells (LSCs) inevitably become the bottleneck of cure. Therefore, we need to explore novel treatment strategies based on conventional treatment strategies. Our previous study found that CML cell senescence may be one of the main factors to achieve clinical cure of CML. Studies have shown that lipid metabolism plays a key role in cellular senescence. Here, we found that long-chain acyl-CoA synthetase 1 (ACSL1) was significantly up-regulated in senescent CML cells. Furthermore, we demonstrated that overexpression of ACSL1 induces senescence and inhibits cell growth in K562 cells by altering cell cycle progression, and enhances the proliferation-inhibiting effect of imatinib. Overexpression of ACSL1 enhances imatinib-induced tumorigenic decline in K562 cells in vivo. Knockdown of ACSL1 reverses imatinib-induced senescence in K562 cells. Mechanistically, overexpression of ACSL1 induced senescence in K562 cells via the SIRT1/p53/p21 axis. Collectively, our study showed that ACSL1 promotes imatinib-induced K562 cells senescence and tumor growth by regulating SIRT1/p53/p21 pathway. The ACSL1/SIRT1/p53 signal axis is a novel mechanism of cell senescence in CML and a new potential target for eradication of CML LSCs.

Genome-Wide Identification and Expression Profiling Analysis of the Long-Chain Acyl-CoA Synthetases Reveal Their Potential Roles in Wheat Male Fertility.

Long-chain acyl-CoA synthetase (LACS), responsible for the conversion of free FAs into acyl-CoAs, is involved in multiple pathways of lipid metabolism. Although LACS genes in Arabidopsis have been well characterized, no detailed information concerning this family is available for wheat. In the present study, a systematic analysis was carried out for the wheat LACS family. As a result, 30 putative TaLACSs were identified. Expression analysis revealed that 22 Takacs were expressed in wheat anthers. Two orthologs of AtLACS1, TaLACS2 and TaLACS3, were repressed at the vacuolated stage in the cold-treated BS366 (a temperature-sensitive genic male-sterile line). Thus, TaLACS2 and TaLACS3 may function like AtLACS1 in wax biosynthesis in anthers, and the repression of both genes may be correlated with the male sterility of BS366. TaLACS5 is an ortholog of AtLACS5, which was expressed exclusively in anthers. TaLACS5 was repressed in the cold-treated BS366 at the tetrad, uninucleate, and vacuolated stages. The negative correlation between TaLACS5 and TaGAMYB-B, and the MYB domain found in the promoter sequence suggested that TaLACS5 may be negatively regulated by TaGAMYB-B to participate in wheat fertility. These findings will provide a valuable foundation for the understanding of the wheat LACS gene family in male fertility.

Maternal Low-Protein Diet during Puberty and Adulthood Aggravates Lipid Metabolism of Their Offspring Fed a High-Fat Diet in Mice.

A maternal low-protein (LP) diet during gestation and/or lactation results in metabolic syndrome in their offspring. Here, we investigated the effect of maternal LP diet during puberty and adulthood on the metabolic homeostasis of glucose and lipids in offspring. Female mice were fed with normal-protein (NP) diet or a LP diet for 11 weeks. Male offspring were then fed with a high-fat diet (NP-HFD and LP-HFD groups) or standard chow diet (NP-Chow and LP-Chow groups) for 4 months. Results showed that maternal LP diet during puberty and adulthood did not alter the insulin sensitivity and hepatic lipid homeostasis of their offspring under chow diet, but aggravated insulin resistance, hepatic steatosis, and hypercholesterolemia of offspring in response to a post-weaning HFD. Accordingly, transcriptomics study with offspring’s liver indicated that several genes related to glucose and lipid metabolism, including lipoprotein lipase (Lpl), long-chain acyl-CoA synthetase 1 (Acsl1), Apoprotein A1 (Apoa1), major urinary protein 19 (Mup19), cholesterol 7α hydroxylase (Cyp7a1) and fibroblast growth factor 1 (Fgf1), were changed by maternal LP diet. Taken together, maternal LP diet during puberty and adulthood could disarrange the expression of metabolic genes in the liver of offspring and aggravate insulin resistance and hepatic steatosis in offspring fed a HFD.

High Expression of ACOT2 Predicts Worse Overall Survival and Abnormal Lipid Metabolism: A Potential Target for Acute Myeloid Leukemia.

Acyl-CoA thioesterase (ACOT) plays a considerable role in lipid metabolism, which is closely related to the occurrence and development of cancer, nevertheless, its role has not been fully elucidated in acute myeloid leukemia (AML). To explore the role of ACOT2 in AML and to provide a potential therapeutic target for AML, the expression pattern of ACOT was investigated based on the TNMplot, Gene Expression Profiling Interactive Analysis (GEPIA), and Cancer Cell Line Encyclopedia (CCLE) database, and diagnostic value, prognostic value, and clinical phenotype of ACOT were explored based on data from The Cancer Genome Atlas (TCGA). Functional annotation and enrichment analysis of the common targets between ACOT2 coexpressed and AML-related genes were further performed by Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene Set Enrichment Analysis (GSEA) analyses. The protein-protein interaction (PPI) network of ACOT2 coexpressed genes and functional ACOT2-related metabolites association network were constructed based on GeneMANIA and Human Metabolome Database. Among ACOTs, ACOT2 was highly expressed in AML compared to normal control subjects according to TNMplot, GEPIA, and CCLE database, which was significantly associated with poor overall survival (OS) in AML (P=0.003). Moreover, ACOT2 exhibited excellent diagnostic efficiency for AML (AUC: 1.000) and related to French-American-British (FAB) classification and cytogenetics. GO, KEGG, and GSEA analyses of 71 common targets between ACOT2 coexpressed and AML-related genes revealed that ACOT2 is closely related to ACOT1, ACOT4, enoyl-acyl carrier protein reductase, mitochondrial (MECR), puromycin-sensitive aminopeptidase (NPEPPS), SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily B member 1 (SMARCB1), and long-chain fatty acid-CoA ligase 1 (ACSL1) in PPI network, and plays a significant role in lipid metabolism, that is, involved in fatty acid elongation and biosynthesis of unsaturated fatty acids. Collectively, the increase of ACOT2 may be an important characteristic of worse OS and abnormal lipid metabolism, suggesting that ACOT2 may become a potential therapeutic target for AML.

Enhanced production of iturin A by strengthening fatty acid synthesis modules in Bacillus amyloliquefaciens.

Iturin A is a biosurfactant with various applications, and its low synthesis capability limits its production and application development. Fatty acids play a critical role in cellular metabolism and target product syntheses, and the relationship between fatty acid supplies and iturin A synthesis is unclear. In this study, we attempted to increase iturin A production via strengthening fatty acid synthesis pathways in Bacillus amyloliquefaciens. First, acetyl-CoA carboxylase AccAD and ACP S-malonyltransferase fabD were overexpressed via promoter replacement, and iturin A yield was increased to 1.36 g/L by 2.78-fold in the resultant strain HZ-ADF1. Then, soluble acyl-ACP thioesterase derived from Escherichia coli showed the best performance for iturin A synthesis, as compared to those derived from B. amyloliquefaciens and Corynebacterium glutamicum, the introduction of which in HZ-ADF1 further led to a 57.35% increase of iturin A yield, reaching 2.14 g/L. Finally, long-chain fatty acid-CoA ligase LcfA was overexpressed in HZ-ADFT to attain the final strain HZ-ADFTL2, and iturin A yield reached 2.96 g/L, increasing by 6.59-fold, and the contents of fatty acids were enhanced significantly in HZ-ADFTL2, as compared to the original strain HZ-12. Taken together, our results implied that strengthening fatty acid supplies was an efficient approach for iturin A production, and this research provided a promising strain for industrial production of iturin A.

Genomic and transcriptomic analyses provide insights into valuable fatty acid biosynthesis and environmental adaptation of yellowhorn.

Yellowhorn (Xanthoceras sorbifolium) is an oil-bearing tree species growing naturally in poor soil. The kernel of yellowhorn contains valuable fatty acids like nervonic acid. However, the genetic basis underlying the biosynthesis of valued fatty acids and adaptation to harsh environments is mainly unexplored in yellowhorn. Here, we presented a haplotype-resolved chromosome-scale genome assembly of yellowhorn with the size of 490.44 Mb containing scaffold N50 of 34.27 Mb. Comparative genomics, in combination with transcriptome profiling analyses, showed that expansion of gene families like long-chain acyl-CoA synthetase and ankyrins contribute to yellowhorn fatty acid biosynthesis and defense against abiotic stresses, respectively. By integrating genomic and transcriptomic data of yellowhorn, we found that the transcription of 3-ketoacyl-CoA synthase gene XS04G00959 was consistent with the accumulation of nervonic and erucic acid biosynthesis, suggesting its critical regulatory roles in their biosynthesis. Collectively, these results enhance our understanding of the genetic basis underlying the biosynthesis of valuable fatty acids and adaptation to harsh environments in yellowhorn and provide foundations for its genetic improvement.

Repositioning of FDA-Approved antifungal agents to interrogate Acyl-CoA synthetase long chain family member 4 (ACSL4) in ferroptosis

Ferroptosis, first coined in 2012, is an iron-dependent regulated cell death (RCD) characterized by the accumulation of lipid peroxides to toxic levels. This mechanism is currently being evaluated as a target for a variety of diseases offering new opportunities for drug design and development. Recent reports uncovered acyl-CoA synthetase long-chain 4 (ACSL4) as a critical contributor to ferroptosis execution. Therefore, ACSL4 inhibitors are emerging as attractive anti-ferroptotic agents. Herein, we developed a robust screening cascade with orthogonal biophysical and biochemical techniques to identify original human ACSL4 inhibitors. By screening an FDA-approved drug library, we were able to identify and validate new inhibitors with micromolar-range activities against ACSL4. With an IC50 of 280 nM against hACSL4, antifungal agent sertaconazole is to our knowledge, the most potent ACSL4 inhibitor identified so far. In addition, sertaconazole significantly reduced lipid peroxidation and ferroptosis in human differentiated dopaminergic neurons (Lund human mesencephalic LUHMES cells), demonstrating that it is a valuable chemical tool for further investigating the role of ACSL4 in ferroptosis. This study highlights the phenethyl-imidazole scaffold as a novel and promising starting point for the development of anti-ferroptotic agents targeting ACSL4.

The PoLACS4 Gene May Participate in Drought Stress Resistance in Tree Peony (Paeonia ostii 'Feng Dan Bai').

The tree peony (Paeonia ostii ‘Feng Dan Bai’) has excellent drought tolerance. Although it has already been reported that the cuticle is an essential barrier against drought stress, the critical genes for cuticle resistance to drought remain unclear. However, the long-chain acyl-CoA synthetases (LACS) family of genes may be significant for the synthesis of cuticle wax. To test whether the LACS gene family is involved in cuticle response to drought stress in tree peony, we measure the thickness of cuticle stems and leaves alongside LACS enzyme activity. It is found that the cuticle thickens and the LACS enzyme increases with the maturation of stems and leaves, and there is a positive correlation between them. The LACS enzyme increases within 12 h under drought stress induced by polyethylene glycol (PEG). The transcriptome sequencing result (BioProject accession number PRJNA317164) is searched for, and a LACS gene with high expression is cloned. This gene has high homology and similarity with LACS4 from Arabidopsis thaliana. The gene is named PoLACS4. It is show to be highly expressed in mature leaves and peaks within 1 h under drought and salt stresses. All these results suggest that the LACS family of genes may be involved in cuticle response to drought stress and that PoLACS4 is a crucial gene which responds rapidly to drought in the tree peony.