Transcriptomic analysis of short/branched-chain acyl-coenzyme A dehydrogenase knocked out bMECs revealed its regulatory effect on lipid metabolism
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ABSTRACT:
PROVIDER: PRJNA750762 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR15298988_1.fastq.gz | Fastqsanger.gz | |||
| SRR15298988_2.fastq.gz | Fastqsanger.gz | |||
| SRR15298989_1.fastq.gz | Fastqsanger.gz | |||
| SRR15298989_2.fastq.gz | Fastqsanger.gz | |||
| SRR15298990_1.fastq.gz | Fastqsanger.gz |
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Project description:The acyl-CoA dehydrogenase family of enzymes includes short/branched-chain acyl-CoA dehydrogenase (ACADSB), which catalyzes the dehydrogenation of acyl-CoA derivatives in fatty acid metabolism. Our previous findings suggested that ACADSB was a critical candidate gene affecting milk fat synthesis by comparing the transcriptome in bovine mammary epithelial cells (bMECs) from Chinese Holstein dairy cows producing high-fat and low-fat milk as well as gene functional validation studies on the cellular level. In the present study, ACADSB in bMECs was knocked out (KO) using a CRISPR/Cas9 system, and mRNA transcriptome was further sequenced to verify the function of the ACADSB gene and analyze its correlation with lipid metabolism. The findings revealed that 15,693 genes were expressed, 1,548 genes were differentially expressed genes (DEGs), and 6,098 GO terms were enriched, of which 637 GO terms were greatly enhanced, such as phospholipid-translocation ATPase activity (GO:0004012), lipoprotein lipase activity (GO:0004465), acyl-CoA desaturase activity (GO:0016215), and so on. The analysis by KEGG showed that DEGs were distributed over 247 pathogens, of which 49 were significantly enriched, including the metabolism of fatty acids (PATH: 01212), metabolism of glycerolipid (PATH: 00561), and signaling of adipocytokines (PATH: 04920). The CHOL, TGs and FFA contents in bMECs were reduced when the ACADSB gene was knocked out. The RT2 Profiler PCR array also revealed that the loss of the ACADSB gene changed the expression levels of functional genes involved in lipid metabolism, including ACADL, ACOX2, ACAT2, and FABP3. In conclusion, the current findings show that ACADSB is a key regulator of lipid metabolism in bMECs. The ACADSB-/- bMECs could also be useful genetic material and tools for future research into gene functions related to lipid and fatty acid metabolism. It will be valuable for revealing the gene regulatory roles and molecular mechanisms in milk fat synthesis.
| S-EPMC8453006 | biostudies-literature
Project description:During fasting, mitochondrial fatty-acid β-oxidation (mFAO) is essential for the generation of glucose by the liver. Children with a loss-of-function deficiency in the mFAO enzyme medium-chain acyl-Coenzyme A dehydrogenase (MCAD) are at serious risk of life-threatening low blood glucose levels during fasting in combination with intercurrent disease. However, a subset of these children remains asymptomatic throughout life. In MCAD-deficient (MCAD-KO) mice, glucose levels are similar to those of wild-type (WT) mice, even during fasting. We investigated if metabolic adaptations in the liver may underlie the robustness of this KO mouse. WT and KO mice were given a high- or low-fat diet and subsequently fasted. We analyzed histology, mitochondrial function, targeted mitochondrial proteomics, and transcriptome in liver tissue. Loss of MCAD led to a decreased capacity to oxidize octanoyl-CoA. This was not compensated for by altered protein levels of the short- and long-chain isoenzymes SCAD and LCAD. In the transcriptome, we identified subtle adaptations in the expression of genes encoding enzymes catalyzing CoA- and NAD(P)(H)-involving reactions and of genes involved in detoxification mechanisms. We discuss how these processes may contribute to robustness in MCAD-KO mice and potentially also in asymptomatic human subjects with a complete loss of MCAD activity.
2019-10-21 | GSE136309 | GEO
Project description:Acyl coenzyme A binding protein (ACBP), encoded by the diazepam binding protein (DBI) gene, plays a pivotal role in stimulating appetite and lipo-anabolic reactions, showing correlations with laboratory indications of metabolic syndrome in ostensibly healthy individuals. In a screening effort targeting inhibitors of ACBP/DBI expression among distinct neuroendocrine factors, we discovered that glucocorticoids induce ACBP/DBI secretion in cultured cells. In mouse models of iatrogenic Cushing syndrome, antibody-mediated neutralization of ACBP/DBI prevented the metabolic consequences of prolonged glucocorticoid administration. Our findings suggest that a surge in extracellular ACBP/DBI may mediate crucial aspects of Cushing syndrome.
2024-10-02 | GSE248672 | GEO
Project description:The 21st century is an era of molecular breeding, leading to fundamental dairy market and production system changes. Milk fat is the main economic trait in dairy cattle production. Our previous study revealed that the ACADSB gene has a crucial regulatory role in lipid metabolism, which can alter the contents of TGs, CHOL and fatty acids by regulating some related gene which involve in lipid metabolism. As usual, when we explored the function of interest genes, we often design interference and overexpression vectors to regulate the expression level of related gene, and transiently transfect vectors into cells, however, it is limited by transfection efficiency. therefore, we committed to finding a stable mode of gene expression. Knocking out of the ACADSB gene in bovine mammalian epithelial cells (bMECs), which represents a promising and effective means of further research on the effects of ACADSB in vivo lipid metabolism of dairy cattle. At the same time, the knock-out ACADSB gene's bMECs could also be useful genetic material and tools for future research into gene functions related to lipid and fatty acid metabolism, which also can directly use for further exploring the gene molecular mechanism or related pathway.
2021-08-10 | GSE181131 | GEO
Project description:Implication of Acyl Coenzyme A Binding Protein (ACBP) in Cushing Syndrome
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Project description:Transcriptome analysis suggests a compensatory role of the cofactors coenzyme A and NAD+ in medium-chain acyl-CoA dehydrogenase knockout mice
| PRJNA562153 | ENA
Project description:Cross-species investigations of cancer invasiveness are a new approach that has already identified new biomarkers which are potentially useful for improving tumor diagnosis and prognosis in clinical medicine and veterinary science. In this study, we combined proteomic analysis of four experimental rat malignant mesothelioma (MM) tumors with analysis of ten patient-derived cell lines to identify common features associated with mitochondrial proteome rewiring. A comparison of significant abundance changes between invasive and non-invasive rat tumors gave a list of 433 proteins, including 26 proteins reported to be exclusively located in mitochondria. Next, we analyzed the differential expression of genes encoding the mitochondrial proteins of interest in five primary epithelioid and five primary sarcomatoid human MM cell lines; the most impressive increase was observed in the expression of the long-chain acyl coenzyme A dehydrogenase (ACADL). To evaluate the role of this enzyme in migration/invasiveness, two epithelioid and two sarcomatoid human MM cell lines derived from patients with the highest and lowest overall survival were studied. Interestingly, sarcomatoid vs. epithelioid cell lines were characterized by higher migration and fatty oxidation rates, in agreement with ACADL findings. These results suggest that evaluating mitochondrial proteins in MM specimens might identify tumors with higher invasiveness.
2023-06-20 | PXD042942 | Pride
Project description:Medium-chain acyl-coenzyme A (CoA) dehydrogenase (MCAD) catalyzes crucial steps in mitochondrial fatty acid oxidation, a process that is of key relevance for maintenance of energy homeostasis, especially during high metabolic demand. To gain insight into the metabolic consequences of MCAD deficiency under these conditions, we compared hepatic carbohydrate metabolism in vivo in wild-type and MCAD-/- mice during fasting and during a lipopolysaccharide (LPS)-induced acute phase response (APR). MCAD-/- mice did not become more hypoglycemic on fasting or during the APR than wild-type mice did. Nevertheless, microarray analyses revealed increased hepatic peroxisome proliferator-activated receptor gamma coactivator-1a (Pgc-1a) and decreased peroxisome proliferator-activated receptor alpha (Ppar a) and pyruvate dehydrogenase kinase 4 (Pdk4) expression in MCAD-/- mice in both conditions,suggesting altered control of hepatic glucose metabolism. Quantitative flux measurements revealed that the de novo synthesis of glucose-6-phosphate (G6P) was not affected on fasting in MCAD-/- mice. During the APR, however, this flux was significantly decreased (-20%) in MCAD-/- mice compared with wild-type mice. Remarkably, newly formed G6P was preferentially directed toward glycogen in MCAD-/- mice under both conditions. Together with diminished de novo synthesis of G6P, this led to a decreased hepatic glucose output during the APR in MCAD-/- mice; de novo synthesis of G6P and hepatic glucose output were maintained in wild-type mice under both conditions. APR-associated hypoglycemia, which was observed in wild-type mice as well as MCAD-/- mice, was mainly due to enhanced peripheral glucose uptake. Conclusion: Our data demonstrate that MCAD deficiency in mice leads to specific changes in hepatic carbohydrate management on exposure to metabolic stress. This deficiency, however, does not lead to reduced de novo synthesis of G6P during fasting alone, which may be due to the existence of compensatory mechanisms or limited rate control of MCAD in murine mitochondrial fatty acid oxidation. Total RNA obtained from Liver ( 20 samples) , where comparing 4 groups, consisting out of 5 biological replicates, all groups where fasted for 12 hrs, and half of them where injected with LPS ( 100ug/20gr BW) or vehicle
2012-04-25 | E-GEOD-37546 | biostudies-arrayexpress
Project description:Medium-chain acyl-coenzyme A (CoA) dehydrogenase (MCAD) catalyzes crucial steps in mitochondrial fatty acid oxidation, a process that is of key relevance for maintenance of energy homeostasis, especially during high metabolic demand. To gain insight into the metabolic consequences of MCAD deficiency under these conditions, we compared hepatic carbohydrate metabolism in vivo in wild-type and MCAD-/- mice during fasting and during a lipopolysaccharide (LPS)-induced acute phase response (APR). MCAD-/- mice did not become more hypoglycemic on fasting or during the APR than wild-type mice did. Nevertheless, microarray analyses revealed increased hepatic peroxisome proliferator-activated receptor gamma coactivator-1a (Pgc-1a) and decreased peroxisome proliferator-activated receptor alpha (Ppar a) and pyruvate dehydrogenase kinase 4 (Pdk4) expression in MCAD-/- mice in both conditions,suggesting altered control of hepatic glucose metabolism. Quantitative flux measurements revealed that the de novo synthesis of glucose-6-phosphate (G6P) was not affected on fasting in MCAD-/- mice. During the APR, however, this flux was significantly decreased (-20%) in MCAD-/- mice compared with wild-type mice. Remarkably, newly formed G6P was preferentially directed toward glycogen in MCAD-/- mice under both conditions. Together with diminished de novo synthesis of G6P, this led to a decreased hepatic glucose output during the APR in MCAD-/- mice; de novo synthesis of G6P and hepatic glucose output were maintained in wild-type mice under both conditions. APR-associated hypoglycemia, which was observed in wild-type mice as well as MCAD-/- mice, was mainly due to enhanced peripheral glucose uptake. Conclusion: Our data demonstrate that MCAD deficiency in mice leads to specific changes in hepatic carbohydrate management on exposure to metabolic stress. This deficiency, however, does not lead to reduced de novo synthesis of G6P during fasting alone, which may be due to the existence of compensatory mechanisms or limited rate control of MCAD in murine mitochondrial fatty acid oxidation.
2012-04-26 | GSE37546 | GEO
Project description:Purpose: The goals of this study are to find out the differential expression genes in the fadR mutant strain(ΔfadR) compared with wild-type (WT) and to further explore the regulation mechanisms of fadR. Methods: Shewanella oneidensis MR-1 WT and ΔfadR were collected in log phage(OD~0.6). RNA extraction was performed using the RNeasy minikit (Qiagen) and the RNA was quantified by using a NanoVue spectrophotometer (GE Healthcare). RNA seq was performed using Illumina NextSeq 500, 2×150 bp. Results: Our study represents that the expression of 146 genes were decreased and 94 genes were increased inΔfadR compared with WT. Branched-chain keto acid dehydrogenase (BKD) produces corresponding branched-chain acyl coenzyme A which further participating branchend-chain fatty acids synthesis. The expression of bkdA2 was also promoted in △fadR compared with WT. Conclusions: Combined with our expression results, it declared that FadR can suppress bkd operon in some degree,which further increase the synthesis of branched-chain fatty acids in ΔfadR.
2020-01-01 | GSE133375 | GEO