Delta-6 Desaturase Research Articles

Asiatic acid ameliorates rifampicin- and isoniazid-induced liver injury in vivo by regulating sphingolipid metabolism and mitogen-activated protein kinase signalling pathways.

In this study, we aimed to determine whether asiatic acid (AA) exerts any therapeutic effects on rifampicin (RFP)- and isoniazid (INH)-induced liver injury and elucidate the underlying mechanisms. Briefly, liver injury in mice was induced via RFP and INH administration. We investigated the effects and potential action mechanisms of AA on liver injury using transcriptomics, metabolomics and various examinations. We found that AA significantly ameliorated the pathological changes in liver tissues and decreased the transaminase activity, inflammation and oxidative stress damage. Transcriptomics revealed 147 differentially expressed genes (DEGs) between the AA and model groups that were enriched in metabolic and mitogen-activated protein kinase (MAPK) signalling pathways. Metabolomics revealed 778 differentially expressed metabolites between the AA and model groups. Furthermore, integrated transcriptomics and metabolomics analyses revealed strong correlations between DEGs and differentially expressed metabolites and indicated that AA regulates the sphingolipid metabolism by inhibiting the expression of delta 4-desaturase, sphingolipid 1. Experimental results confirmed that AA inhibited the MAPK signalling pathway. In summary, AA inhibits inflammation and oxidative stress damage by regulating the sphingolipid metabolism pathway and blocking the MAPK signalling pathway, thereby relieving the RFP/INH-induced liver injury.

Dietary and plasma retinoids are not associated with fatty acid desaturase indices in healthy young adults.

Past research in rodents suggests that fatty acid (FA) desaturase expression and activity may be modified by vitamin A; however, this has not been investigated in humans. The primary objective of this study was to examine associations between dietary retinoid intakes, plasma retinoid concentrations, and FA desaturase indices in young adults. As a secondary objective, biological sex and estrogen-containing contraceptive (EC) use were investigated due to prior evidence demonstrating that both can influence plasma retinol concentration and FA desaturase indices. Dietary retinoid intake (food frequency questionnaire), plasma retinoid concentrations (high-performance liquid chromatography-tandem mass spectrometry), plasma FA (gas chromatography), and FA desaturase indices (product-to-precursor ratios) from 945 adults recruited for the cross-sectional Toronto Nutrigenomics and Health study were analyzed. Participants were stratified into quartiles based on plasma retinol concentration and data analyzed by one-way analysis of covariance. Dietary retinoid intakes were not associated with the overall n-3 pathway, overall n-6 pathway, delta-5 desaturase, delta-6 desaturase, or delta-9 desaturase indices (all r < 0.10, p > 0.05). The overall n-6 pathway index was significantly higher (p = 0.0004) and the delta-5 desaturase index was significantly lower (p = 0.0003) in individuals with higher plasma retinol levels; however, these differences were lost when participants were grouped by biological sex and EC use. Although weak relationships were observed between plasma retinol and some FA desaturase indices in the total population, these associations appear to be driven by biological sex and EC usage rather than retinoids. We therefore find little evidence of a relationship between retinoids and FA desaturase indices in young, healthy adults.

Transcriptome analysis provides insight into gamma irradiation delaying quality deterioration of postharvest Lentinula edodes during cold storage

To better determine how gamma irradiation (GI) improves abiotic stress resistance, a transcriptome analysis of postharvest L. edodes in response to 1.0 kGy GI was conducted, and further the underlying mechanism of GI in delaying quality deterioration over 20 d of cold storage was explored. The results suggested that GI was involved in multiple metabolic processes in irradiated postharvest L. edodes. In comparison with the control group, the GI group contained 430 differentially expressed genes, including 151 upregulated genes and 279 downregulated genes, which unveiled characteristic expression profiles and pathways. The genes involved in the pentose phosphate pathway were mainly upregulated and the expression level of the gene encoding deoxy-D-gluconate 3-dehydrogenase was 9.151-fold higher. In contrast, the genes related to other energy metabolism pathways were downregulated. Concurrently, GI inhibited the expression of genes associated with delta 9-fatty acid desaturase, ribosomes, and HSP20; thus, GI helped postpone the degradation of lipid components, suppress transcriptional metabolism and regulate the stress response. Additionally, the metabolic behavior of DNA repair induced by GI intensified by noticeable upregulation. These regulatory effects could play a potential and nonnegligible role in delaying the deterioration of L. edodes quality. The results provide new information on the regulatory mechanism of postharvest L. edodes when subjected to 1.0 kGy GI during cold storage.

FADS1-arachidonic acid axis enhances arachidonic acid metabolism by altering intestinal microecology in colorectal cancer

Colonocyte metabolism shapes the microbiome. Metabolites are the main mediators of information exchange between intestine and microbial communities. Arachidonic acid (AA) is an essential polyunsaturated fatty acid and its role in colorectal cancer (CRC) remains unexplored. In this study, we show that AA feeding promotes tumor growth in AOM/DSS and intestinal specific Apc−/− mice via modulating the intestinal microecology of increased gram-negative bacteria. Delta-5 desaturase (FADS1), a rate-limiting enzyme, is upregulated in CRC and effectively mediates AA synthesis. Functionally, FADS1 regulates CRC tumor growth via high AA microenvironment-induced enriched gram-negative microbes. Elimination of gram-negative microbe abolishes FADS1 effect. Mechanistically, gram-negative microbes activate TLR4/MYD88 pathway in CRC cells that contributes FADS1-AA axis to metabolize to prostaglandin E2 (PGE2). Cumulatively, we report a potential cancer-promoting mechanism of FADS1-AA axis in CRC that converts raising synthesized AA to PGE2 via modulating the intestinal microecology of gram-negative.

Gly-Pro-Val-Gly-Pro-Ser Peptide Fish Collagen Improves Skin Moisture and Wrinkles with Ameliorated the Oxidative Stress and Pro-inflammatory Factors in Skin Photoaging Mimic Models.

This study aimed to investigate whether low molecular fish collagen peptide (FC) from Oreochromis niloticus had protective effects on skin of photoaging mimic models. We observed that FC supplementation improved antioxidant enzymes activities and regulated the pro-inflammatory cytokines [e.g., tumor necrosis factor-α, interleukin (IL)-1β, and IL-6] by reducing the protein expressions of pro-inflammatory factors IκBα, p65, and cyclooxygenase-2 in ultraviolet-B (UV-B) irradiated in vitro and in vivo. Furthermore, FC increased hyaluronic acid, sphingomyelin, and skin hydration by reg-ulating the mRNA expression of hyaluronic acid synthases 1∼3, serine palmitoyltransferase 1, delta 4-desaturase, sphingolipid 1, and protein expressions of ceramide synthase 4, matrix metalloproteinase (MMP)-1, -2, and -9. In UV-B irradiated in vitro and in vivo, FC down-regulated the protein expression of the c-Jun N-terminal kinase, c-Fos, c-Jun, and MMP pathways and up-reg-ulated that of the transforming growth factor-β receptor I, collagen type I, procollagen type I, and small mothers against decapentaplegic homolog pathways. Our results suggest that FC can be effective against UV-B induced skin photoaging by improving skin dryness and wrinkle formation through antioxidant and anti-inflammatory properties.

Combining a Mutant Allele of FAD2-1A with HD Improves the ω-6/ω-3 Ratio in Soybeans

The intake of foods with unbalanced ω-6/ω-3 ratios causes various health problems. Commodity soybeans generally have a ω-6/ω-3 ratio of 6–7:1. The recommended ratio in terms of health benefits is &lt;4:1. This study aimed to identify the appropriate combination of mutant alleles that can reduce the ω-6/ω-3 ratio using three segregating soybean populations. F2 individuals from each population were genotyped for three different alleles of microsomal delta-12 fatty acid desaturase 2 enzyme (FAD2-1A) and an allele of homeodomain-like transcriptional regulator (HD) genes, and their five major fatty acids were assessed. F2 seeds carrying both fad2-1a and hd had slightly different ω-6/ω-3 ratios according to the different fad2-1a alleles. The fad2-1aDEL, fad2-1aS117N, and fad2-1aW293STOP alleles combined with a hd allele resulted in ω-6/ω-3 ratios with a range of 1.9–2.7:1, 2.7–3.9:1, and 2.6–3.6:1 in soybean seeds, respectively. This study revealed that the induction of mutations in FAD2-1ADEL and HD was the most efficient strategy to improve the ω-6/ω-3 ratio and elevate the ω-3 fatty acid concentrations in soybean seeds. These results provide useful information in soybean breeding programs to release a new soybean cultivar with a lower ω-6/ω-3 ratio and elevated ω-3 fatty acids, which can be a beneficial ingredient for soybean-based foods.

Genome-wide comparative identification and analysis of membrane-FADS-like superfamily genes in freshwater economic fishes.

Membrane fatty acid desaturase (FADS)-like superfamily proteins (FADSs) are essential for the synthesis of unsaturated fatty acids (UFAs). Recently, studies on FADS in fishes have mostly focused on marine species, and a comprehensive analysis of the FADS superfamily, including the FADS, stearoyl-CoA desaturase (SCD), and sphingolipid delta 4-desaturase (DEGS) families, in freshwater economic fishes is urgently required. To this end, we conducted a thorough analysis of the number, gene/protein structure, chromosomal location, gene linkage map, phylogeny, and expression of the FADS superfamily. We identified 156 FADSs genes in the genome of 27 representative species. Notably, FADS1 and SCD5 were lost in most freshwater fish and other teleosts. All FADSs proteins contain 4 transmembrane helices and 2-3 amphipathic α-helices. FADSs in the same family are often linked on the same chromosome; moreover, FADS and SCD or DEGS are frequently collocated on the same chromosome. In addition, FADS, SCD, and DEGS family proteins share similar evolutionary patterns. Interestingly, FADS6, as a member of the FADS family, exhibits a similar gene structure and chromosome location to that of SCD family members, which may be the transitional form of FADS and SCD. This study shed light on the type, structure, and phylogenetic relationship of FADSs in freshwater fishes, offering a new perspective into the functional mechanism analysis of FADSs.

Effect of Adding Cellulose on Lipid Accumulation in Cellobiohydrolase and Delta-6 Desaturase Engineered Mucor circinelloides Strains

Effect of Adding Cellulose on Lipid Accumulation in Cellobiohydrolase and Delta-6 Desaturase Engineered Mucor circinelloides Strains

Effects of Temperature and Salt Stress on the Expression of delta-12 Fatty Acid Desaturase Genes and Fatty Acid Compositions in Safflower.

The regulation of microsomal (e.g., FAD2) and plastidial (e.g., FAD6) oleate desaturases by cold, heat and salt stress were investigated. Gene expression levels and fatty acid compositions were determined in the roots, stems and leaves of safflower following stress treatments. A safflower plastidial oleate desaturase gene, CtFAD6, was cloned, and oleic acid desaturation was confirmed in Synechococcus sp. strain PCC7942. The results showed that temperature regulated oleate desaturation at the transcriptional level, and this regulation pattern was tissue-specific. CtFAD2-1, CtFAD2-2 and CtFAD6 were significantly induced under cold and heat stress in young leaves, and CtFAD2-2 and CtFAD6 were slightly induced in young stems. In contrast, CtFAD2-1, CtFAD2-11 and CtFAD2-10 were sensitive to salt stress in all safflower tissues (roots, stem and leaves). CtFAD6 was insensitive to salt and was slightly induced in leaves only.

The effect of dietary lecithin and lipid levels on the growth performance, body composition, hemolymph parameters, immune responses, body texture, and gene expression of juvenile white shrimp (Litopenaeus vannamei)

This study evaluated the effects of dietary soy lecithin and lipid levels on lipid utilization by white shrimp (Litopenaeus vannamei). Ten isonitrogenous experimental diets were formulated with three levels of lipid (7%, 9%, and 11%) and three levels of soy lecithin (0.6%, 1.2%, and 1.8%), and one diet with a 7% lipid level and without lecithin was the control diet; all the diets contained approximately 38.5% protein with 20% fish meal. A total of 600 shrimps (initial weight: 1.02 ± 0.01 g) were randomly assigned to thirty 96-L glass tanks (10 dietary groups × 3 replicates) in a recirculation system for 8 weeks. The shrimps were fed to near satiation with three meals daily for 8 weeks. Regardless of lecithin levels, final biomass, biomass gain, whole-body and hepatopancreatic lipid concentrations, hemolymph triglyceride (TG), cholesterol concentrations, superoxide dismutase (SOD), muscle gumminess, chewiness, and cohesiveness values increased with increasing dietary lipid levels. Hemolymph glutathione peroxidase (GPx) and muscle hardness exhibited an increased trend with increment of dietary lipid and lecithin levels. The highest values of these parameters were observed in shrimp fed the diet with 11% lipid and 1.8% lecithin. Delta-6-desaturase (D-6) gene expression in the hepatopancreas of the white shrimp showed the best expression in diets containing 9% lipid and 1.8% lecithin. Hepatopancreatic GPx and lipase expression in the white shrimp fed the 1.8% lecithin diet was higher than those in shrimp fed diets with other lecithin levels. The results suggested that the white shrimp fed the diet with 11% lipid and 1.8% lecithin exhibited the optimal growth performance, hemolymph parameters, body texture, and immune responses.

CRISPR/Cas9-mediated precision integration of fat-1 and fat-2 from Caenorhabditis elegans at long repeated sequence in channel catfish (Ictalurus punctatus) and the impact on n-3 fatty acid level

Omega-3 polyunsaturated fatty acids (n-3 PUFAs), especially eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are essential for the development and health of human and animals. However, n-3 PUFAs in human diets, aquaculture and livestock feed are mainly from oily marine fishes. To improve n-3 fatty acid levels in channel catfish (Ictalurus punctatus), we generated transgenic channel catfish carrying codon optimized Caenorhabditis elegans fat-1 gene encoding an n-3 fatty acid desaturase and fat-2 gene encoding the delta12 fatty acid desaturase using CRISPR/Cas9 technology. We used a special cocktail design of donor plasmid, utilized mixed HDR, MMEJ and NHEJ repair pathways, and targeted long repeated DNA target sequence (LRS) to improve knock-in (KI) efficiency. Our results showed that two donor DNAs precisely inserted into at least four genomic sites. Detectable on-target KI efficiency of fat-1 was 9.1% (55/605), three times higher than that of fat-2, which might due to the smaller size of the donor fat-1. Sanger sequencing results suggested that HDR was the dominant repair pathway using this method, leading to the highest proportion of on-target KI events. Reverse transcription PCR (RT-PCR) and quantitative real-time PCR (qRT-PCR) demonstrated that the fat-1 and fat-2 transgenes had strong expression, and also greatly improved fads6, elovl2 and elovl5 gene expression in liver and muscle tissues of transgenic channel catfish. Fatty acid analysis showed the fat-1-only transgenic channel catfish had the lower levels of 14:0, 16:0, 18:2n-6, total n-6, and the higher levels of DHA, total n-3 and n-3/n-6 ratio than other genotypes including the fat-2-only, co-integration of fat-1 and fat-2, and wild-type control. In particular, DHA, total n-3 and n-3/n-6 ratio were significantly increased by 37%, 19.8% and 25.2%, respectively, in the fat-1-only transgenic fish than that in the wild-type control (P < 0.05). Our fat-1 and fat-2 KI channel catfish hold promise for improving fish nutritional value, reducing fish oil requirement in aquaculture feed, and serving as an alternative source of n-3 PUFAs.

Depletion of stearoyl-CoA desaturase (scd) leads to fatty liver disease and defective mating behavior in zebrafish.

Stearyl coenzyme A desaturase (SCD), also known as delta-9 desaturase, catalyzes the rate-limiting step in the formation of monounsaturated fatty acids. In mammals, depletion or inhibition of SCD activity generally leads to a decrease in triglycerides and cholesteryl esters. However, the endogenous role of scd in teleost fish remains unknown. Here, we generated a zebrafish scd mutant (scd-/-) to elucidate the role of scd in lipid metabolism and sexual development. Gas chromatography-mass spectrometry (GC-MS) showed that the scd-/- mutants had increased levels of saturated fatty acids C16:0 and C18:0, and decreased levels of monounsaturated fatty acids C16:1 and C18:1. The mutant fish displayed a short stature and an enlarged abdomen during development. Unlike Scd-/- mammals, the scd-/- zebrafish showed significantly increased fat accumulation in the whole body, especially in the liver, leading to hepatic mitochondrial dysfunction and severe cell apoptosis. Mechanistically, srebf1, a gene encoding a transcriptional activator related to adipogenesis, acc1 and acaca, genes involved in fatty acid synthesis, and dgat2, a key gene involved in triglyceride synthesis, were significantly upregulated in mutant livers to activate fatty acid biosynthesis and adipogenesis. The scd-/- males exhibited defective natural mating behavior due to defective genital papillae but possessed functional mature sperm. All defects in the scd-/- mutants could be rescued by ubiquitous transgenic overexpression of scd. In conclusion, our study demonstrates that scd is indispensable for maintaining lipid homeostasis and development of secondary sexual characteristics in zebrafish.

Lipid desaturation regulates the balance between self-renewal and differentiation in mouse blastocyst-derived stem cells

Stem cells are defined by their ability to self-renew and differentiate, both shown in multiple studies to be regulated by metabolic processes. To decipher metabolic signatures of self-renewal in blastocyst-derived stem cells, we compared early differentiating embryonic stem cells (ESCs) and their extra-embryonic counterparts, trophoblast (T)SCs to their self-renewing counterparts. A metabolomics analysis pointed to the desaturation of fatty acyl chains as a metabolic signature of differentiating blastocyst-derived SCs via the upregulation of delta-6 desaturase (D6D; FADS2) and delta-5 desaturase (D5D; FADS1), key enzymes in the biosynthesis of polyunsaturated fatty acids (PUFAs). The inhibition of D6D or D5D by specific inhibitors or SiRNA retained stemness in ESCs and TSCs, and attenuated endoplasmic reticulum (ER) stress-related apoptosis. D6D inhibition in ESCs upregulated stearoyl-CoA desaturase-1 (Scd1), essential to maintain ER homeostasis. In TSCs, however, D6D inhibition downregulated Scd1. TSCs show higher Scd1 mRNA expression and high levels of monounsaturated fatty acyl chain products in comparison to ESCs. The addition of oleic acid, the product of Scd1 (essential for ESCs), to culture medium, was detrimental to TSCs. Interestingly, TSCs express a high molecular mass variant of Scd1 protein, hardly expressed by ESCs. Taken together, our data suggest that lipid desaturation is a metabolic regulator of the balance between differentiation and self-renewal of ESCs and TSCs. They point to lipid polydesaturation as a driver of differentiation in both cell types. Monounsaturated fatty acids (MUFAs), essential for ESCs are detrimental to TSCs.

Age-associated changes in circulatory fatty acids: new insights on adults and long-lived individuals.

Long-lived individuals (LLIs) are considered an ideal model to study healthy human aging. Blood fatty acid (FA) profile of a cohort of LLIs (90-111years old, n = 49) from Sicily was compared to adults (18-64years old, n = 69) and older adults (65-89years old, n = 54) from the same area. Genetic variants in key enzymes related to FA biosynthesis and metabolism were also genotyped to investigate a potential genetic predisposition in determining the FA profile. Gas chromatography was employed to determine the FA profile, and genotyping was performed using high-resolution melt (HRM) analysis. Blood levels of total polyunsaturated FA (PUFA) and total trans-FA decreased with age, while the levels of saturated FA (SFA) remained unchanged. Interestingly, distinctively higher circulatory levels of monounsaturated FA (MUFA) in LLIs compared to adults and older adults were observed. In addition, among LLIs, rs174537 in the FA desaturase 1/2 (FADS1/2) gene was associated with linoleic acid (LA, 18:2n-6) and docosatetraenoic acid (DTA, 22:4n-6) levels, and the rs953413 in the elongase of very long FA 2 (ELOVL2) was associated with DTA levels. We further observed that rs174579 and rs174626 genotypes in FADS1/2 significantly affect delta-6 desaturase (D6D) activity. In conclusion, our results suggest that the LLIs have a different FA profile characterized by high MUFA content, which indicates reduced peroxidation while maintaining membrane fluidity.

NSCLC Cells Resistance to PI3K/mTOR Inhibitors Is Mediated by Delta-6 Fatty Acid Desaturase (FADS2)

Hyperactivation of the phosphatidylinositol-3-kinase (PI3K) pathway is one of the most common events in human cancers. Several efforts have been made toward the identification of selective PI3K pathway inhibitors. However, the success of these molecules has been partially limited due to unexpected toxicities, the selection of potentially responsive patients, and intrinsic resistance to treatments. Metabolic alterations are intimately linked to drug resistance; altered metabolic pathways can help cancer cells adapt to continuous drug exposure and develop resistant phenotypes. Here we report the metabolic alterations underlying the non-small cell lung cancer (NSCLC) cell lines resistant to the usual PI3K-mTOR inhibitor BEZ235. In this study, we identified that an increased unsaturation degree of lipid species is associated with increased plasma membrane fluidity in cells with the resistant phenotype and that fatty acid desaturase FADS2 mediates the acquisition of chemoresistance. Therefore, new studies focused on reversing drug resistance based on membrane lipid modifications should consider the contribution of desaturase activity.

Maternal Plasma Glycerophospholipids LC-PUFA Levels Have a Sex-Specific Association with the Offspring's Cord Plasma Glycerophospholipids-Fatty Acid Desaturation Indices at Birth.

Fatty acid desaturases, the enzymes responsible for the production of unsaturated fatty acids (FA) in fetal tissues, are known to be influenced by maternal-placental supply of nutrients and hormones for their function. We hypothesize that there could be a gender-specific regulation of unsaturated FA metabolism at birth, dependent on the maternal fatty acid levels. In this study, 153 mother-newborn pairs of uncomplicated and 'full-term' pregnancies were selected and the FA composition of plasma glycerophospholipids (GP) was quantified by gas chromatography. The FA composition of mother blood plasma (MB) was compared with the respective cord blood plasma (CB) of male newborns or female newborns. Product to substrate ratios were estimated to calculate delta 5 desaturase (D5D), delta 6 desaturase (D6D) and delta 9 stearoyl-CoA-desaturase (D9D/SCD) indices. Pearson correlations and linear regression analyses were employed to determine the associations between MB and CB pairs. In the results, the male infant's MB-CB association was positively correlated with the SCD index of carbon-16 FA, while no correlation was seen for the SCD index of carbon-18 FA. Unlike for males, the CB-D5D index of female neonates presented a strong positive association with the maternal n-6 long chain-polyunsaturated FA (LC-PUFA), arachidonic acid. In addition, the lipogenic desaturation index of SCD18 in the CB of female new-borns was negatively correlated with their MB n-3 DHA. In conclusion, sex-related differences in new-borns' CB desaturation indices are associated with maternal LC-PUFA status at the time of the birth. This examined relationship appears to predict the origin of sex-specific unsaturated FA metabolism seen in later life.

Gene family expansions in Antarctic winged midge as a strategy for adaptation to cold environments

Parochlus steinenii is the only flying insect native to Antarctica. To elucidate the molecular mechanisms underlying its adaptation to cold environments, we conducted comparative genomic analyses of P. steinenii and closely related lineages. In an analysis of gene family evolution, 68 rapidly evolving gene families, involved in the innate immune system, unfolded protein response, DNA packaging, protein folding, and unsaturated fatty acid biosynthesis were detected. Some gene families were P. steinenii-specific and showed phylogenetic instability. Acyl-CoA delta desaturase and heat shock cognate protein 70 (Hsc70) were representative gene families, showing signatures of positive selection with multiple gene duplication events. Acyl-CoA delta desaturases may play pivotal roles in membrane fluidity, and expanded Hsc70 genes may function as chaperones or thermal sensors in cold environments. These findings suggest that multiple gene family expansions contributed to the adaptation of P. steinenii to cold environments.

Engineering and fermenter production of fungi GLA in Pichia pastoris GS115 using oil waste.

γ-Linolenic acid (GLA) is an essential n-6 polyunsaturated fatty acid (PUFA) that has received considerable attention in human and animal feed. GLA is used in many nutritional and medicinal applications, such as the treatment of cancer, inflammatory disorders, and diabetes. Currently, plant seed is the primary dietary source of GLA that is not enough to utilize on an industrial scale. To generate a sustainable novel source of GLA, the gene of delta-6 desaturase, one of the essential enzymes in the GLA production pathway, was isolated from Mucor rouxii DSM1194 and expressed in P. pastoris GS115 by pPICZC vector. The recombinant yeast expressed the GLA up to 19.2% (72mg/g) of total fatty acids. GLA production of recombinant yeast was studied in a fermenter by oil waste for 5 days, and results detected 6.3g/l lipid, and 103mg/g GLA was produced in 72h. The present study may provide an opportunity to develop an alternative host for manufacturing GLA on an industrial scale.

Comparative Genomics of Mortierellaceae Provides Insights into Lipid Metabolism: Two Novel Types of Fatty Acid Synthase.

Fungal species in the family Mortierellaceae are important for their remarkable capability to synthesize large amounts of polyunsaturated fatty acids, especially arachidonic acid (ARA). Although many genomes have been published, the quality of these data is not satisfactory, resulting in an incomplete understanding of the lipid pathway in Mortierellaceae. We provide herein two novel and high-quality genomes with 55.32% of syntenic gene pairs for Mortierella alpina CGMCC 20262 and M. schmuckeri CGMCC 20261, spanning 28 scaffolds of 40.22 Mb and 25 scaffolds of 49.24 Mb, respectively. The relative smaller genome for the former is due to fewer protein-coding gene models (11,761 vs. 13,051). The former yields 45.57% of ARA in total fatty acids, while the latter 6.95%. The accumulation of ARA is speculated to be associated with delta-5 desaturase (Delta5) and elongation of very long chain fatty acids protein 3 (ELOVL3). A further genomic comparison of 19 strains in 10 species in three genera in the Mortierellaceae reveals three types of fatty acid synthase (FAS), two of which are new to science. The most common type I exists in 16 strains of eight species of three genera, and was discovered previously and consists of a single unit with eight active sites. The newly revealed type II exists only in M. antarctica KOD 1030 where the unit is separated into two subunits α and β comprised of three and five active sites, respectively. Another newly revealed type III exists in M. alpina AD071 and Dissophora globulifera REB-010B, similar to type II but different in having one more acyl carrier protein domain in the α subunit. This study provides novel insights into the enzymes related to the lipid metabolism, especially the ARA-related Delta5, ELOVL3, and FAS, laying a foundation for genetic engineering of Mortierellaceae to modulate yield in polyunsaturated fatty acids.

Fatty acid desaturase 1 (FADS1) is a cancer marker for patient survival and a potential novel target for precision cancer treatment.

Fatty Acid Desaturase-1 (FADS1) or delta 5 desaturase (D5D) is a rate-limiting enzyme involved in the biosynthesis of long-chain polyunsaturated fatty acids (LC-PUFAs), i.e., arachidonic acid (ARA) and eicosapentaenoic (EPA). These LC-PUFAs and their metabolites play essential and broad roles in cancer cell proliferation, metastasis, and tumor microenvironment. However, the role of FADS1 in cancers remains incompletely understood. Utilizing The Cancer Genome Atlas (TCGA) database, we explored the role of FADS1 across different cancer types using multiple bioinformatics and statistical tools. Moreover, we studied the impact of a FADS1 inhibitor (D5D-IN-326) on proliferation of multiple cancer cell lines. We identified that FADS1 gene is a predictor for cancer survival in multiple cancer types. Compared to normal tissue, the mRNA expression of FADS1 is significantly increased in primary tumors while even higher in metastatic and recurrent tumors. Mechanistically, pathway analysis demonstrated that FADS1 is associated with cholesterol biosynthesis and cell cycle control genes. Interestingly, FADS1 expression is higher when TP53 is mutated. Tumors with increased FADS1 expression also demonstrated an increased signatures of fibroblasts and macrophages infiltration among most cancer types. Our in vitro assays showed that D5D-IN-326 significantly inhibited cell proliferation of kidney, colon, breast, and lung cancer cell lines in a dose-dependent manner. Lastly, single nucleotide polymorphisms (SNPs) which are well-established expression quantitative trait loci (eQTLs) for FADS1 in normal human tissues are also significantly correlated with FADS1 expression in tumors of multiple tissue types, potentially serving as a marker to stratify cancer patients with high/low FADS1 expression in their tumor tissue. Our study suggests that FADS1 plays multiple roles in cancer biology and is potentially a novel target for precision cancer treatment.