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Sebaceous glands drive acne, however, their role in other inflammatory skin diseases remains unclear. To shed light on their potential contribution to disease development, we investigated the spatial transcriptome of sebaceous glands in psoriasis and atopic dermatitis patients across lesional and non-lesional human skin samples. Both atopic dermatitis and psoriasis sebaceous glands expressed genes encoding key proteins for lipid metabolism and transport such as Show less

Obesity is prevalent with the adult population in the United States. Energy-dense diets and erratic eating behavior contribute to obesity. Time-restricted eating is a dietary strategy in humans that has been advanced to reduce the propensity for obesity. We hypothesized that time-restricted feeding (TRF) would improve metabolic flexibility and normalize metabolic function in adult mice with established excess adiposity. Male C57BL/6NHsd mice were initially fed a high-fat diet (HFD) for 12 weeks to establish excess body adiposity, while control mice were fed a normal diet. Then, the HFD-fed mice were assigned to two groups, either Energy intake and body fat mass were similar in TRF and HFD-fed mice. TRF restored rhythmic oscillations of respiratory exchange ratio (RER), which had been flattened by the HFD, with greater RER amplitude in the dark phase. Insulin sensitivity was improved and plasma cholesterol and hepatic triacylglycerol were decreased by TRF. When compared to HFD, TRF decreased transcription of circadian genes Show less

The kidding traits of goats are an important index of production. However, the molecular regulatory mechanisms of kidding traits in goats have not been fully elucidated. This study aimed to investigate the molecular regulatory network of kidding traits in goats. Multi-omics revealed the enrichment of 10 signaling pathways, with fatty acid biosynthesis, biosynthesis of unsaturated fatty acids, and steroid hormone biosynthesis pathways being closely related to reproduction. Interestingly, the key rate-limiting enzymes, fatty acid synthase (FASN), stearoyl-CoA desaturase 5 (SCD5), fatty acid desaturase 1 (FADS1), 3β-hydroxysteroid dehydrogenase/isomerase (3BHSD), and steroidogenic acute regulatory protein (STAR) enriched in these pathways regulate changes in reproduction-related metabolites. In interference experiments, it was observed that suppressing these key rate-limiting enzymes inhibited the expression of CYP19A1, ESR2, and FSHR. Furthermore, interference inhibited granulosa cell proliferation, caused cell cycle arrest, and promoted apoptosis. Thus, these results suggest that the specific markers of nanny goats with multiple kids are the key rate-limiting enzymes FASN, SCD5, FADS1, 3BHSD, and STAR. These findings may greatly enhance the understanding of regulatory mechanisms that govern goat parturition. Show less

RNA helicase DHX33 has been identified as a critical factor promoting cancer development. In the present study, a previously developed small molecule inhibitor for DHX33, KY386, was found to robustly kill cancer cells via a new path, the ferroptosis pathway. Mechanistically, DHX33 promotes the expression of critical players in lipid metabolism including FADS1, FADS2, and SCD1 genes, thereby sensitizing cancer cells to ferroptosis mediated cell death. Our study reveals a novel mechanism of DHX33 in promoting tumorigenesis and highlights that pharmacological targeting DHX33 can be a feasible option in human cancers. Normally differentiated cells are insensitive to DHX33 inhibition, and DHX33 inhibitors have little cellular toxicity in vitro and in vivo. Our studies demonstrated that DHX33 inhibitors can be promising anticancer agents with great potential for cancer treatment. Show less

The metabolic patterns of human placental-derived mesenchymal stem cell (hP-MSC) treatment for primary sclerosing cholangitis (PSC) remain unclear, and therapeutic effects significantly vary due to individual differences. Therefore, it is crucial to investigate the serological response to hP-MSC transplantation through small molecular metabolites and identify easily detectable markers for efficacy evaluation. Using Mdr2 Collectively, the results of the liver histology, serum liver enzyme levels, and inflammatory factors supported the therapeutic efficacy of hP-MSC treatment. Based on significant differences, 41 differentially expressed metabolites were initially identified; these were enriched in bile acid, lipid, and hydroxyproline metabolism. After treatment, bile acid transport was accelerated, whereas bile acid production was reduced; unsaturated fatty acid synthesis was upregulated overall, with increased FADS2 and elongase expression and enhanced fatty acid β-oxidation; hepatic proline 4-hydroxylase expression was decreased, leading to reduced hydroxyproline production. Correlation analysis of liver enzymes and metabolites, combined with time trends, identified eight potential biomarkers: 2-aminomuconate semialdehyde, L-1-pyrroline-3-hydroxy-5-carboxylic acid, L-isoglutamine, and maleamic acid were more abundant in model mice but decreased after hP-MSC treatment. Conversely, 15-methylpalmitic, eicosenoic, nonadecanoic, and octadecanoic acids were less abundant in model mice but increased after hP-MSC treatment. This study revealed metabolic regulatory changes in PSC model mice after hP-MSC treatment and identified eight promising biomarkers, providing preclinical evidence to support therapeutic applications of hP-MSC. Show less

There was no significant difference in the composition and content of fatty acids in eggs among different breeds initially, but following the supplementation of flaxseed oil, Dwarf Layer were observed to deposit more n-3 polyunsaturated fatty acid (PUFA) in eggs. Currently, there is limited research on the mechanisms underlying the differences in egg composition among different breeds. Therefore, in this study, 150 twenty-four-wk-old hens of each breed, including the Dwarf Layer and White Leghorn, were fed either a basal diet or a diet supplemented with 2.5% flaxseed oil. After 28 d, eggs and liver samples were collected to determine fatty acid composition, and serum, liver, intestine, and follicles were collected for subsequent biochemical, intestinal morphology, and lipid metabolism-related genes expression analysis. Duodenal contents were collected for microbial analysis. The results showed that there was no significant difference in the content and deposition efficiency of total n-3 PUFA in the liver of the 2 breeds, but the content and deposition efficiency of total n-3 PUFA in the egg of Dwarf Layer were significantly higher than those of White Leghorn after feeding flaxseed oil. Flaxseed oil and breeds did not have significant effects on cholesterol (CHO), free fatty acids (NEFA), low-density lipoprotein (LDL), and estrogen (E Show less

This study replicated a mouse model of sperm DNA damage induced by benzo(a)pyrene (BaP), and the transcriptomic and proteomic features of the model were examined to clarify the pathways related to BaP-induced damage to sperm DNA. Male mice in the BaP group were subjected to BaP at a dosage of 100 mg/kg/d or an equivalent quantity of saline solution in the control group for 60 days. Subsequently, the DNA fragmentation index (DFI) in sperm was assessed using a sperm chromatin structure assay (SCSA). RNA-seq and data-independent acquisition (DIA) were used to identify the mRNA and protein expression patterns in the testis. The sperm DFI significantly increased in the BaP group. Compared to the control group, the BaP group exhibited differential expression of 240 genes (referred to as DEGs) and 616 proteins (referred to as DEPs). These molecules included Aldh1a1, Cyb5r3, Fads1, Oxsm, Rcn3, and Prss45. Pathways in cancer, the PI3K-Akt signaling pathway, metabolic pathways, and the MAPK signaling pathway were the primary areas where these genes showed enrichment. BaP can damage the DNA of sperm and affect metabolism, the PI3K-Akt pathway, and pathways associated with cancer signaling. Show less

Previous studies have indicated that activity of fatty acid desaturase 1 (FADS1), is involved in cardiometabolic risk. Recent experimental data have shown that FADS1 knockdown can promote lipid accumulation and lipid droplet formation in liver cells. In this study, we aimed to characterize whether different FADS1 genotypes affect liver fat content, essential fatty acid content and free oxylipin mediators in the blood. We analyzed the impact of FADS1 single-nucleotide polymorphisms (SNPs) rs174546, rs174547, and rs174550 on blood fatty acids and free oxylipins in a cohort of 85 patients from an academic metabolic medicine outpatient center. Patients were grouped based on their genotype into the homozygous major (derived) allele group, the heterozygous allele group, and the homozygous minor (ancestral) allele group. Omega-3 polyunsaturated fatty acids (n-3 PUFA) and omega-6 polyunsaturated fatty acids (n-6 PUFA) in the blood cell and plasma samples were analyzed by gas chromatography. Free Oxylipins in plasma samples were analyzed using HPLC-MS/MS. Liver fat content and fibrosis were evaluated using Fibroscan technology. Patients with the homozygous ancestral (minor) FADS1 genotype exhibited significantly lower blood levels of the n-6 PUFA arachidonic acid (AA), but no significant differences in the n-3 PUFAs eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). There were no significant differences in liver fat content or arachidonic acid-derived lipid mediators, such as thromboxane B2 (TXB2), although there was a trend toward lower levels in the homozygous ancestral genotype group. Our findings suggest that FADS1 genotypes influence the blood levels of n-6 PUFAs, while not significantly affecting the n-3 PUFAs EPA and DHA. The lack of significant differences in liver fat content and arachidonic acid-derived lipid mediators suggests that the genotype-related variations in fatty acid levels may not directly translate to differences in liver fat or inflammatory lipid mediators in this cohort. However, the trend towards lower levels of certain lipid mediators in the homozygous ancestral genotype group warrants further investigation to elucidate the underlying mechanisms of different FADS1 genotypes and potential implications for cardiometabolic risk. Show less

Adaptation to cold was essential for human migration across Eurasia. Non-shivering thermogenesis through brown adipose tissue (BAT) participates in cold adaptation because some genes involved in the differentiation and function of BAT exhibit signatures of positive natural selection in populations at high latitudes. Whether these genes are associated with the inter-individual variability in BAT thermogenesis remains unclear. In this study, we evaluated the potential associations between BAT activity and single nucleotide polymorphisms (SNPs) in candidate gene regions in East Asian populations. BAT activity induced by mild cold exposure was measured in 399 healthy Japanese men and women using fluorodeoxyglucose-positron emission tomography and computed tomography (FDG-PET/CT). The capacity for cold-induced thermogenesis and fat oxidation was measured in 56 men. Association analyses with physiological traits were performed for 11 SNPs at six loci (LEPR, ANGPTL8, PLA2G2A, PLIN1, TBX15-WARS2, and FADS1) reported to be under positive natural selection. Associations found in the FDG-PET/CT population were further validated in 84 healthy East Asian men and women, in whom BAT activity was measured using infrared thermography. Associations between the SNP genotypes and BAT activity or other related traits were tested using multiple logistic and linear regression models. Of the 11 putative adaptive alleles of the six genes, two intronic SNPs in LEPR (rs1022981 and rs12405556) tended to be associated with higher BAT activity. However, these did not survive multiple test comparisons. Associations with lower body fat percentage, plasma triglyceride, insulin, and HOMA-IR levels were observed in the FDG-PET/CT population (P < 0.05). Other loci, including TBX15-WARS2, which is speculated to mediate cold adaptation in Greenland Inuits, did not show significant differences in BAT thermogenesis. Our results suggest a marginal but significant association between LEPR SNPs. However, robust supporting evidence was not established for the involvement of other loci under positive natural selection in cold adaptation through BAT thermogenesis in East Asian adults. Given the pleiotropic function of these genes, factors other than cold adaptation through BAT thermogenesis, such as diet adaptation, may contribute to positive natural selection at these loci. Show less

The lion-head goose is the only large goose species in China, and it is one of the largest goose species in the world. Lion-head geese have a strong tolerance for massive energy intake and show a priority of fat accumulation in liver tissue through special feeding. Therefore, the aim of this study was to investigate the impact of high feed intake compared to normal feeding conditions on the transcriptome changes associated with fatty liver development in lion-head geese. In this study, 20 healthy adult lion-head geese were randomly assigned to a control group (CONTROL, n = 10) and high-intake-fed group (CASE, n = 10). After 38 d of treatment, all geese were sacrificed, and liver samples were collected. Three geese were randomly selected from the CONTROL and CASE groups, respectively, to perform whole-transcriptome analysis to analyze the key regulatory genes. We identified 716 differentially expressed mRNAs, 145 differentially expressed circRNAs, and 39 differentially expressed lncRNAs, including upregulated and downregulated genes. GO enrichment analysis showed that these genes were significantly enriched in molecular function. The node degree analysis and centrality metrics of the mRNA-lncRNA-circRNA triple regulatory network indicate the presence of crucial functional nodes in the network. We identified differentially expressed genes, including Show less

We present a case of fetal akinesia deformation sequence due to nemaline myopathy (NM). In addition to the muscle manifestations, prenatal observations included an enlarged subarachnoid space and delayed cortical development. Trio whole-exome sequencing revealed a de novo novel pathogenic variant in the ACTA1 gene, which encodes skeletal muscle alpha-actin. Our findings suggest that brain abnormalities can occur prenatally in NM and support the potential role of skeletal muscle alpha-actin in the central nervous system. Show less

Prolonged adaptation of ancestors of indigenous peoples of the Far North of Asia and America to extreme natural and climatic conditions of the Arctic has resulted in changes in genes controlling various metabolic processes. However, most genetic variability observed in the Eskimo and Paleoasians (the Chukchi and Koryaks) is related to adaptation to the traditional Arctic diet, which is rich in lipids and proteins but extremely poor in plant carbohydrates. The results of population genetic studies have demonstrated that specific polymorphic variants in genes related to lipid metabolism ( Show less

Fatty acid desaturase (FADS1) variant-rs174550 strongly regulates polyunsaturated fatty acid (PUFA) biosynthesis. Additionally, the FADS1 is related to mitochondrial function. Thus, we investigated whether changes in mitochondrial function are associated with the genetic variation in FADS1 (rs174550) in human adipocytes isolated from individuals consuming diets enriched with either dietary alpha-linolenic (ALA) or linoleic acid (LA). Two cohorts of men homozygous for the genotype of FADS1 (rs174550) were studied: FADSDIET2 dietary intervention study with ALA- and LA-enriched diets and Kuopio Obesity Surgery study (KOBS), respectively. We could demonstrate that differentiated human adipose-derived stromal cells from subjects with the TT genotype had higher mitochondrial metabolism compared with subjects with the CC genotype of FADS1-rs174550 in the FADSDIET2. Responses to PUFA-enriched diets differed between the genotypes of FADS1-rs174550, showing that ALA, but not LA, -enriched diet stimulated mitochondrial metabolism more in subjects with the CC genotype when compared with subjects with the TT genotype. ALA, but not LA, proportion in plasma phospholipid fraction correlated positively with adipose tissue mitochondrial-DNA amount in subjects with the CC genotype of FADS1-rs174550 in the KOBS. These findings demonstrate that the FADS1-rs174550 is associated with modification in mitochondrial function in human adipocytes. Additionally, subjects with the CC genotype, when compared with the TT genotype, benefit more from the ALA-enriched diet, leading to enhanced energy metabolism in human adipocytes. Altogether, the FADS1-rs174550 could be a genetic marker to identify subjects who are most suitable to receive dietary PUFA supplementation, establishing also a personalized therapeutic strategy to improve mitochondrial function in metabolic diseases. Show less

Thermal adaptation to environmental temperature is a driving force in animal evolution. This chapter presents thermal adaptation in ectotherms and endotherms from the perspective of developmental biology. In ectotherms, there are known examples of temperature influencing morphological characteristics, such as seasonal color change, melanization, and sex determination. Furthermore, the timing of embryonic development also varies with environmental temperature. This review will introduce the cellular and molecular mechanisms underlying temperature-dependent embryogenesis. The evolution of thermal adaptation in endotherms is also important for survival in cold climates. Recent genome-wide studies have revealed adaptive mutations in the genomes of extant humans as well as extinct species such as woolly mammoths and Neanderthals. These studies have shown that single-nucleotide polymorphisms in physiologically related genes (e.g., CPT1A, LRP5, THATA, PRKG1, and FADS1-3) allow humans to live in cold climates. At the end of this chapter, we present the remaining questions in terms of genetic assimilation, heat shock protein Hsp90, and embryonic development. Show less

Beef flavor plays a crucial role in consumer preference, yet research on this trait has been limited by past technological constraints. Intramuscular fat (IMF) is a key determinant of beef quality, influencing taste, marbling, and overall flavor. Xinjiang brown cattle (XBC), an indigenous breed from northern Xinjiang, China, presents significant variation in meat quality, with IMF content ranging from 0.2 % to 4.3 % within the population. This variation suggests strong potential for breeding improvement. In this study, we selected 82 XBC for slaughter and meat quality analysis, categorizing them based on IMF content. Using two-dimensional gas chromatography-time-of-flight mass spectrometry (GC×GC-TOF MS), we analyzed volatile flavor compounds across different beef cuts (Longissimus dorsi, Semitendinosus, Supraspinatus). Our results showed that beef with higher IMF levels exhibited enhanced flavor profiles, characterized by sweet, green, fruity, and waxy notes, while castrated bulls displayed the weakest flavor intensity. Metabolomic analysis further revealed significant differences in flavor substances between high and low IMF content beef. RNA-Seq analysis identified key genes (AQP4, FZD2, FADS1, BPG1, CEBPD, FABP4) associated with flavor formation, offering valuable insights for breeding strategies aimed at improving XBC meat quality. This comprehensive study provides a robust theoretical foundation for advancing the genetic improvement of XBC. Show less

Extracellular vesicles in human milk are critical in supporting newborn growth and development. Bioavailability of dietary extracellular vesicles may depend on the composition of membrane lipids. Single-nucleotide polymorphisms (SNPs) in the fatty acid desaturase gene cluster impact the content of long-chain polyunsaturated fatty acids in human milk phospholipids. This study investigated the relation between variation in FADS1 and FADS2 with the content of polyunsaturated fatty acids in extracellular vesicles from human milk. Milk was obtained from a cohort of mothers (N = 70) at 2-4 weeks of lactation. SNPs in the FADS gene locus were determined using pyrosequencing for rs174546 in FADS1 and rs174575 in FADS2. Quantitative lipidomic analysis of polyunsaturated fatty acids in human milk and extracellular vesicles from human milk was completed by gas chromatography-mass spectrometry. The rs174546 and rs174575 genotypes were independent predictors of the arachidonic acid content in extracellular vesicles. The rs174546 genotype also predicted eicosapentaenoic acid and docosahexaenoic acid in extracellular vesicles. The reduced content of long-chain polyunsaturated fatty acids in extracellular vesicles in human milk may be due to lower fatty acid desaturase activity in mothers who are carriers of the A allele in rs174546 or the G allele in rs174575. The polyunsaturated fatty acid composition of milk extracellular vesicles is predicted by the FADS genotype. These findings yield novel insights regarding extracellular vesicle content and composition that can inform the design of future research to explore how lipid metabolites impact the bioavailability of human milk extracellular vesicles. Show less

The production of the omega-3 long-chain polyunsaturated fatty acids (n-3 LCPUFA) eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) from alpha-linolenic acid (ALA) relies on the delta-6 desaturase (D6D) enzyme encoded by the Fads2 gene. While EPA and DHA reduce hepatic triacylglycerol (TAG) storage and regulate lipogenesis, the independent impact of ALA is less understood. To address this gap in knowledge, hepatic fatty acid metabolism was investigated in male wild-type (WT) and Fads2 knockout (KO) mice fed diets (16% kcal from fat) containing either lard (no n-3 LCPUFA), flaxseed oil (ALA-rich), or menhaden oil (EPA/DHA rich) for 21 weeks. Fat content and composition, as well as markers of lipogenesis, glyceroneogenesis, and TAG synthesis, were analyzed using histology, gas chromatography, and reverse transcription quantitative PCR (RT-qPCR). Mice fed the menhaden diet had significantly lower hepatic TAG compared to both lard- and flax-fed mice, concomitant with changes in n-3 and n-6 LCPUFA in both TAG and phospholipid (PL) fractions (all P < 0.05). Flax-fed WT mice had lower liver TAG content compared to their KO counterparts. Menhaden-fed mice had significantly lower expression of key lipogenic (Scd1, Srebp-1c, Fasn, Fads1, and Fads2), glyceroneogenic (Pck1), and TAG synthesis (Agpat3) genes compared to lard, with flax-fed mice showing some intermediate effects. Gene expression effects were independent of D6D activity, since no differences were detected between WT and KO mice fed the same diet. This study demonstrates that EPA/DHA and not ALA itself is critical for the prevention of hepatic steatosis. Show less

Discovery and translation of gene-environment interactions (GxEs) influencing clinical outcomes is limited by low statistical power and poor mechanistic understanding. Molecular omics data may help address these limitations, but their incorporation into GxE testing requires principled analytic approaches. We focused on genetic modification of the established mechanistic link between dietary long-chain omega-3 fatty acid (dN3FA) intake, plasma N3FA (pN3FA), and chronic inflammation as measured by high sensitivity CRP (hsCRP). We considered an approach that decomposes the overall genetic effect modification into components upstream and downstream of a molecular mediator to increase the potential to discover gene-N3FA interactions. Simulations demonstrated improved power of the upstream and downstream tests compared to the standard approach when the molecular mediator for many biologically plausible scenarios. The approach was applied in the UK Biobank (N = 188,700) with regression models that used measures of dN3FA (based on fish and fish oil intake), pN3FA (% of total fatty acids measured by nuclear magnetic resonance), and hsCRP. Mediation analysis showed that pN3FA fully mediated the dN3FA-hsCRP main effect relationship. Next, we separately tested modification of the dN3FA-hsCRP ("standard"), dN3FA-pN3FA ("upstream"), and pN3FA-hsCRP ("downstream") associations. The known Show less

Long-chain polyunsaturated fatty acids (LCPUFAs) are essential for both fetal and placental development. We characterized the FA composition and gene expression levels of FA-metabolizing enzymes in rabbit placentas. Total FA compositions from term rabbit placentas (n = 7), livers, and plasma (both n = 4) were examined: among LCPUFAs with more than three double bonds, dihomo-γ-linolenic acid (DGLA) was the most abundant (11.4 ± 0.69 %, mean ± SE), while arachidonic acid was the second-most rich component (6.90 ± 0.56 %). DGLA was barely detectable (<1 %) in livers and plasma from term rabbits, which was significantly lower than in placentas (both p < 0.0001). Compared with the liver, transcript levels of the LCPUFA-metabolizing enzymes FADS2 and ELOVL5 were 7- and 4.5-fold higher in placentas (both p < 0.05), but levels of FADS1 and ELOVL2 were significantly lower (both p < 0.01). Our results suggest a placenta-specific enzyme expression pattern and LCPUFA profile in term rabbits, which may support a healthy pregnancy. Show less

The composition and distribution of fatty acids (FA) are important factors determining the quality, flavor, and nutrient value of meat. In addition, FAs synthesized in the body participate in energy metabolism and are involved in different regulatory pathways in the form of signaling molecules or by acting as agonist or antagonist ligands of different nuclear receptors. Finally, synthesis and catabolism of FAs affect adaptive immunity by regulating lymphocyte metabolism. The present study performed genome-wide association studies using FA profiles of blood, liver, backfat and muscle from 432 commercial Duroc pigs. Twenty-five genomic regions located on 15 Sus scrofa chromosomes (SSC) were detected. Annotation of the quantitative trait locus (QTL) regions identified 49 lipid metabolism-related candidate genes. Among these QTLs, four were identified in more than one tissue. The ratio of C20:4n-6/C20:3n-6 was associated with the region on SSC2 at 7.56-14.26 Mb for backfat, liver, and muscle. Members of the fatty acid desaturase gene cluster (FADS1, FADS2, and FADS3) are the most promising candidate genes in this region. Two QTL regions on SSC14 (103.81-115.64 Mb and 100.91-128.14 Mb) were identified for FA desaturation in backfat and muscle. In addition, two separate regions on SSC9 at 0 - 14.55 Mb and on SSC12 at 0-1.91 Mb were both associated with the same multiple FA traits for backfat, with candidate genes involved in de novo FA synthesis and triacylglycerol (TAG) metabolism, such as DGAT2 and FASN. The ratio C20:0/C18:0 was associated with the region on SSC5 at 64.84-78.32 Mb for backfat. Furthermore, the association of the C16:0 content with the region at 118.92-123.95 Mb on SSC4 was blood specific. Finally, candidate genes involved in de novo lipogenesis regulate T cell differentiation and promote the generation of palmitoleate, an adipokine that alleviates inflammation. Several SNPs and candidate genes were associated with lipid metabolism in blood, liver, backfat, and muscle. These results contribute to elucidating the molecular mechanisms implicated in the determination of the FA profile in different pig tissues and can be useful in selection programs that aim to improve health and energy metabolism in pigs. Show less

Single nucleotide polymorphisms (SNP) in the fatty acid desaturase 1 (FADS1) gene is suggested as risk factor of metabolic diseases in genome-wide association studies (GWAS). This study hypothesized that FADS1_rs174546T associates with serum triglycerides (TG) in Korean Genome and Epidemiology Study (KoGES). In addition, functional study of SNP genotypes in cultured cells is performed. FADS1_rs174546T is associated with high level of serum TG (effect size of variant: 6.48 ± 1.84 mg dL FADS1_rs174546T is a crucial risk factor for hypertriglyceridemia in the Koreans potentially through the interaction with miR-6728-3p. Formononetin can be a potent dietary intervention to prevent and improve hypertriglyceridemia in both rs174546 (C/T) populations. Show less

Although antipsychotics constitute the best treatment for patients with schizophrenia, this treatment class carries a high risk of metabolic disarrangements thus developing metabolic syndrome (MetS). Altered fatty acid (FA) composition and desaturase indices have been associated with several metabolic diseases, including MetS. Herein, we determined fatty acid desaturase 1 (FADS1) and FADS2 gene expressions, serum delta-5 desaturase (D5D) and D6D indices in female adults with first-episode schizophrenia after olanzapine medication, as well as their relationship with the incidence of MetS. This study prospectively recruited 120 female patients with first-episode schizophrenia who completed 6-month olanzapine medication. Among these female patients, 31 patients developed MetS and 89 patients did not. The mRNA expression levels of FADS1 and FADS2 in patients were analyzed according to the presence of MetS and evaluation times with results of two-way ANOVAs (FADS1: P The study suggests changes of FADS1, FADS2 expressions, and fatty acid desaturase indices including D5D, D6D, and SCD-16 may be associated with the development of MetS in female adults with first-episode schizophrenia after olanzapine medication. Show less

The pathogenesis of renal calcium-oxalate (CaOx) stones is complex and influenced by various metabolic factors. In parallel, palmitic acid (PA) has been identified as an upregulated lipid metabolite in the urine and serum of patients with renal CaOx stones via untargeted metabolomics. Thus, this study aimed to mechanistically assess whether PA is involved in stone formation. Lipidomics analysis of PA-treated renal tubular epithelial cells compared with the control samples revealed that α-linoleic acid and α-linolenic acid were desaturated and elongated, resulting in the formation of downstream polyunsaturated fatty acids (PUFAs). In correlation, the levels of fatty acid desaturase 1 and 2 (FADS1 and FADS2) and peroxisome proliferator-activated receptor α (PPARα) in these cells treated with PA were increased relative to the control levels, suggesting that PA-induced upregulation of PPARα, which in turn upregulated these two enzymes, forming the observed PUFAs. Lipid peroxidation occurred in these downstream PUFAs under oxidative stress and Fenton Reaction. Furthermore, transcriptomics analysis revealed significant changes in the expression levels of ferroptosis-related genes in PA-treated renal tubular epithelial cells, induced by PUFA peroxides. In addition, phosphatidyl ethanolamine binding protein 1 (PEBP1) formed a complex with 15-lipoxygenase (15-LO) to exacerbate PUFA peroxidation under protein kinase C ζ (PKC ζ) phosphorylation, and PKC ζ was activated by phosphatidic acid derived from PA. In conclusion, this study found that the formation of renal CaOx stones is promoted by ferroptosis of renal tubular epithelial cells resulting from PA-induced dysregulation of PUFA and phosphatidic acid metabolism, and PA can promote the renal adhesion and deposition of CaOx crystals by injuring renal tubular epithelial cells, consequently upregulating adhesion molecules. Accordingly, this study provides a new theoretical basis for understanding the correlation between fatty acid metabolism and the formation of renal CaOx stones, offering potential targets for clinical applications. Show less

Triple-negative breast cancer (TNBC) has limited therapeutic options, is highly metastatic and characterized by early recurrence. Lipid metabolism is generally deregulated in TNBC and might reveal vulnerabilities to be targeted or used as biomarkers with clinical value. Ferroptosis is a type of cell death caused by iron-dependent lipid peroxidation which is facilitated by the presence of polyunsaturated fatty acids (PUFA). Here we identify fatty acid desaturases 1 and 2 (FADS1/2), which are responsible for PUFA biosynthesis, to be highly expressed in a subset of TNBC with a poorer prognosis. Lipidomic analysis, coupled with functional metabolic assays, showed that FADS1/2 high-expressing TNBC are susceptible to ferroptosis-inducing agents and that targeting FADS1/2 by both genetic interference and pharmacological approach renders those tumors ferroptosis-resistant while unbalancing PUFA/MUFA ratio by the supplementation of exogenous PUFA sensitizes resistant tumors to ferroptosis induction. Last, inhibiting lipid droplet (LD) formation and turnover suppresses the buffering capacity of LD and potentiates iron-dependent cell death. These findings have been validated in vitro and in vivo in mouse- and human-derived clinically relevant models and in a retrospective cohort of TNBC patients. Show less

Childhood malnutrition is a major global health problem with long-term sequelae, including non-communicable diseases (NCDs). Mechanisms are unknown but may involve metabolic programming, resulting from "short-term" solutions to optimise survival by compromising non-priority organs. As key players in lipid metabolism, desaturases have been shown to be predictive of NCDs. We hypothesised that the association between specific desaturase activities and NCD risk determinants (including body composition, serum glucose, insulin levels, and blood pressure) are influenced by childhood post-malnutrition weight gain. 278 Afro-Caribbean adults with well-documented clinical history of severe malnutrition in childhood were studied. Extensive metabolic analyses including body composition (DXA), fasting serum glucose and lipidomics (n = 101), and fasting serum insulin (n = 83) were performed in malnutrition survivors and matched community controls (n = 90). Established lipid ratios were used as proxies of desaturase activities: CE 16:1/CE 16:0 for stearoyl-CoA desaturase (SCD1), LysoPC 20:4/20:3 for fatty acid desaturase 1 (FADS1), and LysoPC 20:3/18:2 for FADS2. Compared to community controls, adult malnutrition survivors (mean ± SD) age 28.3 ± 7.8 and BMI 23.6 ± 5.2 had higher SCD1 and FADS1 activity, (B ± SE) 0.07 ± 0.02 and 0.7 ± 0.08, respectively, but lower FADS2 activities (B ± SE) -0.05 ± 0.01, adjusted for sex and age (p < 0.0005). SCD1 was positively associated with adult BMI and body fat percentage, and negatively associated with lean mass and height. Stratification based on weight gain during nutritional rehabilitation among malnutrition survivors might signal the potential associations between weight gain during that critical period, desaturase activities, and some of adult metabolic parameters, with the lowest tertiles (slowest catch-up weight gain) performing more similarly to controls. In adult survivors of early-life severe acute malnutrition, desaturase activity is associated with markers of NCD risk, especially adiposity. These associations seem to be strengthened by faster weight gain during nutritional rehabilitation. Show less

A fatty acid desaturase (FADS) insertion-deletion (Indel) polymorphism (rs66698963) influences the expression of FADS1, which controls the synthesis of n-6 highly unsaturated fatty acid (HUFA) arachidonic acid (AA). The anti-inflammatory activity of the n-3 HUFA eicosapentaenoic acid (EPA) may be explained by competition with AA for proinflammatory lipid mediator synthesis. A precision medicine approach based on stratification by FADS Indel genotype could identify individuals, who benefit from greatest disease risk reduction by n-3 HUFAs. We tested the hypothesis that the FADS insertion (I) allele predicts colorectal polyp risk reduction in a secondary analysis of the randomized, placebo-controlled, 2×2 factorial seAFOod polyp prevention trial of EPA 2000 mg daily and aspirin 300 mg daily for 12 mo (ISRCTN05926847). Participant Indel genotype was determined by polymerase chain reaction (PCR) blind to trial outcomes. Colorectal polyp outcomes were included in negative binomial (polyp number) and logistic (polyp detection rate [PDR; percentage with one or more polyps]) regression models comparing each active intervention with its placebo. Presence of ≥1 Indel I allele and an interaction term (I allele × active intervention) were covariates. In 528 participants with colonoscopy and FADS Indel data, EPA use irrespective of Indel genotype, was not associated with reduced colorectal polyp number (incidence rate ratio [IRR]: 0.92; 95% confidence interval: 0.74, 1.16), mirroring original seAFOod trial analysis. However, the presence of ≥1 I allele identified EPA users with a significant reduction in colorectal polyp number (IRR: 0.50 [0.28, 0.90]), unlike aspirin, for which there was no interaction. Similar findings were obtained for the PDR. The FADS Indel I allele identified individuals, who displayed colorectal polyp prevention by EPA with a similar effect size to aspirin. Assessment of rs66698963 as a biomarker of therapeutic response to n-3 HUFAs in other populations and healthcare settings is warranted. The seAFOod polyp prevention trial and STOP-ADENOMA study were registered at International Standard Randomised Controlled Trial Number registry as ISRCTN05926847. Show less

To investigate associations between substitutions of foods varying in fat quality and all-cause mortality in elderly Swedish men and to examine effect measure modification by a gene involved in fatty acid desaturation (rs174550 FADS1). Using Cox-regression models in the ULSAM cohort (n = 1133 men aged 71), we aimed to investigate; (1) Associations between the substitution of a nutrient or food for another on all-cause mortality (primary outcome) and CVD (secondary outcome) and (2) Associations between the addition of various fat-rich foods to the habitual diet and all-cause mortality and CVD. Subgroup analyses based on the rs174550 FADS1 genotype were conducted. Over a mean follow-up of 11.6-13.7 years, n = 774 died and n = 494 developed CVD, respectively. No clear associations were observed for the vast majority of substitution nor addition models. Adding saturated fatty acids (SFA) on top of the habitual diet was however associated with an increased risk of mortality in men with the CT/CC-genotype [HR (95% CI) 1.44 (1.05, 1.97)]. Post-hoc analyses showed an inverse association of substituting SFA with carbohydrates [HR (95% CI) 0.79 (0.65, 0.97)], which was somewhat stronger in men with the CT/CC-genotype compared to men carrying the TT-genotype. Few associations were observed between diet and all-cause mortality and CVD in this population. However, substituting SFA with carbohydrates was associated with lower mortality in post-hoc analyses and adding SFA to the habitual diet increased mortality in men with the CT/CC-genotype. The latter observation is novel and warrants further investigation in larger cohort studies including women. Show less

Despite enormous research efforts, a sufficiently sensitive and reliable biomarker for the assessment of zinc (Zn) status has not been identified to date. Zn affects fatty acid metabolism and alters the activity of certain desaturases; thus, desaturase activity has been proposed as a potential new biomarker of Zn status. This systematic review complied and assessed studies that examined changes in fatty acid desaturase 1 (FADS1) and fatty acid desaturase 2 (FADS2) activities in relation to modifications in dietary Zn intake. A systematic search was performed in PubMed, Web of Science, Scopus, Web of Knowledge, and Central with strictly defined search, inclusion, and exclusion criteria. Twenty-one studies were included, 8 animal and 13 human trials (5 randomized controlled trials, two non-randomized controlled trials, and 6 cross-sectional studies). This systematic review was performed using PRISMA guidelines and where feasible a random-effects meta-analysis was conducted. No significant correlation was seen between the delta 6 desaturase and Zn status (-0.0958, 95% CIs (-0.2912; 0.1074), p = 0.2928). Delta 6 desaturase seems to respond in a greater magnitude than Zn status to Zn-containing interventions (the standardized mean difference for delta 6 desaturase was -0.6052, 95% CIs (-2.7162; 1.5058), p = 0.4289, while for plasma/serum Zn it was 0.0319, 95% CIs (-0.9133; 0.9770), p = 0.9213). Finally, two separate meta-analyses on same studies that assessed the correlations between LA:DGLA and Zn intake and Zn status and Zn intake revealed that the magnitude of correlations was only slightly different (the pooled correlation coefficient between the LA:DGLA ratio and Zn intake had a value of -0.1050, 95% CIs (-0.5356; 0.3690), p = 0.454, while between plasma Zn and Zn intake had a value of -0.0647, 95% CIs (-0.4224; 0.3106), p = 0.5453). According to the descriptive analysis, the magnitude of variation in desaturase activities in response to Zn intake was not consistent among studies, FADS1 and FADS2 activity corresponded to dietary Zn manipulations, both in animals and humans. A plausible explanation for this observation might be the difference between the studies in study populations, types of dietary interventions, study durations, etc. In addition, several potential confounders and covariates are identified from the qualitative synthesis, such as gender, age, the type of fat provided within the dietary intervention, the size of Zn particles, among others. Further high-quality studies are needed to additionally clarify the suggested associations and applicability of utilizing fatty acid desaturase activities as Zn status biomarkers. Show less