Mechanisms Of Fatty Acid Metabolism Research Articles

Association between fatty acid metabolism gene mutations and Mycobacterium tuberculosis transmission revealed by whole genome sequencing

BackgroundFatty acid metabolism greatly promotes the virulence and pathogenicity of Mycobacterium tuberculosis (M.tb). However, the regulatory mechanism of fatty acid metabolism in M.tb remains to be elucidated, and limited evidence about the effects of gene mutations in fatty acid metabolism on the transmission of M.tb was reported.ResultsOverall, a total of 3193 M.tb isolates were included in the study, of which 1596 (50%) were genomic clustered isolates. Most of the tuberculosis isolates belonged to lineage2(n = 2744,85.93%), followed by lineage4(n = 439,13.75%) and lineage3(n = 10,0.31%).Regression results showed that the mutations of gca (136,605, 317G > C, Arg106Pro; OR, 22.144; 95% CI, 2.591-189.272), ogt(1,477,346, 286G > C ,Gly96Arg; OR, 3.893; 95%CI, 1.432–10.583), and rpsA (1,834,776, 1235 C > T, Ala412Val; OR, 3.674; 95% CI, 1.217–11.091) were significantly associated with clustering; mutations in gca and rpsA were also significantly associated with clustering of lineage2. Mutation in arsA(3,001,498, 885 C > G, Thr295Thr; OR, 6.278; 95% CI, 2.508–15.711) was significantly associated with cross-regional clusters. We also found that 20 mutation sites were positively correlated with cluster size, while 11 fatty acid mutation sites were negatively correlated with cluster size.ConclusionOur research results suggested that mutations in genes related to fatty acid metabolism were related to the transmission of M.tb. This research could help in the future control of the transmission of M.tb.

NSD2 methylates AROS to promote SIRT1 activation and regulates fatty acid metabolism-mediated cancer radiotherapy

Fatty acid metabolism plays a critical role in both tumorigenesis and cancer radiotherapy. However, the regulatory mechanism of fatty acid metabolism has not been fully elucidated. NSD2, a histone methyltransferase that catalyzes di-methylation of histone H3 at lysine 36, has been shown to play an essential role in tumorigenesis and cancer progression. Here, we show that NSD2 promotes fatty acid oxidation (FAO) by methylating AROS (active regulator of SIRT1) at lysine 27, facilitating the physical interaction between AROS and SIRT1. The mutation of lysine 27 to arginine weakens the interaction between AROS and SIRT1 and impairs AROS-SIRT1-mediated FAO. Additionally, we examine the effect of NSD2 inhibition on radiotherapy efficacy and find an enhanced effectiveness of radiotherapy. Together, our findings identify a NSD2-dependent methylation regulation pattern of the AROS-SIRT1 axis, suggesting that NSD2 inhibition may be a potential adjunct for tumor radiotherapy.

Huangqin Decoction ameliorates ulcerative colitis by regulating fatty acid metabolism to mediate macrophage polarization via activating FFAR4-AMPK-PPARα pathway.

Huangqin Decoction (HQD), a traditional Chinese medicine (TCM) formula chronicled in Shang Han Lun, is safe and effective for treatment of ulcerative colitis (UC). To investigate the effect of HQD against dextran sulfate sodium (DSS)-induced UC mice by regulating gut microbiota and metabolites, and further explore the mechanism of fatty acid metabolism on macrophage polarization. Based on 3% dextran sulfate sodium (DSS)-induced UC mice model, clinical symptoms observation (body weight, DAI, and colon length) and histological inspection were used to evaluate the efficacy of HQD and fecal microbiota transplantation (FMT) from HQD-treated mice. The gut microbiota and metabolites were detected by 16S rRNA sequencing and metabolomics analysis. The parameters of fatty acid metabolism, macrophage polarization, and FFAR1/FFAR4-AMPK-PPARα pathway were analyzed by immunofluorescence analysis, western blotting, and real-time PCR. Then, the effects of FFAR1 and FFAR4 on macrophage polarization were examined by agonists based on LPS-induced RAW264.7cell model. The results showed that FMT, like HQD, ameliorated UC by improving weight loss, restoring colon length, and reducing DAI scores and histopathological scores. Besides, HQD and FMT both enhanced the richness of gut microbiota, and modulated intestinal bacteria and metabolites to achieve a new balance. Untargeted metabolomics analysis revealed that fatty acids, especially long-chain fatty acids (LCFAs), dominated in HQD against DSS-induced UC by regulating the gut microenvironment. Further, FMT and HQD recovered the expression of fatty acid metabolism-related enzymes, and simultaneously activated FFAR1/FFAR4-AMPK-PPARα pathway but suppressed NF-κB pathway. Combined with cell experiment, HQD and FMT promoted macrophage polarization from M1 toward M2, which were well associated with anti-inflammatory cytokines and combined with the activated FFAR4. The mechanism of HQD against UC was related to regulating fatty acid metabolism to mediate M2 macrophage polarization by activating the FFAR4-AMPK-PPARα pathway.

Identification of fatty acid signature to predict prognosis and guide clinical therapy in patients with ovarian cancer.

High-grade serous ovarian cancer (HGSOC) is a heterogeneous cancer characterized by high relapse rate. Approximately 80% of women are diagnosed with late-stage disease, and 15–25% of patients experience primary treatment resistance. Ovarian cancer brings tremendous suffering and is the most malignant type in all gynecologic malignancies. Metabolic reprogramming in tumor microenvironment (TME), especially fatty acid metabolism, has been identified to play a crucial role in cancer prognosis. Yet, the underlying mechanism of fatty acid metabolism on ovarian cancer progression is severely understudied. Recently, studies have demonstrated the role of fatty acid metabolism reprogramming in immune cells, but their roles on cancer cell metastasis and cancer immunotherapy response are poorly characterized. Here, we reported that the fatty acid–related genes are aberrantly varied between ovarian cancer and normal samples. Using samples in publicly databases and bio-informatic analyses with fatty acid–related genes, we disentangled that cancer cases can be classified into high- and low-risk groups related with prognosis. Furthermore, the nomogram model was constructed to predict the overall survival. Additionally, we reported that different immune cells infiltration was presented between groups, and immunotherapy response differed in two groups. Results showed that our signature may have good prediction value on immunotherapy efficacy, especially for anti–PD-1 and anti–CTLA-4. Our study systematically marked the critical association between cancer immunity in TME and fatty acid metabolism, and bridged immune phenotype and metabolism programming in tumors, thereby constructed the metabolic-related prognostic model and help to understand the underlying mechanism of immunotherapy response.

EPHX2 Inhibits Colon Cancer Progression by Promoting Fatty Acid Degradation

Tumor cells use metabolic reprogramming to keep up with the need for bioenergy, biosynthesis, and oxidation balance needed for rapid tumor division. This phenomenon is considered a marker of tumors, including colon cancer (CRC). As an important pathway of cellular energy metabolism, fatty acid metabolism plays an important role in cellular energy supply and oxidation balance, but presently, our understanding of the exact role of fatty acid metabolism in CRC is limited. Currently, no lipid metabolism therapy is available for the treatment of CRC. The establishment of a lipidmetabolism model regulated by oncogenes/tumor suppressor genes and associated with the clinical characteristics of CRC is necessary to further understand the mechanism of fatty acid metabolism in CRC. In this study, through multi-data combined with bioinformatic analysis and basic experiments, we introduced a tumor suppressor gene, EPHX2, which is rarely reported in CRC, and confirmed that its inhibitory effect on CRC is related to fatty acid degradation.

Circ01592 regulates unsaturated fatty acid metabolism through adsorbing miR-218 in bovine mammary epithelial cells.

The composition of fatty acids plays a key role in regulating milk flavor and quality. Therefore, to improve the quality of milk, it is particularly important to study the regulatory mechanism of fatty acid metabolism in dairy cows. In this study, the expression profiles at non-lactation, peak-lactation, mid-lactation and late-lactation were constructed by high-throughput sequencing. Considering non-lactation as the control group and the other points as the experimental groups, the differentially expressed genes were screened. ELOVL5 was significantly upregulated and was selected for subsequent analyses. Bioinformatics prediction, a dual-luciferase assay, qPCR analysis and western blot analysis were used for verification. The results showed that ELOVL5 was a downstream target gene of miR-218 that regulated milk fat metabolism. A dual-luciferase assay and expression level analysis showed that circ01592 can directly bind to miR-218 and that overexpression of circ01592 (pcDNA-circ01592) significantly reduced the expression of miR-218 and enhanced the expression of ELOVL5, the target gene of miR-218 in BMECs. A functional study of BMECs showed that circ01592 promoted the synthesis of TAG and increased the content of UFA. The function of miR-218 was opposite to that of circ01592. Overall, the data showed that circ01592 promoted TAG synthesis and fatty acid composition by binding miR-218, alleviating the inhibitory effect of miR-218 on ELOVL5 expression. These mechanisms provide a new research approach and theoretical basis for improving milk quality.

Complementary transcriptome and proteome profiling in the mature seeds of Camellia oleifera from Hainan Island.

Camellia oleifera Abel. (C. oleifera), as an important woody tree species producing edible oils in China, has attracted enormous attention due to its abundant unsaturated fatty acids and their associated benefits to human health. To reveal novel insights into the characters during the maturation period of this plant as well as the molecular basis of fatty acid biosynthesis and degradation, we conducted a conjoint analysis of the transcriptome and proteome of C. oleifera seeds from Hainan Island. Using RNA sequencing (RNA-seq) technology and shotgun proteomic method, 59,391 transcripts and 40,500 unigenes were obtained by TIGR Gene Indices Clustering Tools (TGICL), while 1691 protein species were identified from Mass Spectrometry (MS). Subsequently, all genes and proteins were employed in euKaryotic Orthologous Groups (KOG) classification, Gene Ontology (GO) annotation, and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis to investigate their essential functions. The results indicated that the most abundant pathways were biological metabolic processes. There were 946 unigenes associated with lipid metabolism at the transcriptome level, with 116 proteins at the proteome level; among these, 38 specific proteins were involved in protein-protein interactions, with the majority being related to fatty acid catabolic process. The expression levels of 21 candidate unigenes encoding target proteins were further detected by quantitative real-time polymerase chain reaction (qRT-PCR). Finally, Gas Chromatography Mass Spectrometry (GC-MS) was carried out to determine the fatty acid composition of C. oleifera oil. These findings not only deepened our understanding about the molecular mechanisms of fatty acid metabolism but also offered new evidence concerning the roles of relevant proteins in oil-bearing crops. Furthermore, the lipid-associated proteins recognized in this research might be helpful in providing a reference for the synthetic regulation of C. oleifera oil quality by genetic engineering techniques, thus resulting in potential application in agriculture.

A novel quantitative trait locus on chromosome A9 controlling oleic acid content in Brassica napus.

SummaryOne of the most important goals in the breeding of oilseed crops, including Brassica napus, is to improve the quality of edible vegetable oil, which is mainly determined by the seed fatty acid composition, particularly the C18:1 content. Previous studies have indicated that the C18:1 content is a polygenic trait, and no stable quantitative trait loci (QTLs) except for FAD2 have been reported. By performing a GWAS using 375 low erucic acid B. napus accessions genotyped with the Brassica 60K SNP array and constructing a high‐density SNP‐based genetic map of a 150 DH population, we identified a novel QTL on the A9 chromosome. The novel locus could explain 11.25%, 5.72% and 6.29% of phenotypic variation during three consecutive seasons and increased the C18:1 content by approximately 3%–5%. By fine mapping and gene expression analysis, we found three potential candidate genes and verified the fatty acids in a homologous gene mutant of Arabidopsis. A metal ion‐binding protein was found to be the most likely candidate gene in the region. Thus, the C18:1 content can be further increased to about 80% with this novel locus together with FAD2 mutant allele without compromise of agronomic performance. A closely linked marker, BnA129, for this novel QTL (OLEA9) was developed so that we can effectively identify materials with high C18:1 content at an early growth stage by marker‐assisted selection. Our results may also provide new insight for understanding the complex genetic mechanism of fatty acid metabolism.

Enhancing microRNA167A expression in seed decreases the α-linolenic acid content and increases seed size in Camelina sativa.

Despite well established roles of microRNAs in plant development, few aspects have been addressed to understand their effects in seeds especially on lipid metabolism. In this study, we showed that overexpressing microRNA167A (miR167OE) in camelina (Camelina sativa) under a seed-specific promoter changed fatty acid composition and increased seed size. Specifically, the miR167OE seeds had a lower α-linolenic acid with a concomitantly higher linoleic acid content than the wild-type. This decreased level of fatty acid desaturation corresponded to a decreased transcriptional expression of the camelina fatty acid desaturase3 (CsFAD3) in developing seeds. MiR167 targeted the transcription factor auxin response factor (CsARF8) in camelina, as had been reported previously in Arabidopsis. Chromatin immunoprecipitation experiments combined with transcriptome analysis indicated that CsARF8 bound to promoters of camelina bZIP67 and ABI3 genes. These transcription factors directly or through the ABI3-bZIP12 pathway regulate CsFAD3 expression and affect α-linolenic acid accumulation. In addition, to decipher the miR167A-CsARF8 mediated transcriptional cascade for CsFAD3 suppression, transcriptome analysis was conducted to implicate mechanisms that regulate seed size in camelina. Expression levels of many genes were altered in miR167OE, including orthologs that have previously been identified to affect seed size in other plants. Most notably, genes for seed coat development such as suberin and lignin biosynthesis were down-regulated. This study provides valuable insights into the regulatory mechanism of fatty acid metabolism and seed size determination, and suggests possible approaches to improve these important traits in camelina.

Cloning and functional expression of a cDNA encoding stearoyl-ACP Δ9-desaturase from the endosperm of coconut (Cocos nucifera L.)

Coconut (Cocos nucifera L.) is an economically tropical fruit tree with special fatty acid compositions. The stearoyl-acyl carrier protein (ACP) desaturase (SAD) plays a key role in the properties of the majority of cellular glycerolipids. In this paper, a full-length cDNA of a stearoyl-acyl carrier protein desaturase, designated CocoFAD, was isolated from cDNA library prepared from the endosperm of coconut (C. nucifera L.). An 1176bp cDNA from overlapped PCR products containing ORF encoding a 391-amino acid (aa) protein was obtained. The coded protein was virtually identical and shared the homology to other Δ9-desaturase plant sequences (greater than 80% as similarity to that of Elaeis guineensis Jacq). The real-time fluorescent quantitative PCR result indicated that the yield of CocoFAD was the highest in the endosperm of 8-month-old coconut and leaf, and the yield was reduced to 50% of the highest level in the endosperm of 15-month-old coconut. The coding region showed heterologous expression in strain INVSc1 of yeast (Saccharomyces cerevisiae). GC–MS analysis showed that the levels of palmitoleic acid (16:1) and oleic acid (18:1) were improved significantly; meanwhile stearic acid (18:0) was reduced. These results indicated that the plastidial Δ9 desaturase from the endosperm of coconut was involved in the biosynthesis of hexadecenoic acid and octadecenoic acid, which was similar with other plants. These results may be valuable for understanding the mechanism of fatty acid metabolism and the genetic improvement of CocoFAD gene in palm plants in the future.

Overexpression of NgAUREO1, the gene coding for aurechrome 1 from Nannochloropsis gaditana, into Saccharomyces cerevisiae leads to a 1.6-fold increase in lipid accumulation

Aureochrome-1 (AUREO1) is a transcription factor that is induced by blue light and controls branching of Vaucheria frigida. We have cloned the gene, NgAUREO1, coding for AUREO1 from Nannochloropsis gaditana, and report that the lipid content in recombinant Saccharomyces cerevisiae was 1.6-fold more than in wild-type S. cerevisiae (6.3 % lipid increased to 10 %). Over-expression of AUREO1 in S. cerevisiae up-regulated the expression of acetyl-CoA carboxylase and acyl-CoA:diacylglycerol acyl-transferase but down-regulated the expression of long-chain-acyl CoA synthetase. This enhanced the accumulation of lipid. This study highlights a novel function of AUREO1 and allows a better understanding of the regulation mechanism of fatty acid metabolism.

Effect of SCD and SREBP genotypes on fatty acid composition in adipose tissue of Japanese Black cattle herds

Fatty acid composition of beef adipose tissue is one of important traits because high proportions of monounsaturated fatty acid are related to favorable beef flavor and tenderness. In this study, we investigated effects of genetic factors such as stearoyl-CoA desaturase (SCD) and sterol regulatory element binding protein (SREBP) on beef carcass traits including fatty acid composition using two cattle populations. Sire effect was significantly related to almost all traits except BMS, suggesting that the trait examined in this study is highly controlled by genetic factors. The effect of SCD genotype on fatty acid composition was detected remarkably in both cattle groups, especially on stearic and oleic acids. This result was consistent with our previous studies and suggests that SCD is associated with fatty acid composition. Unlike SCD genotyping, the effect of SREBP genotype was not identified in this study. Our results suggested that SCD genotype would contribute to improving beef quality in field populations. Further studies about the relationship among these factors will bring an insight into the molecular mechanism of fatty acid metabolism in cattle.

Regulatory Mechanism of Fatty Acid Metabolism

Regulatory Mechanism of Fatty Acid Metabolism

Ethyl ω-Fluoroacetoacetate

ACETOACETIC acid is an important and widespread intermediary metabolite, being formed in the oxida-tive degradation of fatty acids and of certain amino-acids. For comparison with acetoacetic acid, we have prepared1 the compound ethyl ω-fluoroacetoacetate, FCH2COCH2COOC2H5. From a consideration of its structural similarity to 4-fluorobutyric acid2 and of its probable interference with the mechanism of fatty acid metabolism, we predicted that it would produce toxic symptoms.