Fatty Acid Metabolism Research Articles

Comparative study on gene expression profiles in the liver of male neonatal mice prenatally exposed to PFOA and its alternative HFPO-DA.

Hexafluoropropylene oxide dimer acid (HFPO-DA), which belongs to the class of perfluoroalkyl ether carboxylic acid (PFECA), is a new alternative to perfluorooctanoic acid (PFOA). However, whether HFPO-DA is a safer alternative to PFOA in neonates remains unclear. In this study, we evaluated neonatal hepatic toxicity on postnatal days 9-10 by orally exposing pregnant CD-1 mice to 0.3 or 3.0mg/kg/day (low or high doses) of HFPO-DA or PFOA from gestation days 15 to 17. The results showed that exposure of pregnant mice to HFPO-DA and PFOA induced similar phenotypic effects, including significant decreases in neonatal body weight (BW) and significant increases in liver weight relative to BW in the high-dose. Notably, HFPO-DA exposure significantly decreased in neonatal BW in the low-dose group, whereas PFOA did not. Comprehensive gene expression analysis revealed significant alterations in 408 and 1402 differentially expressed genes (DEGs) in the liver of neonates from the low- and high-dose HFPO-DA groups, respectively, while PFOA significantly altered 0 and 292 DEGs in the corresponding groups. Gene set enrichment analysis indicated that the DEGs induced by HFPO-DA and PFOA were enriched in pathway related to "PPAR signaling", "fatty acid metabolism", and "biological oxidations". In addition, transactivation assays revealed that mouse (m)PPARα and mPPARγ activity of HFPO-DA exceeds that of PFOA and molecular docking simulations analysis predicted that the binding conformation differ between PFOA and HFPO-DA. Overall, our findings demonstrate that HFPO-DA consistently affected neonatal phenotypes, liver gene expression and the molecular initiating events involving PPARα/γ, at lower concentrations than PFOA.

GATAD1 is involved in sphingosylphosphorylcholine-attenuated myocardial ischemia-reperfusion injury by modulating myocardial fatty acid oxidation and glucose oxidation

Modulating the equilibrium between glucose metabolism and lipid metabolism represents highly promising novel strategies for therapy of myocardial ischemia/reperfusion (I/R) injury. Sphingosylphosphorylcholine (SPC), an intermediate metabolite of sphingolipids, has shown cardioprotective roles during myocardial infarction by regulating the activities of various transcript factors. Gene microarray revealed that SPC significantly upregulated the expression of GATA zinc finger domain protein 1 (GATAD1), which is a vital transcript factor affecting heart development and various heart diseases. However, it remains unclear whether SPC is involved in the regulation of cardiac fatty acid and glucose metabolism via GATAD1. In this study, we found that myocardium-specific Gatad1 knockout (Gatad1 CKO) significantly increased the myocardial infarct size, impaired cardiac function in I/R mice, and disrupted the protective effect of SPC on the hearts of I/R mice. Immunofluorescence experiment and western blot evaluation of the nuclear-cytoplasmic fractionation sample showed that GATAD1 acted as a transcription factor and was regulated by SPC. Double fluorescence reporting experiment and quantitative polymerase chain reaction (qPCR) revealed that GATAD1 could inhibit the expression of genes involved in fatty acid oxidation (FAO), i.e., acetyl-coenzyme A acyltransferase 2 (Acaa2) and medium-chain acyl-CoA dehydrogenase (Acadm), and promoted the expression of genes involved in glucose oxidation, i.e., pyruvate dehydrogenase E1 α subunit (Pdha1). Small interfering RNA (SiRNA) or overexpression strategies confirmed the pro-apoptotic roles of Acaa2 and Acadm and anti-apoptotic role of Pdha1 in cardiac myocytes challenged with I/R treatment. In summary, our findings suggest that SPC can be used as a candidate to prevent I/R injury by reshaping fatty acid and glucose metabolism. Transcription factor GATAD1 plays a crucial role in regulating fatty acid oxidation and glucose oxidation homeostasis and is involved in SPC-mediated cardioprotection during I/R of the heart. Our study identifies GATAD1 as a new therapeutic target for clinical treatment of myocardial I/R injury.

Adiponectin regulates proliferation and differentiation of chicken skeletal muscle satellite cells via ERK1/2 and p38 signaling pathways.

Skeletal muscle satellite cells (SMSCs) are critical for postnatal skeletal muscle growth and regeneration. Adiponectin plays a pivotal role in regulating muscle glucose uptake and fatty acid metabolism. However, its function in the proliferation and differentiation of chicken SMSCs remains poorly understood. In this study, we investigated the effects of adiponectin on the proliferation and differentiation of in vitro cultured chicken SMSCs. Our results demonstrated that adiponectin promoted SMSCs proliferation while inhibiting myogenic differentiation and inducing adipogenic differentiation. RNA-seq analysis revealed enrichment of the MAPK signaling pathway, suggesting its potential involvement in the regulation of adiponectin on SMSCs activity. Western blot analysis revealed that adiponectin activated ERK1/2 phosphorylation and inhibited p38 phosphorylation during the process of the inhibition on myogenic differentiation in chicken SMSCs. Furthermore, suppression of ERK1/2 signaling with U0126 or activation of p38 signaling with SSK1 reversed the downregulated expression of myogenic differentiation marker MyHC, MyOD1, and MyOG induced by adiponectin. These findings validated that adiponectin impeded myogenic differentiation through activation of ERK1/2 and inhibition of p38 signaling pathways. Additionally, activation of p38 signaling pathway reduced the increased percentage of EdU-positive cells induced by adiponectin. Collectively, these findings demonstrated that adiponectin impedes myogenic differentiation of SMSCs through activating ERK1/2 and inhibiting p38 signaling pathways, while promoting proliferation by inhibiting p38 signaling pathway.

Effective analysis of thyroid toxicity and mechanisms of acetyltributyl citrate using network toxicology, molecular docking and machine learning strategies.

The growing prevalence of environmental pollutants has raised concerns about their potential role in thyroid dysfunction and related disorders. Previous research suggests that various chemicals, including plasticizers like acetyl tributyl citrate (ATBC), may adversely affect thyroid health, yet the precise mechanisms remain poorly understood. The objective of this study was to elucidate the complex effects of acetyl tributyl citrate (ATBC) on the thyroid gland and to clarify the potential molecular mechanisms by which environmental pollutants influence the disease process. Through an exhaustive exploration of databases such as ChEMBL, STITCH, and GEO, we identified a comprehensive list of 19 potential targets closely associated with ATBC and the thyroid gland. After rigorous screening using the STRING platform and Cytoscape software, we narrowed this list to 15 candidate targets, ultimately identifying five core targets: CBX5, HADHB, TRIM33, TP53, and CUL4A, utilizing three well-established machine learning methods. In-depth Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses conducted in the DAVID database revealed that the primary pathways through which ATBC affects the thyroid gland involve key signaling cascades, including the FoxO signaling pathway and metabolic pathways such as fatty acid metabolism. Furthermore, molecular docking simulations using Molecular Operating Environment software confirmed strong binding interactions between ATBC and these core targets, enhancing our understanding of their interactions. Overall, our findings provide a theoretical framework for comprehending the intricate molecular mechanisms underlying ATBC's effects on thyroid damage and pave the way for the development of preventive and therapeutic strategies against thyroid disorders caused by exposure to ATBC-containing plastics or overexposure to ATBC.

A computational model of the crosstalk between hepatocyte fatty acid metabolism and oxidative stress highlights the key enzymes, metabolites, and detoxification pathways in the context of MASLD

Metabolic dysfunction-associated steatotic liver disease (MASLD; formerly known as NAFLD) is a common liver disease worldwide and carries the risk of progressing to severe liver conditions, such as fibrosis and liver cancer. In the context of MASLD, evaluating fat accumulation in the liver and the subsequent production of oxidative stress is essential to understand the disease propagation. However, clinical studies using human patients to investigate the fat accumulation and the onset of oxidative stress in MASLD face ethical and technical challenges, highlighting the importance of alternative methods. To understand the relationship between fatty acid metabolism, lipid accumulation, oxidative stress generation, and antioxidant mechanisms in hepatocytes, we proposed a new mathematical model. The importance of this model lies in its ability to track the time-dependent changes in oxidative stress and glutathione concentration in response to the input of fatty acids. Furthermore, the model allows for the evaluation of the effects of altering the activity of the key enzymes involved in those mechanisms. Our model is anticipated to provide new insights into MASLD therapy strategies by identifying key pathways and predicting the effects of drug-induced changes in enzyme activity.

Integrated analysis of methylome and transcriptome responses to exercise training in children with overweight/obesity.

We examined the effects of a 20-wk exercise intervention on whole blood genome-wide DNA methylation signature and its association with the exercise-induced changes in gene expression profiles in boys and girls with overweight/obesity (OW/OB). Twenty-three children (10.05 ± 1.39 yr, 56% girls) with OW/OB were randomized to either a 20-wk exercise intervention [exercise group (EG); n = 10; 4 boys/6 girls] or to usual lifestyle [control group (CG); n = 13; 6 boys/7 girls]. Whole blood genome-wide methylome (CpG sites) analysis using Infinium Methylation EPIC array and transcriptome analysis using RNA-seq (STRT2 protocol) were performed. Exercise-induced modifications in DNA methylation at 485 and 386 CpGs sites in boys and girls, respectively. These CpG sites are mapped to loci enriched in distinct gene pathways related to metabolic diseases, fatty acid metabolism, and immune function. In boys, changes in the DNA methylation of 87 CpG sites (18% of the 485 CpGs sites altered by exercise) were associated with changes in the gene expression levels of 51 genes also regulated by exercise. Among girls, changes in DNA methylation at 46 CpG sites (12% of the initial 386 significant CpGs) were associated with changes in the expression levels of 30 exercise-affected genes. Genes affected by exercise that were associated with DNA methylation are related to obesity, metabolic syndrome, and inflammation. Multiomics analysis of whole blood samples from children with OW/OB suggests that gene expression response to exercise may be modulated by DNA methylation and involve gene pathways related to metabolism and immune functions.NEW & NOTEWORTHY This study pioneers the exploration into the effects of exercise on whole blood genome-wide DNA methylation patterns and its association with changes in transcriptome profiles in children with overweight/obesity. Exercise potentially impacts molecular pathways involved in metabolism and immune functions in children with overweight/obesity (sex-specific responses) through the modification of epigenetic and transcriptomic profiles. Our preliminary results provide initial steps to understand better the molecular mechanisms underlying cardiometabolic benefits of exercise in children with overweight/obesity.

Comparative transcriptomic and metabolomics analysis of ovary in Nilaparvata lugens after trehalase inhibition

The fecundity of Nilaparvata lugens (brown planthopper) is influenced by trehalase (TRE). To investigate the mechanism by which trehalose affects the reproduction of N. lugens, we conducted a comparative transcriptomic and metabolomic analysis of the ovaries of N. lugens following injection with dsTREs and validamycin (a TRE inhibitor). The results revealed that 844 differentially expressed genes (DEGs) were identified between the dsGFP and dsTREs injection groups, with 317 up-regulated genes and 527 down-regulated genes. Additionally, 1451 DEGs were identified between the water and validamycin injection groups, with 637 up-regulated genes and 814 down-regulated genes. The total number of DEGs identified between the two comparison groups was 236. The overlapping DEGs were implicated in various biological processes, including protein metabolism, fatty acid metabolism, AMPK signaling, mTOR signaling, insulin/insulin-like growth factor signaling (IIS), the tricarboxylic acid (TCA) cycle, oxidative phosphorylation, and the cellular process of meiosis in oocytes. These results suggest that the inhibition of TRE expression may lead to alterations in ovarian nutrient and energy metabolism by modulating glucose transport and affecting amino acid metabolic pathways. These alterations may influence the reproduction of N. lugens by modulating reproductive regulatory signals. These findings provide robust evidence supporting the mechanism through which trehalase inhibition reduces the reproductive capacity of N. lugens.

MtrAB two-component system is crucial for the intrinsic resistance and virulence of Mycobacterium abscessus.

Mycobacterium abscessus (Mab) poses serious therapeutic challenges, largely due to its intrinsic resistance to many antibiotics. The development of targeted therapeutic strategies necessitates the identification of bacterial factors that contribute to its reduced susceptibility to antibiotics and/or to the killing by its host cells. In this study, we discovered that Mab strains with disrupted mtrA, mtrB or both, or a gene-edited mtrA encoding MtrA with Tyr102Cys mutation, exhibited highly increased sensitivity to various drugs compared to the wild-type Mab. In a murine model, three antibiotics inactive against the wild-type Mab demonstrated efficacy against the mtrA and mtrB knockout strains, significantly reducing pulmonary bacterial burdens compared to untreated controls. Notably, the virulence of all the mtrA, mtrB and mtrAB knockout mutants was highly diminished, evidenced by a reduced bacterial load in mouse lungs, undetectable level in spleens, and defective growth in macrophage RAW264.7. Morphological analysis revealed elongated cell length and multiple septa in knockout strains, suggesting both MtrA and MtrB regulate cell division of Mab. Furthermore, the absence of mtrA, mtrB or both significantly increased cell envelope permeability and reduced biofilm formation. Transcriptome sequencing showed altered expression levels of multiple genes related to plasma membrane, fatty acid metabolism and biosynthesis pathways in wild-type Mab and mtrA knockout strain. In summary, this study suggests that MtrA and MtrB play a crucial role in the intrinsic resistance and virulence of Mab by affecting cell division and altering cell permeability. Consequently, MtrA and MtrB represent promising targets for the discovery of anti-Mab drugs.

Impact of expression of metabolic genes on patient (pts) outcomes in metastatic colorectal cancer (mCRC): Data from CALGB/SWOG 80405 (Alliance).

224 Background: Metabolic pathways are reprogrammed during CRC development, leading to increased glycolysis, glutaminolysis, and fatty acid synthesis. Understanding the impact of metabolic reprogramming on treatment outcomes is paramount. Hence, we investigated whether the tumor gene expression of 4 selected major metabolic genes ( PKM, SLC2A1 , SLC16A1 , and CAV1 ) could affect treatment response in pts enrolled in the CALGB/SWOG 80405 trial. Methods: 433 mCRC pts treated with either bevacizumab (bev, n = 226) or cetuximab (cet, n = 207) in combination with first-line chemotherapy were analyzed. RNA was isolated from FFPE tumor samples and sequenced on the HiSeq 2500 (Illumina). Overall survival (OS) and progression-free survival (PFS) were compared between groups of pts categorized by tertiles of gene expression (high [H], medium [M] and low [L]). Logrank P -values provide a non-parametric unadjusted assessment of differences. Likelihood ratio tests (LRT) were computed from multivariate Cox proportional hazards models, adjusting for age, sex, ECOG, tumor side, number of metastatic sites, KRAS , CMS, and treatment. Results: PKM gene expression was associated with cet treatment outcomes with PKM- low tumors showing significantly longer PFS and OS (median PFS: 14.3 vs 9.8 vs 8.1 months, L vs M vs H, P < 0.0001, LRT P = 0.011; median OS: 45.9 vs 31.2 vs 20.9 months, P < 0.0001, LRT P = 0.12). Low SLC2A1 was also associated with longer OS in cet-treated pts (32.4 vs 35.8 vs 25.2 months, P = 0.02, LRT P < 0.0001). Similar results were observed in bev-treated pts where low SLC2A1 expressing tumors had longer OS (37.4 vs 26.1 vs 29 months, P = 0.037, LRT P = 0.069) and a non-significant trend for longer PFS (13.1 vs 11 vs 9.5 months, P = 0.076). CAV1 low gene expression was associated with longer OS in cet-treated pts (37.4 vs 34 vs 21.5 months, P = 0.0048, LRT P = 0.013), while no significant associations were found in bev-treated (interaction LRT P = 0.0009). No significant results were observed for SLC16A1 . Conclusions: The intratumoral expression of metabolic genes was prognostic and predictive in mCRC pts treated with first-line therapy. GLUT1 (encoded by SLC2A1 ) and PKM2 (encoded by PKM ) promote aerobic glycolysis of cancer cells, known as Warburg effect, supporting rapid cell proliferation and survival. CAV1 has been shown to be involved in mitochondrial bioenergetics and fatty acid metabolism and to play either a tumor suppressor or oncogenic role depending on the cancer type and stage. Lower expression of SLC2A1 and PKM was associated with improved survival and increased benefit from cet treatment in our cohort. Low CAV1 expression was also associated with increase survival suggesting a cancer-promoting role in mCRC. Our results suggest that targeting cancer cell metabolism through novel inhibitors of the aforementioned pathways may be a promising therapeutic strategy.

Discovering Phlebia acerina for efficient degradation of bisphenol S and insights into its degradation mechanism

Bisphenol S (BPS) has attracted much attention as an emerging hazardous contaminant due to its endocrine disruption and oncogenic effects. Although white-rot fungi have remarkable bioremediation capabilities for some bisphenols, little is known about their performance in BPS degradation. In this study, the newly discovered Phlebia acerina S-LWZ20190614-6 exhibited high capacity to degrade BPS. To further explore the mechanism of BPS degradation by P. acerina S-LWZ20190614-6, the whole-genome background and degradation pathways were investigated. Five low-toxicity metabolites were detected during the BPS biodegradation process, and a strong correlation was found between this biodegradation process and the interactions between BPS and ligninolytic enzymes. Moreover, transcriptomic analysis revealed that genes related to DNA replication and repair, ABC transporters, and fatty acid metabolism were involved in this BPS degradation process. Overall, this study provides insights into the achievement of BPS biodegradation by white-rot fungi.

The TFEB activator clomiphene citrate ameliorates lipid metabolic syndrome pathology by activating lipophagy and lipolysis

The balance between lipid synthesis and lipid catabolism is critical to maintain energy homeostasis. Lipophagy and lipolysis are two important pathways for lipid selective catabolism. Defects in lipophagy and lipolysis are linked to lipid metabolic diseases. Transcription factor EB (TFEB) is a master regulator of autophagy and lysosome biogenesis, as well as lipid metabolism by promoting expression of genes encoding fat catabolic lipases. Therefore, targeting TFEB provides a novel potential strategy for the treatment of lipid metabolic diseases. In this study, we showed that the TFEB activator clomiphene citrate (CC) activated the autophagy-lysosome and lipolysis pathways, and promoted degradation of lipid droplets induced by the free fatty acids oleate and palmitate in HepG2 cells. Moreover, CC treatment promoted lipid catabolism and attenuated obesity, restored lipid levels, blood glucose levels and insulin resistance, hepatocellular injury and hepatic steatosis, as well as liver inflammation in the HFD fed mice. In addition, we found that En-CC, a trans-isomer of CC, displayed less toxicity and more efficient activation of TFEB. Consistent with CC, En-CC treatment improved lipid metabolic syndrome pathology. These findings demonstrate that CC promotes clearance of lipids and ameliorates HFD-induced lipid metabolic syndrome pathology through activating TFEB-mediated lipophagy and lipolysis, indicating that CC has the potential to be used to treat lipid metabolic diseases.

Effects of targeting CTMP on immunogenicity of MSI-L colon adenocarcinoma cells by metabolism and cell cycle modulation.

246 Background: Regimen of metastatic colon cancer (mCOAD) is moving towards combination of immune checkpoint inhibitors (ICBs) and targeted therapy, however ICBs are rarely effective in MSI-L metastatic colon cancers, limiting options for backline treatments, new targeted therapy is on demand to improve immunogenicity of MSI-L mCOAD. As targeting fatty acid metabolism or cell cycle has shown potential in improving the efficacy of ICBs, our team focused on CTMP, a thioesterase (ACOT) family member, mainly modulates fatty acid β oxidation, meanwhile it binds to phosphorylation sites of AKT thus intervenes cell cycle, currently its role on immunogenicity of COAD is not clear. Methods: Correlation between CTMP and OS in MSI-L colon cancer patients was assessed by KM plotter in GEO database.11 Clinical samples of MSI-L colon cancer, who received a third-line treatment regimen of anti-PD-1 and fruquintinib, were collected then applied in immunofluorescence and western blot analyses to evaluate CTMP and MHC-I expression. In vitro, Lentiviral transfection of targeted genes were stably established,then applied in RNA-seq and metabolic assays. Proteomic analysis and co-IP were applied to explore CTMP-modulating pathway. In vitro, IFNγ was intratumorally injected. Results: KM curve showed CTMP was negatively correlated with OS in MSI-L COAD in GEO database. In clinical samples, lower CTMP expression and higher MHC-I expression were observed in partial response (PR) than progressive disease (PD) group. In vitro, CTMP-OE reduced MHC-I, increased AKT phosphorylation and immune checkpoints (PD-L1, IDO-1), promoted clone formation. Seahorse assay showed increased capacity of glycolysis and oxidative phosphorylation in CTMP-OE than vector. RNA-seq showed CTMP-OE reduced MHC-I augmentation under IFN-γ treatment, meanwhile glucose metabolism genes, ACOT family ,immune checkpoints were also up-regulated, indicating ACOT family related metabolism promotion and immunogenicity suppression of COAD. Proteomic analysis and co-IP assay indicated CTMP interacts REV7, a key mitotic regulatory protein. Enzyme activity assay showed REV7 negatively regulates CDK1. Furthermore, REV7-OE alone is capable to induce MHC I augmentation and G2 arrest, accordingly CTMP-KD enhanced REV7's negative modulation on CDK1,contributing to G2 arrest, that also augmented MHC I . In homologous mice tumor-bearing model, tumor shrinkage was observed in CTMP-KD/ REV7-OE group. CTMP-KD/ REV7-OE increases MHC I expression,CD8+ T cell infiltration under IFN γ intra-tumoral injection. Conclusions: In summary, our studies suggested that CTMP regulates the metabolism of colorectal cancer and intervenes MHC-I molecules expression, and targeting CTMP is potential in suppressing tumor cell cycle and promoting immunogenicity through its modulation on REV7.

Soybean bioactive peptide supplementation improves gut health and metabolism in broiler chickens.

This study aimed to investigate the effects of soybean bioactive peptide (SBP) on the growth performance and intestinal health of yellow-feathered broilers and to further elucidate the regulatory mechanisms of intestinal health using multi-omics analysis. A total of 320 1-day-old yellow-feathered broilers were randomly divided into two groups, with 10 replicates per group and 16 birds per replicate. Broilers in the control group received the basal diet, and those in the experimental group (SBPG) received the basal diet with 0.2 % SBP replacing the same amount of soybean meal. The experiment lasted for 70 d. The results showed that, compared with those in the control group, the final body weight and average daily gain of SBPG broilers were significantly higher (P < 0.05), and the feed conversion ratio was significantly lower (P < 0.05). Notably, SBP significantly improved gut health in chickens, including increased intestinal villus height, decreased levels of proinflammatory factors, such as IL-1β and interferon-γ, and upregulated expression of tight junction proteins, such as ZO-1 and occludin. In addition, transcriptome sequencing results revealed that broilers in the SBP group exhibited significant enrichment in multiple metabolic pathways, including fatty acid metabolism, fatty acid degradation, and the biosynthesis of unsaturated fatty acids (P < 0.05). Cecal 16S rRNA sequencing showed that SBPG increased the abundance of the butyrate-producing beneficial bacteria Muribaculaceae. Subsequent cecal metabolome analysis also revealed that SBPG enhanced lipid-related metabolic pathways, such as alpha-linolenic acid metabolism and GPI-anchor biosynthesis. In conclusion, SBP is a potential feed additive that can improve intestinal morphology, enhance intestinal immunity and barrier function, optimize the structure of the intestinal microbiota, and enhance metabolic function.

In silico analysis of non-conventional gene targets for genetic interventions to enhance fatty acid production: a review.

Since the 1990s, fatty acids (FA) have drawn significant industrial attention due to their diverse applications creating a demand for biological systems capable of producing high FA titers. While various strategies have been explored to achieve this, many of the conventional approaches rely on extensive genetic manipulations, which often result in strain instability, thus limiting its potential to yield better FA titers. Moreover, stresses such as pH, osmotic, and oxidative imbalances generated during FA production aggravate these challenges, further limiting FA titers. Under stress conditions, the cellular system responds by regulating stress-response proteins to bring about homeostasis. Recent findings suggest that transmembrane proteins, regulators of two-component systems, and cytoplasmic regulators can be strategically leveraged to address the problems related to stress-induced strain instability. Thus, non-conventional genetic targets, like chaperones (e.g., heat shock proteins) and DNA-binding transcriptional regulators (e.g., RcdA), which are not directly involved in FA metabolism, represent promising candidates to enhance strain stability and FA yields. Tools like Opt-Box and Weighted Gene Co-expression Network Analysis (WGCNA) serve as excellent platforms for understanding the cross-talk between these regulators and downstream enzymes. This review emphasizes the need for a shift towards identifying novel genetic targets by employing advanced in silico analysis and explains several molecular techniques that can aid in strain construction. Lastly, it discusses certain non-conventional gene targets that can help to overcome strain instability arising due to various stresses generated during/due to FA production.

Transferrin promotes fatty acid oxidation and liver tumor growth through PHD2-mediated PPARα hydroxylation in an iron-dependent manner

Tumor cells reshape iron and lipid metabolism for their rapid proliferation. However, how tumor cells coordinate the interplay between tumor cell-specific iron homeostasis and lipid metabolism reprogramming to counteract energy shortages remains unclear. Here, we demonstrated that glucose deprivation in hepatocellular carcinoma (HCC) cells induced AMPK-dependent Transferrin S685 phosphorylation, which exposed Transferrin nuclear localization signal (NLS) for binding to importin α7 and subsequent nuclear translocation. Nucleus-translocated Transferrin interacts with PPARα and enhance its protein stability to increase fatty acid oxidation (FAO) upon glucose deprivation. Mechanistically, PPARα-associated Transferrin upregulates iron-dependent PHD2-mediated PPARα P87 hydroxylation and subsequently disrupts the binding of MDM2 to PPARα, therefore inhibiting MDM2-mediated PPARα ubiquitination and degradation. Reconstitution of Transferrin S685A and NLS mutation or knock-in expression of PPARα P87A inhibited PPARα-mediated FAO upon energy stress, enhanced HCC cell apoptosis, and impeded liver tumor growth in mice. Importantly, combined treatment with Transferrin pS685 blocking peptide suppressing AMPK-Transferrin-PPARα axis could synergize with a well-established AMPK activator Metformin to inhibit tumor growth. Additionally, Transferrin pS685-mediated PPARα P87 hydroxylation is positively correlated with PPARα expression levels in human HCC specimens and poor patient prognosis. These findings revealed a mechanism by which Transferrin can sense energy stress to promote the hydroxylation and protein stability of PPARα through iron-dependent activation of PHD2 and underscore the moonlighting function of Transferrin in lipid catabolism and liver tumor development.

Ketogenesis supports hepatic polyunsaturated fatty acid homeostasis via fatty acid elongation.

Ketogenesis is a dynamic metabolic conduit supporting hepatic fat oxidation particularly when carbohydrates are in short supply. Ketone bodies may be recycled into anabolic substrates, but a physiological role for this process has not been identified. Here, we use mass spectrometry-based 13C-isotope tracing and shotgun lipidomics to establish a link between hepatic ketogenesis and lipid anabolism. Unexpectedly, mouse liver and primary hepatocytes consumed ketone bodies to support fatty acid biosynthesis via both de novo lipogenesis (DNL) and polyunsaturated fatty acid (PUFA) elongation. While an acetoacetate intermediate was not absolutely required for ketone bodies to source DNL, PUFA elongation required activation of acetoacetate by cytosolic acetoacetyl-coenzyme A synthetase (AACS). Moreover, AACS deficiency diminished free and esterified PUFAs in hepatocytes, while ketogenic insufficiency depleted PUFAs and increased liver triacylglycerols. These findings suggest that hepatic ketogenesis influences PUFA metabolism, representing a molecular mechanism through which ketone bodies could influence systemic physiology and chronic diseases.

A pro-inflammatory diet is associated with growth and virulence of Escherichia coli in pediatric Crohn's disease.

Epidemiological studies have suggested an association between the inflammatory potential of dietary patterns and Crohn's disease (CD). However, relationships of these inflammatory dietary determinants with the microbiome remain largely unknown. In this cross-sectional study, we evaluate the association between the inflammatory potential of habitual diet, as assessed by the modified Children-Dietary Inflammatory Index (mC-DII), and the fecal microbiome and metabolome of children with CD in comparison to healthy children. A cross-sectional study including 51 children with CD between 6 and 18 years of age and 50 healthy controls was conducted. Dietary inflammatory potential was measured using the modified Children-Dietary Inflammatory Index (mC-DII) and diet quality assessed by the Healthy Eating Index (HEI)-2015 and alternate Mediterranean eating index (aMed). Microbiome was analysed using shotgun metagenomic sequencing and untargeted metabolomic analysis. A poor-quality, pro-inflammatory diet with similar mC-DII, HEI-2015 and aMed scores was found across healthy children and children with CD. In children with active disease, a pro-inflammatory diet was associated with decreased diversity, increased virulence potential and expansion of the Proteobacteria phylum dominated by Escherichia coli (E. coli) spp. Positive correlation between E. coli relative abundance and mC-DII was associated with a low intake of a cluster composed of fibers, vitamins and minerals with anti-inflammatory potential. A negative association between metabolites of fatty acid metabolism and HEI was found. In total, our results suggest that a pro-inflammatory diet may potentiate hallmarks of the inflammation-associated dysbiosis in CD and highlight the need for microbiome-targeted dietary interventions optimizing the anti-inflammatory potential of habitual diet in the management of pediatric CD.

The impact of obesity on cardiac energy metabolism and efficiency in heart failure with preserved ejection fraction.

The incidence and prevalence of heart failure with preserved ejection fraction (HFpEF) continues to rise, and now comprises over half of all heart failure cases. There are many risk factors for HFpEF, including older age, hypertension, diabetes, dyslipidemia, sedentary behaviour, and obesity. The rising prevalence of obesity in society is a particularly important contributor to HFpEF development and severity. Obesity can adversely affect the heart, including inducing marked alterations in cardiac energy metabolism. This includes obesity-induced impairments in mitochondrial function, and an increase in fatty acid uptake and mitochondrial fatty acid ß-oxidation. This increase in myocardial fatty acid metabolism is accompanied by an impaired myocardial insulin signalling and a marked decrease in glucose oxidation. This switch from glucose to fatty acid metabolism decreases cardiac efficiency and can contribute to severity of HFpEF. Increased myocardial fatty acid uptake in obesity is also associated with the accumulation of fatty acids, resulting in cardiac lipotoxicity. Obesity also results in dramatic changes in the release of adipokines, which can negatively impact cardiac function and energy metabolism. Obesity-induced increases in epicardial fat can also increase cardiac insulin resistance and negatively impact cardiac energy metabolism and HFpEF. However, optimizing cardiac energy metabolism in obese subjects may be one approach to preventing and treating HFpEF. This review discusses what is presently known about the effects of obesity on cardiac energy metabolism and insulin signaling in HFpEF. The clinical implications of obesity and energy metabolism on HFpEF are also discussed.

Resequencing Composite Kazakh Whiteheaded Cattle: Insights into Ancestral Breed Contributions, Selection Signatures, and Candidate Genetic Variants

This study investigates the genetic architecture of the Kazakh Whiteheaded (KWH) cattle, applying population genetics approaches to resequenced genomes. FST analysis of 66 cattle breeds identified breeds for admixture analysis. At K = 19, the composite KWH breed showed contributions from Hereford, Altai, and Kalmyk cattle. Principal component analysis and ancestry inference confirmed these patterns, with KWH genomes comprising 45% Hereford, 30% Altai, and 25% Kalmyk ancestries. Haplotype analysis revealed 73 regions under putative selection in KWH, some shared with Hereford (e.g., with the gene DCUN1D4) and some KWH-specific (e.g., with the gene SCMH1). FST analysis identified 105 putative intervals under selection, with key genes (KITLG, SLC9C1, and SCMH1) involved in coat colour and physiological adaptations. Functional enrichment using The Database for Annotation, Visualization, and Integrated Discovery (DAVID) in selected regions highlighted clusters associated with developmental processes, ubiquitination, and fatty acid metabolism. Point FST identified 42 missense variants in genes enriched in functions related to economically important traits. Local ancestry inference revealed genomic intervals with predominantly non-Hereford ancestry, including high Altai (e.g., SCAPER) and Kalmyk (e.g., SRD5A2) contributions, while Hereford-dominated regions included genes ENO1 and RERE. This work elucidates the genomic contributions and adaptive signatures of selection shaping the KWH breed, providing candidate genetic variants for breeding program improvement and enhanced genome predictions.

Comparison of Volatile and Non-Volatile Compounds of Ice-Stored Large Yellow Croaker (Larimichthys crocea) Affected by Different Post-Harvest Handling Methods

To compare the impact of different post-harvest handling methods on volatile and non-volatile compounds, a total of 54 live large yellow croakers were subjected to commercial slaughter (CS), spinal cord cutting (SCC), or spinal cord cutting and bleeding (SCCB). The fish samples were ice-stored for 72 h, followed by the analysis of volatile compounds using gas chromatography–ion mobility spectrometry and non-volatile compounds using LC-MS-based untargeted metabolomics. The results revealed the detection of a total of 28 volatile organic compounds, with 23 being successfully identified, predominantly including alcohols, aldehydes, esters, ketones, and heterocyclic compounds. Substances such as (E)-2-nonenal and 2-butanone are highly sensitive to post-harvest handling methods during ice storage. Furthermore, 943 non-volatile metabolites were identified, showing significant differences in 180, 100, 117, and 186 metabolites across comparisons of SCC 0 h/CS 0 h, SCCB 0 h/CS 0 h, SCC 72 h/CS 72 h, and SCCB 72 h/CS 72 h, respectively. Notably, the altered metabolic pathways mainly involved fatty acid and amino acid metabolism, including pathways like glycerophospholipid metabolism and arginine biosynthesis. This study revealed the potential mechanisms underlying the enhancement of fish quality through spinal cord cutting and bleeding.