Lipid Metabolism Genes Research Articles

Network pharmacology and transcriptomics explore the therapeutic effects of Ermiao Wan categorized formulas for diabetes in mice.

Ermiao wan (EMW) is a classical traditional Chinese medicine formula, with two modified versions including Sanmiao wan (SMW) and Simiao wan (FMW). These Ermiao wan categorized formulas (ECFs) are traditionally used to treat gouty arthritis and hyperuricemia. However, their potential benefits and mechanisms on diabetes remain to be explored. This study aims to investigate the overall effects and biological differences of ECFs in high fat diet (HFD)-fed mice based on network pharmacology and transcriptomics. ECFs significantly reduced body weight, improved oral glucose tolerance, decreased fat accumulation, and lowered serum insulin and inflammatory cytokine levels in HFD-fed mice. FMW had better efficacy than EMW and SMW. Network pharmacology analysis revealed that ECFs targeted functional modules associated with chronic inflammation, lipid metabolism, and glucose metabolism. Transcriptome results also showed ECFs could inhibit genes associated with inflammation and upregulated some genes in lipid metabolism. Comprehensive analysis and QPCR verification indicated the beneficial effects of ECFs on diabetes might be attributed to the regulation of Ddit3, Ccl2, Esr1, and Cyp7a1. This study provides a theoretical basis for the clinical use of ECFs.

Identification of Key Genes Related to Immune-Lipid Metabolism in Skin Barrier Damage and Analysis of Immune Infiltration.

Several physical and chemical factors regulate skin barrier function. Skin barrier dysfunction causes many inflammatory skin diseases, such as atopic dermatitis and psoriasis. Activation of the immune response may lead to damage to the epidermal barrier. Abnormal lipid metabolism is defined as abnormally high or low values of plasma lipid components such as plasma cholesterol and triglycerides. The mouse skin barrier damage model was used for RNA sequencing. Bioinformatics analysis and validation were performed. Differently expressed genes (DEGs) related to immune and lipid metabolism were screened by differentially expressed gene analysis, and the enriched biological processes and pathways of these genes were identified by GO-KEGG. The interactions between DEGs were confirmed by constructing a PPI network. GSEA, transcription factor regulatory network, and immune infiltration analyses were performed for the 10 genes. Expression validation was performed by public datasets. The expression of key genes in mouse skin tissue was detected by qPCR. The expression of differentially expressed immune cell markers in the skin was detected by immunofluorescence. Based on the trans epidermal water loss (TEWL) score, the expression of key genes was detected by qPCR before skin barrier injury, at 4h and 7d, and at recovery from injury. Il17a, Il6, Tnf, Itgam, and Cxcl1 were immune-related key genes. Pla2g2f, Ptgs2, Plb1, Pla2g3, and Pla2g2d were key genes for lipid metabolism. Database validation and experimental results revealed that the expression trends of these genes were consistent with our analyses. The research value of these genes has been demonstrated through mouse datasets and experimental validation, and future therapeutic approaches may be able to mitigate the disease by targeting these genes to modulate the function of the skin barrier.

Expression of lipid-metabolism genes is correlated with immune microenvironment and predicts prognosis of hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors. This study was aimed to identify a lipid metabolism-related signature associated with the HCC microenvironment to improve the prognostic prediction of HCC patients. Clinical information and expression profile data were downloaded from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases, including the GEO dataset GSE76427. The gene expression profile of lipid metabolism was downloaded from Molecular Signatures Database (MSigDB) database. The infiltrating immune cells were estimated by the Estimation of Stromal and Immune cells in Malignant Tumor tissues using Expression data (ESTIMATE), MCP-counter, and TIMER algorithms. Functional analysis, including Gene ontology (GO) analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene set enrichment analysis (GSEA) were performed to elucidate the underlying mechanisms. The prognostic risk model was performed by Least absolute shrinkage and selection operator (LASSO) algorithm and Cox regression analysis. Two distinct subgroups of survival were identified. Better prognosis was associated with high immune score, high abundance of immune infiltrating cells, and high immune status. GO and KEGG analysis showed that differentially expressed genes (DEGs) between the two subgroups were mainly enriched in immune related pathways. GSEA analysis suggested that the expression of lipid metabolism related genes (LMRGs) was related to dysregulation of immune in the high-risk group. Risk models and clinical features based on LMRGs predicted HCC prognosis. This study indicated that the lipid metabolism-related signature was important for the prognosis of HCC. The expression of LMRGs was related to the immune microenvironment of HCC patients and could be used to predict the prognosis of HCC.

Apolipoprotein E Induces Lipid Accumulation Through Dgat2 That Is Prevented with Time-Restricted Feeding in Drosophila

Background: Apolipoprotein E (ApoE) is the leading genetic risk factor for late-onset Alzheimer’s disease (AD), which is the leading cause of dementia worldwide. Most people have two ApoE-ε3 (ApoE3) alleles, while ApoE-ε2 (ApoE2) is protective from AD, and ApoE-ε4 (ApoE4) confers AD risk. How these alleles modulate AD risk is not clearly defined, and ApoE’s role in lipid metabolism is also not fully known. Lipid droplets increase in AD. However, how ApoE contributes to lipid accumulation in the brain remains unknown. Methods: Here, we use Drosophila to study the effects of ApoE alleles on lipid accumulation in the brain and muscle in a cell-autonomous and non-cell-autonomous manner. Results: We report that pan-neuronal expression of each ApoE allele induces lipid accumulation specifically in the brain, but not in the muscle. However, this was not the case when expressed with muscle-specific drivers. ApoE2- and ApoE3-induced lipid accumulation is dependent on the expression of Dgat2, a key regulator of triacylglycerol production, while ApoE4 still induces lipid accumulation even with knock-down of Dgat2. Additionally, we find that implementation of time-restricted feeding (TRF), a dietary intervention in which food access only occurs in the active period (day), prevents ApoE-induced lipid accumulation in the brain of flies and modulates lipid metabolism genes. Conclusions: Altogether, our results demonstrate that ApoE induces lipid accumulation in the brain, that ApoE4 is unique in causing lipid accumulation independent of Dgat2, and that TRF prevents ApoE-induced lipid accumulation. These results support the idea that lipid metabolism is critical in AD, and that TRF could be a promising therapeutic approach to prevent ApoE-associated dysfunction in lipid metabolism.

Early-Stage Infection-Specific Heterobasidion annosum (Fr.) Bref. Transcripts in H. annosum–Pinus sylvestris L. Pathosystem

Transcriptomes from stem-inoculated Scots pine saplings were analyzed to identify unique and enriched H. annosum transcripts in the early stages of infection. Comparing different time points since inoculation identified 131 differentially expressed H. annosum genes with p-values of ≤0.01. Our research supports the results of previous studies on the Norway spruce–Heterobasidion annosum s.l. pathosystem, indicating the role of carbohydrate and lignin degradation genes in pathogenesis at different time points post-inoculation and the role of lipid metabolism genes (including but not limited to the delta-12 fatty acid desaturase gene previously reported to be an important factor). The results of this study indicate that the malic enzyme could be a potential gene of interest in the context of H. annosum virulence. During this study, difficulties related to incomplete reference material of the host plant species and a low proportion of H. annosum transcripts in the RNA pool were encountered. In addition, H. annosum transcripts are currently not well annotated. Improvements in sequencing technologies (including sequencing depth) or bioinformatics focusing on small subpopulations of RNA would be welcome.

Venous thromboembolism and ovarian cancer risk: a Mendelian randomized study

IntroductionA potential link between venous thromboembolism and the risk of ovarian cancer has been identified in clinical practice. However, it is unclear whether there is a causal relationship between the two. In this study, we applied a univariate two-sample Mendelian randomization method to explain the possible link between venous thromboembolism and ovarian cancer pathogenesis at the genetic level, and pointed out that lipid metabolism and ovarian cancer pathogenesis have innovative basic experimental directions.ObjectiveThis study explored the causal effect between a history of venous thromboembolism and the risk of ovarian cancer.MethodsGenome-Wide Association Study (GWAS) data of venous thromboembolism patients (n = 9176) of the same ethnicity were selected as study exposures, and GWAS data of ovarian cancer patients (n = 1218) of the same ethnicity were selected as study exposures. In this study, univariate two-sample Mendelian randomization analysis (UVMR) was performed separately using inverse variance weighted (IVW), MR-Egger regression, and weighted median (WM) to assess causal effects. In this study, Cochran’s Q test, MR-Egger regression intercept term, MR-PRESSO, and leave-one-out method were used for sensitivity analysis to assess the stability and reliability of the results.ResultsThe GWAS data screened in this study were all European ethnicity data. In this study, we found that genetically predicted history of venous thromboembolism was associated with an upward trend in ovarian cancer incidence, and the results of Weighted median, Simple mode, Weighted mode, and MR Egger showed a similar trend (OR = 1.0006, 95% CI: 1.00007–1.0013, p < 0.05). There was no heterogeneity of results (p = 0.18) and no horizontal pleiotropy (p = 0.77). The instrumental variables selected for venous thromboembolism in this study were all strong instrumental variables (F = 669.7). The results of the sensitivity analysis remained consistent.ConclusionThe results of this study indicate that patients with a history of venous thromboembolism are at increased risk of developing ovarian cancer and point to possible associations between lipid metabolism genes, such as CYP4V2, and the development of ovarian cancer, which provide interesting directions for further basic research.

Secreted Apoe rewires melanoma cell state vulnerability to ferroptosis.

A major therapeutic barrier in melanoma is the coexistence of diverse cellular states marked by distinct metabolic traits. Transitioning from a proliferative to an invasive melanoma phenotype is coupled with increased ferroptosis vulnerability. However, the regulatory circuits controlling ferroptosis susceptibility across melanoma cell states are unknown. In this work, we identified Apolipoprotein E (APOE) as the top lipid-metabolism gene segregating the melanoma MITFhigh/AXLlow proliferative/ferroptosis-resistant from MITFlow/AXLhigh invasive/ferroptosis-sensitive state. Mechanistically, ApoE secreted by the MITFhigh/AXLlow cells protects the invasive phenotype from ferroptosis-inducing agents by reducing the content of peroxidation-prone polyunsaturated fatty acids and boosting GPX4 levels both in vitro and in vivo. Whole-exome sequencing indicates that APOEhigh expression in patients with melanoma is associated with resistance to ferroptosis, regardless of APOE germline status. In aggregate, we found a ferroptosis-resistance mechanism between melanoma cell states relying on secreted ApoE and APOEhigh expression as a potential biomarker for poor ferroptosis response in melanoma.

Effects of Cannabidiol on Intestinal Myofibroblast Fibrotic PathwaysPATHWAYS

Inflammatory bowel disease (IBD) includes two immune-mediated disorders, Crohn’s disease (CD) and ulcerative colitis (UC). IBD is characterized by recurrent and chronic inflammation of the gastrointestinal tract. IBD is lifelong, and there is no cure. There has been an interest in new advanced medications to decrease inflammation and manage symptoms. Many of these new medications are expensive and depress the immune system, leaving many patients looking for alternatives to current medical therapies. Some IBD patients use medical marijuana to relieve the symptoms of this disease, and cannabidiol (CBD) in particular shows potential for reducing inflammation. This study investigates the potential therapeutic effects of CBD on IBD by examining its impact on fibrotic pathways in human intestinal myofibroblast (InMyoFib) cells. Cultured InMyoFibs were pre-treated with CBD, followed by transforming growth factor-beta 1 (TGF-β1) to stimulate a pro-fibrotic phenotype and mimic human IBD in the lab. Expression of genes associated with fibrosis, inflammation, and cannabinoid signaling was measured by quantitative polymerase chain reaction (qPCR). Fibrotic protein expression in the culture media was analyzed using enzyme-linked immunosorbent assays (ELISA). CBD pre-treatment before TGF-β1 stimulation significantly reduced the expression of pro-fibrotic genes ACTA2, CCN2, COL1A1, and SERPINH1 compared to cells stimulated with TGF-β1 alone. Additionally, CBD increased the expression of inflammation-related genes IL6 and PTGS2 and the lipid metabolism gene PPARG, known to have anti-fibrotic properties. These findings suggest that CBD may modulate fibrotic and inflammatory signaling pathways, providing a potential therapeutic avenue for IBD treatment.

ERICH4 is not involved in the assembly and secretion of intestinal lipoproteins

Background and AimsThe small intestine plays a central role in lipid metabolism, most notably the uptake of dietary fats that are packaged into chylomicrons and secreted into the circulation for utilisation by peripheral tissues. While microsomal triglyceride transfer protein (MTP) is known to play a key role in this pathway, the intracellular assembly, trafficking, and secretion of chylomicrons is incompletely understood. Methods and ResultsUsing human transcriptome datasets to find genes co-regulated with MTTP, we identified ERICH4 as a top hit. The gene encodes for glutamate-rich protein 4, a protein of unknown function. REACTOME gene-function prediction tools indicated that ERICH4 is involved in intestinal lipid metabolism. In addition, GWAS data point to a strong relationship between ERICH4 and plasma lipids. To validate ERICH4 as a lipid gene, we generated whole-body Erich4 knockout (Erich4-/-) mice. ERICH4 deficiency, however, did not result in changes in body weight and composition, food intake, circulating plasma lipids, energy absorption and excretion, and tissue weights compared to controls. Additionally, there were no morphological abnormalities seen in the small intestine. Challenging mice with a high-fat diet did not give rise to a phenotype either. ConclusionsDespite prediction tools indicating ERICH4 as a strong candidate gene in intestinal lipid metabolism, we here show that ERICH4 does not play a role in intestinal lipid metabolism in mice. It remains to be established whether ERICH4 plays a role in human lipid metabolism.

429 Maternal rate of gain and one-carbon metabolites supplementation alters the gene expression profile of fetal brain during early gestation in beef heifers

Abstract Maternal nutritional plane during pregnancy may leave lifelong impacts on offspring in beef cattle. Given that, we hypothesized that the supplementation of one-carbon metabolites (OCM) during pregnancy would mitigate the negative effects of maternal rate of gain through brain gene expression regulation in early developing bovine fetuses. The objective of this study was to evaluate the effects of OCM supplementation and maternal rate of gain on gene expression in the developing fetal brain in gestating beef heifers. Herein, Angus crossbred heifers (n = 72, body weight = 406 ± 33 kg) were randomly assigned to 2 × 2 factorial arrangement of treatments with two levels of maternal rate of gain (CON, 0.60 kg/d; and RES, -0.23 kg/d) each with or without OCM supplementation (+OCM, and -OCM). Heifers were fed individually and were bred using female-sexed semen from a single sire. The OCM supplementation included rumen-protected choline (44.4 g/d) and methionine (7.4 g/d) in corn carrier fed daily and weekly injections of folate (320 mg) and vitamin B12 (20 mg). The -OCM heifers received the corn carrier and saline injections. The treatments started at the time of breeding and continued until d 63 of gestation when pregnant heifers (n = 29) were slaughtered to collect fetal brain tissues for RNA sequencing. The fetal brain phenotypic data were analyzed using MIXED procedures of SAS, indicating that restricted nutrition affected the fetal right hemisphere weight (P &amp;lt; 0.05), and there was a strong tendency for overall fetal brain weight (0.05 &amp;lt; P &amp;lt; 0.1) to be affected as well. Brain transcriptomics data were analyzed using STAR aligner and a total of 177 differentially expressed genes (DEGs, FDR &amp;lt; 0.05) were identified across all treatment comparisons using DESeq2. Most of the DEGs were either isoforms of spliceosomal non-coding RNAs or micro-RNAs (miRNAs) associated with biological processes (FDR &amp;lt; 0.1) like mRNA processing, cellular nitrogen metabolism, lipid metabolism, and post-transcriptional gene silencing. The key miRNAs upregulated in the brain tissue of restricted fetuses without OCM supplementation, bta-mir-2375, bta-mir-876, and bta-mir-196a-1, were found to be associated with early embryogenesis and essential cellular regulatory processes. Conversely, in restricted fetuses with OCM supplementation, upregulated miRNAs such as bta-mir-216b, bta-mir-2285dd, and bta-mir-1298 were linked to early embryonic development, muscular development, and lipid metabolism in cattle. Both phenotypic and transcriptomics data here revealed that the maternal rate of gain altered fetal brain development, with differences seemingly compensated by OCM supplementation. USDA is an equal opportunity provider and employer.

Transcriptomic profiling reveals potential regulatory genes and molecular mechanisms of residual feed intake in Jian carp (Cyprinus carpio var. Jian)

Feed efficiency is one of the most important economic traits in animal production. Improving feed efficiency through genetic selection or other approaches will reduce production costs and mitigate environmental impacts. Residual feed intake (RFI) has some advantages over traditional feed efficiency metrics as a selection criterion for improving feed efficiency, because it is not a ratio and unrelated to growth. In this study, high RFI (HRFI) and low RFI (LRFI) Jian carp (Cyprinus carpio var. Jian) were tested for feed efficiency traits and serum biochemical indices. No significant differences were observed in the growth rates between HRFI and LRFI group, but daily feed intake of LRFI was significantly lower than that of the HRFI group. The results indicated that significantly higher content of triglyceride (TG) and total cholesterol (T-CHO) in the LRFI group was significantly correlated with RFI. We also selected HRFI and LRFI carp for transcriptomic analysis to determine differentially expressed genes (DEGs) in the liver tissues of 12 individuals. A total of 830 DEGs were identified between HRFI and LRFI group, of which 486 genes were up-regulated and 344 genes were down-regulated. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis revealed that DEGs were mainly enriched in fatty acid metabolism, ErbB signaling pathway, phosphatidylinositol signaling system, and autophagy. Lipid metabolism and autophagy-related genes, were considered candidate genes that played a crucial role in regulating feed efficiency. Taken together, these results indicated that differences in RFI affect Jian carp metabolism and cell fate, and that alterations in fatty acid metabolism and autophagy are key physiological modes of regulation in low RFI Jian carp. Our data provide valuable candidate genes and candidate pathways, which will help to study the molecular mechanisms of feed efficiency in carp.

Dietary supplementation of poly-dihydromyricetin-fused zinc nanoparticles alleviates fatty liver hemorrhagic syndrome by improving antioxidant capacity, intestinal health and lipid metabolism of laying hens

Fatty liver hemorrhagic syndrome is the main cause of noninfectious death of laying hens and results in substantial economic losses to the poultry industry. This study focused on evaluating the effects of Poly-dihydromyricetin-fused zinc nanoparticles (PDMY-Zn NPs) on antioxidant capacity, liver lipid metabolism, and intestinal health in laying hens. A total of 288 Jingfen laying hens (52 wk old) with similar body weights were randomly divided into 4 dietary groups with 6 replicates in each group for 8 wk. The control group received a basal diet, while the treatment groups were supplemented with PDMY-Zn NPs at levels of 200, 400, and 600 mg/kg, respectively. The results indicate that PDMY-Zn NPs supplementation can enhance antioxidant parameters (P < 0.05) in the blood and liver of laying hens. Simultaneously, it can mitigate vacuolar degeneration and inflammatory necrosis in hepatocytes, improve the relative expression level of related parameters associated with liver lipid metabolism and key regulatory genes (P < 0.05). Furthermore, it has been observed to reshape the composition and diversity of cecum microbes by increasing beneficial probiotics such as Lactobacillus and Prevotella, while also enhancing villi height and villi/crypt ratio in the duodenum and ileum (P < 0.05). Additionally, it elevates liver bile acid content along with the relative expression of key genes involved in liver synthesis (P < 0.05). In summary, PDMY-Zn NPs showed potential to alleviate fatty liver hemorrhagic syndrome by enhancing antioxidant capacity, regulating liver lipid metabolism, and maintaining intestinal health.

Tangerine Peel-Derived Exosome-Like Nanovesicles Alleviate Hepatic Steatosis Induced by Type 2 Diabetes: Evidenced by Regulating Lipid Metabolism and Intestinal Microflora.

Non-alcoholic fatty liver disease (NAFLD) represents a significant global health burden, exhibiting a strong correlation with insulin resistance, obesity, and type 2 diabetes (T2DM). Despite the severity of hepatic steatosis in T2DM patients, no specific drugs have been approved for clinical treatment of the disease. Tangerine peel is one kind of popular functional food and reported to possess hypoglycemic and lipid-lowering potential. In this study, we investigated the effects of Tangerine-peel-derived exosome-like nanovesicles (TNVs) on hepatic lipotoxicity associated with T2DM. The TNVs was prepared by differential centrifugation of the aqueous extract of Tangerine and chemical properties were characterized using transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA) and LC-MS/MS. The hypoglycemic and lipid-lowering potential of TNVs were possessed by biochemical measurement, RT-PCR, 16S rRNA sequencing, GC/MS, UHPLC-MS/MS, in vivo small animal imaging assay and HE staining. Subsequently, effects of TNVs on lipid accumulation and glycolysis were investigated on 3T3-L1 and AML-12 cells. TNVs significantly inhibited insulin resistance, reduced hepatic lipid accumulation, facilitate intestinal mucosal repair, rescued gut microbiota dysbiosis, regulated colonic SCFA and liver bile acid metabolism in db/db mice. Furthermore, TNVs restored the expression of key genes in glucose and lipid metabolism (ACC, AMPK, CD36, LXRα, PPAR-γ, SREBP-1) while activating the expression of genes related to glycolysis (G6Pase, GLUT2, PCK1, PEPCK) in db/db mice. Further cell-based mechanistic studies revealed that TNVs reduced lipid accumulation in 3T3-L1 and AML-12 cells via regulation of glucose and lipid metabolism-related genes (UCP1, FGFR4, PRDM16, PGC-1α, Tmem26, Cpt1, Cpt2 and PPAR-α). We for the first time demonstrated that TNVs could significantly improve glucose and lipid metabolism via activating the expression of genes related to fatty acid β-oxidation and glycolysis.

Acute waterborne cadmium exposure induces liver ferroptosis in Channa argus

The impact of cadmium (Cd) toxicity on fish liver injury has received much attention in recent years. Currently, autophagy, apoptosis and endoplasmic reticulum stress were reported in Cd exposed fish liver, and if there are other mechanisms (such as ferroptosis) and relevant signaling pathways involved in fish remains unknown. An experiment was conducted to investigate Cd toxicity in Channa argus (Cantor, 1842) exposed to 0, 1.0, and 2.0 mg Cd/L of water for 96 h. Cd disrupted the structure of mitochondria in the liver. Besides, Cd induced ferroptosis by significantly increasing the level of Fe2+, ROS, MDA and significantly decreasing the level of Ferritin, GSH, GSH-Px, GPX4, GST and SOD (p < 0.05 in all cases). In addition, the mRNA expression of ferroptosis related genes, gpx4 and slc7a11, were significantly downregulated by Cd. Moreover, Cd exposure significantly inhibited the Nrf2/Keap1 signaling pathway, one of the pathways involved in ferroptosis, by upregulating the mRNA levels of keap1a and keap1b, and downregulating the mRNA levels of nrf2 and its target genes (ho-1, nqo1 and cat). Cd exposure also caused extensive accumulation of vacuoles and lipid droplets in liver, as well as an increase in triglyceride content. Cd significantly affected lipid metabolism related enzyme activity and gene expression, which were also regulated by Nrf2/Keap1 signaling pathway. In summary, these results indicate that ferroptosis is a mechanism in waterborne Cd exposed fish liver injury via the Nrf2/Keap1 signaling pathway and the Cd induced hepatic steatosis is also modulated by Nrf2/Keap1 pathway at the whole-body level in fish. These findings provide new insights into the fish liver injury and molecular basis of Cd toxicity.

Non-Specific Elevated Serum Free Fatty Acids in Lung Cancer Patients: Nutritional or Pathological?

The reprogramming of lipid metabolism is a significant feature of tumors, yet the circulating levels of fatty acids in lung cancer patients remain to be explored. Moreover, the association between fatty acid levels and related factors, including nutritional intake, tumor metabolism, and tumor immunity, has been rarely discussed. To explore the differences in serum free fatty acids between lung cancer patients and healthy controls, and investigate the factors associated with this phenomenon. A case-control study enrolled 430 primary lung cancer patients and 430 healthy controls. The whole population had a medium [Q1, Q3] age of 48.0 [37.0, 58.9] years, with females comprising 56% of the participants. The absolute quantification of 27 serum free fatty acids (FFAs) was measured using a liquid chromatography-mass spectrometry (LC-MS/MS) detection. Data, including dietary intake, blood indicators, and gene expression of lung tissues, were obtained from questionnaires, blood tests, and RNA-sequencing. Statistical differences in FFA levels between lung cancer patients and healthy controls were investigated, and related contributing factors were explored. Levels of 22 FFAs were significantly higher in lung cancer patients compared to those in healthy controls, with fold changes ranging from 1.14 to 1.69. Lung cancer diagnosis models built with clinical and FFA features yielded an area under the receiver operating characteristic curve (AUROC) of 0.830 (0.780-0.880). Total fatty acids (TFAs), monounsaturated fatty acids (MUFAs), and polyunsaturated fatty acids (PUFAs) showed no significant dietary-serum associations, indicating that the elevations might not be attributed to an excessive intake of relevant fatty acids from the diet. For RNA-sequencing of lung tissues, among the 68 lipid metabolism genes, 26 genes showed significant upregulation (FDR < 0.05), while 33 genes exhibited significant downregulation, indicating the involvement of the fatty acids in the tumor metabolism. Through joint analysis with immune cells and inflammatory factors in the blood, fatty acids might exert suppressing effects on tumor immunity. Lung cancer patients had elevated levels of serum free fatty acids compared to healthy individuals. The elevations might not be attributed to an excessive intake of relevant fatty acids from the diet but related to pathological factors of tumor metabolism and immunity. These findings will complement research on fatty acid metabolism of lung cancer and provide insights into potential intervention targets.

Fatty acid oxidation is critical for the tumorigenic potential and chemoresistance of pancreatic cancer stem cells

BackgroundWe have previously demonstrated the significant reliance of pancreatic Cancer Stem Cells (PaCSCs) on mitochondrial oxidative phosphorylation (OXPHOS), which enables versatile substrate utilization, including fatty acids (FAs). Notably, dysregulated lipid scavenging and aberrant FA metabolism are implicated in PDAC progression.Methods & resultsOur bioinformatics analyses revealed elevated expression of lipid metabolism-related genes in PDAC tissue samples compared to normal tissue samples, which correlated with a stemness signature. Additionally, PaCSCs exhibited heightened expression of diverse lipid metabolism genes and increased lipid droplet accumulation compared to differentiated progenies. Treatment with palmitic, oleic, and linolenic FAs notably augmented the self-renewal and chemotherapy resistance of CD133+ PaCSCs. Conversely, inhibitors of FA uptake, storage and metabolism reduced CSC populations both in vitro and in vivo. Mechanistically, inhibition of FA metabolism suppressed OXPHOS activity, inducing energy depletion and subsequent cell death in PaCSCs. Importantly, combining a FAO inhibitor and Gemcitabine treatment enhanced drug efficacy in vitro and in vivo, effectively diminishing the CSC content and functionality.ConclusionTargeting FAO inhibition represents a promising therapeutic strategy against this highly tumorigenic population.

GCN2 drives diurnal patterns in the hepatic integrated stress response and maintains circadian rhythms in whole body metabolism during amino acid insufficiency.

Disruptions in circadian rhythms are associated with an increased risk of developing metabolic diseases. General control nonderepressible 2 (GCN2), a primary sensor of amino acid insufficiency and activator of the integrated stress response (ISR), has emerged as a conserved regulator of the circadian clock in multiple organisms. The objective of this study was to examine diurnal patterns in hepatic ISR activation in the liver and whole body rhythms in metabolism. We hypothesized that GCN2 activation cues hepatic ISR signaling over a natural 24-h feeding-fasting cycle. To address our objective, wild-type (WT) and whole body Gcn2 knockout (GCN2 KO) mice were housed in metabolic cages and provided free access to either a control or leucine-devoid diet (LeuD) for 8 days in total darkness. On the last day, blood and livers were collected at CT3 (CT = circadian time) and CT15. In livers of WT mice, GCN2 phosphorylation followed a diurnal pattern that was guided by intracellular branched-chain amino acid concentrations (r2 = 0.93). Feeding LeuD to WT mice increased hepatic ISR activation at CT15 only. Diurnal oscillations in hepatic ISR signaling, the hepatic transcriptome including lipid metabolic genes, and triglyceride concentrations were substantially reduced or absent in GCN2 KO mice. Furthermore, mice lacking GCN2 were unable to maintain circadian rhythms in whole body energy expenditure, respiratory exchange ratio, and physical activity when fed LeuD. In conclusion, GCN2 activation functions to maintain diurnal ISR activation in the liver and has a vital role in the mechanisms by which nutrient stress affects whole body metabolism.NEW & NOTEWORTHY This work reveals that the eIF2 kinase GCN2 functions to support diurnal patterns in the hepatic integrated stress response during natural feeding and is necessary to maintain circadian rhythms in energy expenditure, respiratory exchange ratio, and physical activity during amino acid stress.

Biological Roles of Lipids in Rice.

Lipids are organic nonpolar molecules with essential biological and economic importance. While the genetic pathways and regulatory networks of lipid biosynthesis and metabolism have been extensively studied and thoroughly reviewed in oil crops such as soybeans, less attention has been paid to the biological roles of lipids in rice, a staple food for the global population and a model species for plant molecular biology research, leaving a considerable knowledge gap in the biological roles of lipids. In this review, we endeavor to furnish a current overview of the advancements in understanding the genetic foundations and physiological functions of lipids, including triacylglycerol, fatty acids, and very-long-chain fatty acids. We aim to summarize the key genes in lipid biosynthesis, metabolism, and transcriptional regulation underpinning rice's developmental and growth processes, biotic stress responses, abiotic stress responses, fertility, seed longevity, and recent efforts in rice oil genetic improvement.

IGFBP1 promotes the proliferation and migration of lung adenocarcinoma cells through the PPARα pathway

BackgroundThe immune status is closely linked to cancer progression, metastasis, and prognosis. Lipid metabolism, crucial for reshaping immune status, plays a key role in regulating the advancement of lung adenocarcinoma (LUAD) and deserves further investigation. MethodsThis study classifies LUAD patients into different immune subtypes based on lipid metabolism-related genes and compares the clinical characteristics among these subtypes. Single-multi COX analysis screens out key genes related to prognosis, and a risk feature and prognostic model are constructed. Cell cloning, scratch, transwell, western blotting and flow cytometry cell cycle analysis to detect the function of key genes. A subcutaneous tumor animal model is used to investigate the in vivo function and molecular mechanisms of key genes. ResultsLUAD patients are classified into three immune subtypes, among which C3 subtype has lower immune status and higher frequency of gene mutations, and show lower immunoreactivity in immunotherapy. COX analysis identified a prognostic model for four lipid metabolism factors (IGFBP1, NR0B2, PPARA, and POMC). IGFBP1, a core gene in this model, is highly expressed in the C3 subtype. Functionally, knocking down IGFBP1 significantly inhibits tumor cell cloning, scratch, and migration abilities, and downregulates the expression of cell cycle and EMT-related proteins. Knocking down IGFBP1 significantly inhibits tumor burden (P < 0.05). Mechanistically, knocking down IGFBP1 inhibits the activation of PPARα to regulate tumor cell growth. ConclusionsThis study found that lipid metabolism genes are closely related to LUAD, and IGFBP1 may be a key gene in regulating tumor growth and development.

Deciphering the role of lipid metabolism and acetylation in osteosarcoma: A comprehensive molecular analysis.

Osteosarcoma, known for its rapid progression and high metastatic potential, poses significant challenges in adolescent oncology. This study delves into the roles of lipid metabolism and acetylation genes in the disease's pathogenesis. Utilizing gene set variation analysis, we examined 14 lipid metabolism-related pathways in osteosarcoma patients, identifying significant variances in three pathways between metastatic and primary cases. Additionally, differences in four acetylation genes between these groups were observed. A comprehensive analysis pinpointed 62 lipid metabolism-related genes, with 39 exhibiting significant correlations with acetylation genes, termed lipid metabolism acetylation (LMA) genes. Employing machine learning techniques like Lasso+RSF and GBM, we developed a predictive model for overall survival based on LMA genes. This model, with an average c-index of 0.771, focuses on three key genes: CYP2C8, PAFAH2, and ACOX3, whose prognostic value was confirmed through survival and receiver operating characteristic curve analyses. Quantitative RT-PCR results indicated higher expression levels of ACOX3 and PAFAH2 in OS cells (143B, HOS, MG63) than in osteoblasts (hFOB1.19), while CYP2C8 was lower in OS cells. Furthermore, drug sensitivity analysis through the pRRophetic algorithm suggested potential targeted therapies, revealing drugs with differential sensitivity based on LMA scores and varied treatment responses related to the expression of core genes. This study not only highlights the crucial role of lipid metabolism and acetylation in osteosarcoma but also offers a foundation for personalized treatment strategies, marking a notable advancement in combating this severe form of adolescent cancer.