Lipid Metabolism Genes Research Articles

Lipid metabolism-related gene signature predicts prognosis and unveils novel anti-tumor drugs in specific type of diffuse large B cell lymphoma.

Diffuse large B-cell lymphoma (DLBCL) is the most common type of lymphoma which possess highly aggressive and heterogeneous. Despite advances in understanding heterogeneity and development of novel targeted agents, the prognosis of DLBCL patients remains unsatisfied. Lipids are crucial components of biological membranes and signal transduction while accumulating evidence has supported the vital roles of abnormal lipid metabolism in tumorigenesis. Furthermore, some related pathways could serve as prognostic biomarkers and potential therapeutic targets. However, the clinical significance of abnormal lipid metabolism reprogramming in DLBCL has not been investigated. In the current study, we developed a prognostic risk model for DLBCL based on the abnormal expressed lipid metabolism genes and moreover based on our risk model we classified patients with DLBCL into novel subtypes and identified potential drugs for DLBCL patients with certain lipid metabolism profiles. We utilized univariate Cox regression analysis to identify the prognosis-related lipid metabolism genes, and then performed LASSO Cox regression to identify prognostic related lipid metabolism related genes. Multivariate cox regression was used to establish the prognostic model. Patients were divided in to high and low risk groups based on the median risk score. Immune cell infiltration and GSEA were used to identify the pathways between high and low risk groups. Oncopredict algorithm was utilized to identify potential drug for high-risk patients. In vitro cell apoptosis and viability analysis were employed to verify the specific tumor inhibition effects of AZD5153. Nineteen survival related lipid metabolism genes TMEM176B, LAYN, RAB6B, MMP9, ATAD3B, SLC2A11, CD3E, SLIT2, SLC2A13, SLC43A3, CD6, SIRPG, NEK6, LCP2, CTTN, CXCL2, SNX22, BCL6 and FABP4 were identified and subjected to build the prognostic model which was further verified in four external microarray cohorts and one RNA seq cohorts. Tumor immune microenvironment analysis and GSEA results showed that the activation of MYC targets genes rather than immunosuppression contribute to the poor survival outcome of patients in the high-risk group. AZD5153, a novel bivalent BET bromodomain inhibitor which could inhibit the transcription of MYC and E2F exhibited specific antitumor function for cells with high-risk score. Our results provide the first lipid metabolism-based gene signature for predicting the survival of patients with DLBCL. Furthermore, by determining novel subtypes with our lipid metabolism prognostic model we illustrated that drugs that compromising MYC target genes rather than immune checkpoint inhibitors may be beneficial to DLBCL patients with certain lipid metabolism profiles.

Favorable inhibitory effect of clodronate on hepatic steatosis in short bowel syndrome model rats.

This study investigated the anti-inflammatory effect of clodronate, a vesicular nucleotide transporter (VNUT) inhibitor, on intestinal-failure-associated liver disease (IFALD) in a rat model of short bowel syndrome (SBS). The rats underwent jugular vein catheterization for continuous total parenteral nutrition (TPN) and 90% small bowel resection. The animals were divided into the following groups: TPN/SBS (Control group), TPN/SBS/intravenous administration of low-dose clodronate (20mg/kg twice per week; Low group), or TPN/SBS/intravenous administration of high-dose clodronate (60mg/kg twice per week; High group). On day 7, the rats were euthanized. Hepatic steatosis and hepatocellular injury were also assessed. Hepatic steatosis and lobular inflammation in the liver were observed in all groups. The High group showed histologically reduced hepatic steatosis compared with the Control group. IL-6 and Nlrp3 expression in the High group was significantly suppressed compared to that in the Control group. The expression of other inflammatory cytokines tended to be lower in the High dose group than in the control group. The lipid metabolism gene expression in the liver specimens showed no significant differences among the groups. The high-dose administration of clodronate may, therefore, inhibit hepatic steatosis and inflammation associated with IFALD in patients with SBS.

EPCO-17. CARM1 METHYLATES GLIOBLASTOMA TUMOR SUPPRESSOR QUAKING TO REGULATE ITS TRANSCRIPTIONAL COACTIVATOR FUNCTION

Abstract Glioblastoma (GBM) represents the most prevalent and deadly primary brain tumor in adults, and it remains highly refractory to current therapeutic interventions. Significant intratumor heterogeneity drives rapid invasion, immune escape, and therapeutic resistance. Therapeutic paradigms based on deconvoluting key molecular mechanisms driving gliomagenesis are urgently needed. Quaking (Qki, encoded by Qk) is frequently altered in GBM patients; Qk mutations or deletions occur in 35% percent of cases, and the Qki protein is absent in 50-60% of cases. Our lab has characterized Qki as important tumor suppressor in GBM, where deletion of Qk enables pre-malignant neural stem cells to expand outside their niche and develop into tumors that recapitulate human GBM. We discovered that Qki functions as a transcriptional coactivator of lipid metabolism genes, whereby Qki loss disrupts lipid homeostasis and compromises the integrity of various membrane structures. Several downstream processes governed by Qki have been delineated; however, upstream regulators of Qki have yet to be identified. Recurrent cancer mutations to specific Qki arginine sites implicate the dysregulation of arginine methylation, a common post-translational modification catalyzed by protein arginine methyltransferases (PRMTs). Leveraging in vitro methylation assays, we demonstrate that Qki is selectively methylated by the PRMT coactivator-associated arginine methyltransferase 1 (CARM1), specifically in the Quaking regulatory domain where cancer mutations are reported. We observe that Qki interacts with known CARM1 substrates, functioning in the transcriptional complex assembled by CARM1. Through mutagenesis studies, we identified arginine 242 (R242) and arginine 256 (R256) as specific CARM1-mediated methylation sites on Qki. Importantly, mutations to these sites compromise Qki’s activity as a transcriptional coactivator. Moreover, brain-specific deletion of CARM1 in vivo results in neurological phenotypes reminiscent of Qki deletion. Altogether, we provide evidence that CARM1 represents a novel tumor suppressor in GBM that functions through the arginine methylation of Qki.

TMET-17. LIPID METABOLIC HETEROGENEITY OF GLIOMA CELLULAR STATES REVEALS ENVIRONMENTAL DEPENDENCIES

Abstract Malignant growth and survival of cancer is supported through reprogrammed lipid metabolism. In gliomas, genetic alterations can drive lipid metabolic dysregulation revealing therapeutic opportunities to exploit lipid metabolic vulnerabilities within genetically defined subsets of glioma tumors. However, it remains unclear whether inter- and intra-tumoral transcriptomic heterogeneity in gliomas relates to distinct lipid programs and potential dependencies. Here we set out to characterize pan-glioma lipid metabolic heterogeneity through genomic, transcriptomic, and lipidomic profiling of a large and diverse cohort of patient tumor samples. We define key axes of lipid metabolic variability across gliomas and identify relationships between lipid metabolic gene expression programs and glioma lipidomic profiles. Intriguingly, intersection of lipid gene expression signatures with single cell RNA sequencing revealed patterns of lipid metabolic heterogeneity that distinguish neurodevelopmental cellular states of gliomas, mirroring patterns of lipid metabolic diversity across cell types within the normal brain. Consequently, tumors with opposing cellular state enrichment have distinct lipid metabolism and environmental dependencies. Tumors enriched for Radial Glia-like states have high capacity for de novo fatty acid synthesis while tumors enriched for oligodendrocyte progenitor-like states are dependent on exogenous sources of lipids for survival and growth. These findings connect inter- and intra-tumoral heterogeneity of cellular states to variability in lipid metabolic reprogramming to reveal future avenues for precision medicine.

Characterization and expression analysis of the B3 gene family during seed development in Akebia trifoliata

BackgroundB3 genes encode transcription factors that play key roles in plant growth and development. However, the specific B3 genes involved in the seed development of Akebia trifoliata remain unexplored.ResultsA total of 72 AktB3 genes were identified and classified into five subfamilies (ARF, LAV, RAV, HSI, and REM) based on phylogenetic analysis. These 72 AktB3 genes were unevenly distributed across 16 chromosomes. Collinear analysis indicated that segmental duplication has played a significant role in the evolution of AktB3 genes, and underwent purification selection. Expression profiling across seed development stages revealed that seven AktB3 genes, particularly from the LAV subfamily (AktABI3, AktFUS3, AktLEC2), were up-regulated at 70 days after flowering (DAF). Notably, the expression of oleosin exhibited a strong positive correlation with LAV subfamily genes, highlighting their potential roles as hub genes in lipid metabolism and seed development. Yeast two-hybrid (Y2H) and yeast one-hybrid (Y1H) experiments confirmed that AktFUS3-1, AktFUS3-2, and AktLEC2 form protein complexes and individually bind to the AktOLE1 promoter, thereby regulating downstream gene expression. These results provide direct evidence of the cooperative role these transcription factors play in controlling lipid metabolism, particularly related to oleosin proteins. Additionally, miRNA sequencing across three seed developmental stages identified 591 miRNAs and 1,673 target gene pairs. A total of 23 AktB3 genes were predicted to be targets of 20 miRNAs, with 11 miRNAs specifically targeting the ARF subfamily genes. Particularly, miR160-x, miR160-z, and miR167-z were predicted to target ARF subfamily genes, potentially influencing seed development. Moreover, the miRNA-B3 regulatory modules, especially involving ARF genes and miR160/167, require further study to clarify their roles in seed development.ConclusionsThese findings contribute valuable resources for future functional studies of the molecular regulatory networks governing seed development in A. trifoliata.

Genetic Polymorphisms in Obesity: How Variants in Lipid Metabolism Genes Contribute to Hyperlipidemia

Obesity is a complex metabolic disorder influenced by both environmental and genetic factors. Among the genetic contributors, polymorphisms in lipid metabolism genes play a significant role in regulating lipid profiles and promoting hyperlipidemia. This review aims to explore the impact of genetic variants on lipid metabolism in individuals with obesity, focusing on genes such as APOE, LPL, FTO, PCSK9, CETP, and FABP. These polymorphisms alter lipid processing, transportation, and storage, leading to aberrant lipid levels, which contribute to hyperlipidemia and subsequent cardiometabolic complications. We will also discuss the gene-environment interactions that modulate these genetic effects and review potential therapeutic interventions targeting lipid metabolism to manage hyperlipidemia in obese individuals. Keywords: Genetic polymorphisms, obesity, lipid metabolism, hyperlipidemia, gene-environment interactions, cardiometabolic disease

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.

MiRNA-148a-3p targets to regulate the lipid metabolism gene SOCS3 to reduce myocardial ischemia/reperfusion injury.

Acute myocardial infarction (AMI) is a major cause of death in cardiovascular patients. SOCS3's protective role in cardiac I/R-I is being explored, and miRNAs, particularly miRNA-148a-3p, are suspected to target SOCS3. To elucidate the role of miRNA-148a-3p targeting lipid metabolism gene SOCS3 in cardiac ischemia-reperfusion injury (I/R-I) in rats. Derived mRNA expression data GSE59867 from GEO, identified 558 lipid metabolism genes from KEGG and GSEA, and screened for differentially expressed genes in acute myocardial infarction (AMI). Predicted miRNA-148a-3p targeting SOCS3 using TargetScanHuman, validated binding via luciferase assay and 3'UTR mutation. Established a rat I/R-I model to assess miRNA-148a-3p and SOCS3 expression, and investigated SOCS3 regulation by miRNA-148a-3p overexpression. Analyzed expression of NF-κB p65, IL-1β, and TNF-α-related proteins, and evaluated cardiac hemodynamics post-SOCS3 regulation by miRNA-148a-3p. In GSE59867, TSPO, SOCS3, LRP1, PLB1, CYP1B1, PPARG, ACSL1, and CYP27A1 were identified as differentially expressed lipid metabolism genes in AMI. The results of immune infiltration showed a close relationship between the differential lipid metabolism genes and the infiltration of immune cells such as macrophages and monocytes. The random forest algorithm identified SOCS3 as the key gene. The luciferase reporter gene demonstrated the participation of miRNA-148a-3p in the regulation of SOCS3 by binding to its 3'UTR. In vivo experiments revealed low expression of miRNA-148a-3p in myocardial I/R, while SOCS3 was highly expressed. Elevated miRNA-148a-3p expression led to a decrease in SOCS3, NF-κB p65, IL-1β, and TNF-α levels during cardiac I/R-I. Overexpression of miRNA-148a-3p enhanced the cardiac performance in rats experiencing cardiac I/R-I. Overexpression of miRNA-148a-3p regulates NF-κB signaling pathway by targeting lipid metabolism gene SOCS3, reduces inflammatory response, and then reduces cardiac I/R-I in rats.

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.