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Is there a role for fatty acid synthase in the diagnosis of prostatic adenocarcinoma?: A comparison with AMACR.
Wu X, Zayzafoon M, Zhang X, Hameed O
(2011) Am J Clin Pathol 136: 239-46
MeSH Terms: Adenocarcinoma, Area Under Curve, Biomarkers, Tumor, Fatty Acid Synthases, Humans, Male, Prostatic Neoplasms, ROC Curve, Racemases and Epimerases, Sensitivity and Specificity, Tissue Array Analysis
Show Abstract · Added March 21, 2014
Our aim was to compare the usefulness of fatty acid synthase (FASn) with that of α-methylacyl coenzyme-A racemase (AMACR) in the diagnosis of prostatic adenocarcinoma. The expression of these 2 markers was compared in a tissue microarray containing 62 foci of benign glands and 36 foci of prostatic adenocarcinoma. Similar to AMACR, there was significantly higher FASn expression in adenocarcinoma compared with that in benign glands. The optimal accuracy rate and area under curve (AUC) by receiver operating characteristic analysis for FASn were not significantly different from those for AMACR (accuracy, 80% vs 87%; AUC, 0.942 vs 0.956; P for both, > .05). Moreover, in cases with coexistent malignant and benign glands on the same core, FASn could selectively distinguish a proportion of cases (17/21 [81%]) similar to using AMACR. We conclude that FASn may aid in the diagnosis of prostatic adenocarcinoma, at least to supplement AMACR as another positive marker of carcinoma and potentially increase diagnostic accuracy.
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11 MeSH Terms
Molecular consequences of altered neuronal cholesterol biosynthesis.
Korade Z, Kenworthy AK, Mirnics K
(2009) J Neurosci Res 87: 866-75
MeSH Terms: Animals, Blotting, Northern, Cell Line, Cholesterol, Down-Regulation, Farnesyl-Diphosphate Farnesyltransferase, Fatty Acid Synthases, Fatty Acids, Gene Expression, Gene Expression Profiling, Intracellular Signaling Peptides and Proteins, Mice, Neurons, Oxidoreductases Acting on CH-CH Group Donors, Polymerase Chain Reaction, Proprotein Convertases, RNA, Small Interfering, Serine Endopeptidases, Sterol Regulatory Element Binding Protein 2, Sterols, Transfection, Vesicular Transport Proteins
Show Abstract · Added December 10, 2013
The first dedicated step in de novo cholesterol biosynthesis begins with formation of squalene and ends with the reduction of 7-dehydrocholesterol by 7-dehydrocholesterol reductase (Dhcr7) into cholesterol, which is an essential structural and signaling molecule. Mutations in the Dhcr7 gene lead to Smith-Lemli-Opitz syndrome (SLOS), which is characterized by developmental deformities, incomplete myelination, and mental retardation. To understand better the molecular consequences of Dhcr7 deficiency in neuronal tissue, we analyzed the effect of cholesterol deficiency on the transcriptome in Neuro2a cells. Transient down-regulation of Dhcr7 by siRNA led to altered expression of multiple molecules that play critical roles in intracellular signaling or vesicular transport or are inserted into membrane rafts (e.g. Egr1, Snx, and Adam19). A similar down-regulation was also observed in stable Dhrc7-shRNA-transfected cell lines, and the findings were verified by qPCR. Furthermore, we investigated the Dhcr7-deficient and control cells for the expression of several critical genes involved in lipid biosynthesis. Among these, fatty acid synthase, sterol-regulatory element binding protein 2, SREBF chaperone, site-1 protease, and squalene synthase showed a significant down-regulation, suggesting that, in a neuronal cell line, Dhcr7 is a potent regulator of lipid biosynthesis. Importantly, the gene expression changes were present in both lipid-containing and cholesterol-deficient media, suggesting that intrinsic cholesterol biosynthesis is necessary for normal neuronal function and cannot be supplemented from extrinsic sources.
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22 MeSH Terms
Fatty acid synthase gene regulation in primary hypothalamic neurons.
Kim EK, Kleman AM, Ronnett GV
(2007) Neurosci Lett 423: 200-4
MeSH Terms: Aminoimidazole Carboxamide, Animals, Cells, Cultured, Dose-Response Relationship, Drug, Fatty Acid Synthases, Fetus, Gene Expression Regulation, Glucose, Hypothalamus, Insulin, Neurons, Protein Isoforms, RNA, Messenger, Rats, Rats, Sprague-Dawley, Ribonucleotides, Sterol Regulatory Element Binding Protein 1, Time Factors
Show Abstract · Added August 14, 2014
Understanding the mechanisms that regulate feeding is critical to the development of therapeutic interventions for obesity. Many studies indicate that enzymes within fatty acid metabolic pathways may serve as targets for pharmacological tools to treat this epidemic. We, and others have previously demonstrated that C75, a fatty acid synthase (FAS) inhibitor, induced significant anorexia and weight loss by both central and peripheral mechanisms. Because the hypothalamus is important in the regulation of homeostatic processes for feeding control, we have identified pathways that alter the gene expression of FAS in primary hypothalamic neuronal cultures. Insulin, glucose and AICAR (an activator of AMP-activated protein kinase) affected changes in hypothalamic FAS mRNA, which may be regulated via the SREBP1c dependent or independent pathway.
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18 MeSH Terms
Fatty acid metabolism, the central nervous system, and feeding.
Ronnett GV, Kleman AM, Kim EK, Landree LE, Tu Y
(2006) Obesity (Silver Spring) 14 Suppl 5: 201S-207S
MeSH Terms: 4-Butyrolactone, Central Nervous System, Eating, Energy Intake, Energy Metabolism, Fatty Acid Synthases, Fatty Acids, Gene Expression, Humans, Obesity, Oxidation-Reduction, Weight Loss
Show Abstract · Added August 14, 2014
A potential role for fatty acid metabolism in the regulation of energy balance in the brain or in the periphery has been considered only recently. Fatty acid synthase (FAS) catalyzes the synthesis of long-chain fatty acids, whereas the breakdown of fatty acids by beta-oxidation is regulated by carnitine palmitoyltransferase-1, the rate-limiting enzyme for the entry of fatty acids into the mitochondria for oxidation. While the question of the physiological role of fatty acid metabolism remains to be resolved, studies indicate that inhibition of FAS or stimulation of carnitine palmitoyltransferase-1 using cerulenin or synthetic FAS inhibitors reduces food intake and incurs profound and reversible weight loss. Several hypotheses regarding the mechanisms by which these small molecules mediate their effects have been entertained. Centrally, these compounds alter the expression of hypothalamic neuropeptides, generally reducing the expression of orexigenic peptides. Whether through central, peripheral, or combined central and peripheral mechanisms, these compounds also increase energy consumption to augment weight loss. In vitro and in vivo studies indicate that at least part of C75's effects is mediated by modulation of adenosine monophosphate-activated protein kinase, a member of an energy-sensing kinase family. These compounds, with chronic treatment, also alter gene expression peripherally to favor a state of enhanced energy consumption. Together, these effects raise the possibility that pharmacological alterations in fatty acid synthesis/degradation may serve as a target for obesity therapeutics.
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12 MeSH Terms
Gene induction during differentiation of human pulmonary type II cells in vitro.
Wade KC, Guttentag SH, Gonzales LW, Maschhoff KL, Gonzales J, Kolla V, Singhal S, Ballard PL
(2006) Am J Respir Cell Mol Biol 34: 727-37
MeSH Terms: 8-Bromo Cyclic Adenosine Monophosphate, Cell Differentiation, Cells, Cultured, Dexamethasone, Epithelial Cells, Fatty Acid Synthases, Fetal Proteins, Fetus, Gene Expression Profiling, Gene Expression Regulation, Developmental, Glycerol Kinase, Humans, Infant, Infant, Newborn, Lipoprotein Lipase, Lung, Lysosome-Associated Membrane Glycoproteins, Phospholipids, RNA, Messenger, Subcellular Fractions, Time Factors, Transcriptional Activation, Transferases (Other Substituted Phosphate Groups)
Show Abstract · Added January 20, 2015
Mature alveolar type II cells that produce pulmonary surfactant are essential for adaptation to extrauterine life. We profiled gene expression in human fetal lung epithelial cells cultured in serum-free medium containing dexamethasone and cyclic AMP, a treatment that induces differentiation of type II cells. Microarray analysis identified 388 genes that were induced > 1.5-fold by 72 h of hormone treatment. Induced genes represented all categories of molecular function and subcellular location, with increased frequency in the categories of ionic channel, cell adhesion, surface film, lysosome, extracellular matrix, and basement membrane. In time-course experiments, self-organizing map analysis identified a cluster of 17 genes that were slowly but highly induced (5- to approximately 190-fold) and represented four functional categories: surfactant-related (SFTPC, SFTPA, PGC, SFTPB, LAMP3, LPL), regulatory (WIF2, IGF2, IL1RL1, NR4A2, HIF3A), metabolic (MAOA, ADH1B, SEPP1), and transport (SCNN1A, CLDN18, AQP4). Induction of both mRNA and protein for these genes, which included nine newly identified regulated genes, was confirmed, and cellular localization was determined in both fetal and postnatal tissue. Induction of lysosomal-associated membrane protein 3 required both hormones, and expression was localized to limiting membranes of lamellar bodies. Hormone-induced differentiation of human type II cells is associated with genome-wide increased expression of genes with diverse functions.
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23 MeSH Terms
Hepatic glucokinase is required for the synergistic action of ChREBP and SREBP-1c on glycolytic and lipogenic gene expression.
Dentin R, Pégorier JP, Benhamed F, Foufelle F, Ferré P, Fauveau V, Magnuson MA, Girard J, Postic C
(2004) J Biol Chem 279: 20314-26
MeSH Terms: Acetyl-CoA Carboxylase, Adenoviridae, Animals, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors, Blotting, Northern, CCAAT-Enhancer-Binding Proteins, Carbohydrate Metabolism, Cell Nucleus, Cells, Cultured, DNA-Binding Proteins, Fatty Acid Synthases, Gene Expression Regulation, Glucokinase, Glucose, Glucose-6-Phosphate, Glycogen, Hepatocytes, Immunoblotting, Kinetics, Lipid Metabolism, Liver, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Microscopy, Fluorescence, Nuclear Proteins, Pentosephosphates, Proteins, Pyruvate Kinase, RNA, RNA, Messenger, RNA, Small Interfering, Reverse Transcriptase Polymerase Chain Reaction, Signal Transduction, Sterol Regulatory Element Binding Protein 1, Time Factors, Transcription Factors, Transcription, Genetic
Show Abstract · Added February 23, 2011
Hepatic glucokinase (GK) catalyzes the phosphorylation of glucose to glucose 6-phosphate (G6P), a step which is essential for glucose metabolism in liver as well as for the induction of glycolytic and lipogenic genes. The sterol regulatory element-binding protein-1c (SREBP-1c) has emerged as a major mediator of insulin action on hepatic gene expression, but the extent to which its transcriptional effect is caused by an increased glucose metabolism remains unclear. Through the use of hepatic GK knockout mice (hGK-KO) we have shown that the acute stimulation by glucose of l-pyruvate kinase (l-PK), fatty acid synthase (FAS), acetyl-CoA carboxylase (ACC), and Spot 14 genes requires GK expression. To determine whether the effect of SREBP-1c requires GK expression and subsequent glucose metabolism, a transcriptionally active form of SREBP-1c was overexpressed both in vivo and in primary cultures of control and hGK-KO hepatocytes. Our results demonstrate that the synergistic action of SREBP-1c and glucose metabolism via GK is necessary for the maximal induction of l-PK, ACC, FAS, and Spot 14 gene expression. Indeed, in hGK-KO hepatocytes overexpressing SREBP-1c, the effect of glucose on glycolytic and lipogenic genes is lost because of the impaired ability of these hepatocytes to efficiently metabolize glucose, despite a marked increase in low K(m) hexokinase activity. Our studies also reveal that the loss of glucose effect observed in hGK-KO hepatocytes is associated with a decreased in the carbohydrate responsive element-binding protein (ChREBP) gene expression, a transcription factor suggested to mediate glucose signaling in liver. Decreased ChREBP gene expression, achieved using small interfering RNA, results in a loss of glucose effect on endogenous glycolytic (l-PK) and lipogenic (FAS, ACC) gene expression, thereby demonstrating the direct implication of ChREBP in glucose action. Together these results support a model whereby both SREBP-1c and glucose metabolism, acting via ChREBP, are necessary for the dietary induction of glycolytic and lipogenic gene expression in liver.
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39 MeSH Terms
Differentiation of human pulmonary type II cells in vitro by glucocorticoid plus cAMP.
Gonzales LW, Guttentag SH, Wade KC, Postle AD, Ballard PL
(2002) Am J Physiol Lung Cell Mol Physiol 283: L940-51
MeSH Terms: 1-Methyl-3-isobutylxanthine, Cell Differentiation, Cyclic AMP, Dexamethasone, Enzymes, Fatty Acid Synthases, Female, Fetus, Fluorescent Dyes, Gene Expression Regulation, Glucocorticoids, Humans, Keratins, Lung, Oligonucleotide Array Sequence Analysis, Pregnancy, Proteins, Respiratory Mucosa, Transcription, Genetic
Show Abstract · Added January 20, 2015
Mature alveolar type II cells that produce pulmonary surfactant are essential for adaptation to extrauterine life and prevention of infant respiratory distress syndrome. We have developed a new in vitro model to further investigate regulation of type II cell differentiation. Epithelial cells isolated from human fetal lung were cultured in serum-free medium on plastic. Cells treated with dexamethasone + cAMP analog and isobutylmethylxanthine for 4 days exhibited increased phosphatidylcholine synthesis and content of disaturated phosphatidylcholine species, manyfold increases in all surfactant proteins with processing to mature forms, and abundant lamellar bodies. DNA microarray analysis identified approximately 3,100 expressed genes, including subsets of genes induced 2- to >100-fold (approximately 2.5%) or repressed 2- to 18-fold (approximately 1.2%) by hormone treatment. Of the highly regulated genes, most were coregulated in an additive or synergistic manner by dexamethasone and cAMP agents. Approximately 90% of the regulated genes identified by this initial microarray analysis have not been previously recognized as hormone responsive. One newly identified hormone-induced gene is Nkx2.1 (thyroid transcription factor-1), which has a critical role in surfactant protein gene expression. Our findings indicate that glucocorticoid + cAMP is sufficient and necessary for precocious induction of functional type II cells in this in vitro system and that these hormones act primarily in combination to regulate expression of a subset of specific genes.
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19 MeSH Terms
Transcriptional activities of nuclear SREBP-1a, -1c, and -2 to different target promoters of lipogenic and cholesterogenic genes.
Amemiya-Kudo M, Shimano H, Hasty AH, Yahagi N, Yoshikawa T, Matsuzaka T, Okazaki H, Tamura Y, Iizuka Y, Ohashi K, Osuga J, Harada K, Gotoda T, Sato R, Kimura S, Ishibashi S, Yamada N
(2002) J Lipid Res 43: 1220-35
MeSH Terms: ATP Citrate (pro-S)-Lyase, Animals, Base Sequence, CCAAT-Enhancer-Binding Proteins, Cholesterol, DNA Primers, DNA-Binding Proteins, Enhancer Elements, Genetic, Fatty Acid Synthases, Glucokinase, Glucosephosphate Dehydrogenase, Humans, Lipids, Malate Dehydrogenase, Mice, Mice, Transgenic, Promoter Regions, Genetic, Pyruvate Kinase, Sterol Regulatory Element Binding Protein 1, Sterol Regulatory Element Binding Protein 2, Transcription Factors, Transcription, Genetic, Tumor Cells, Cultured
Show Abstract · Added March 27, 2013
Recent studies on the in vivo roles of the sterol regulatory element binding protein (SREBP) family indicate that SREBP-2 is more specific to cholesterogenic gene expression whereas SREBP-1 targets lipogenic genes. To define the molecular mechanism involved in this differential regulation, luciferase-reporter gene assays were performed in HepG2 cells to compare the transactivities of nuclear SREBP-1a, -1c, and -2 on a battery of SREBP-target promoters containing sterol regulatory element (SRE), SRE-like, or E-box sequences. The results show first that cholesterogenic genes containing classic SREs in their promoters are strongly and efficiently activated by both SREBP-1a and SREBP-2, but not by SREBP-1c. Second, an E-box containing reporter gene is much less efficiently activated by SREBP-1a and -1c, and SREBP-2 was inactive in spite of its ability to bind to the E-box. Third, promoters of lipogenic enzymes containing variations of SRE (SRE-like sequences) are strongly activated by SREBP-1a, and only modestly and equally by both SREBP-1c and -2. Finally, substitution of the unique tyrosine residue within the basic helix-loop-helix (bHLH) portion of nuclear SREBPs with arginine, the conserved residue found in all other bHLH proteins, abolishes the transactivity of all SREBPs for SRE, and conversely results in markedly increased activity of SREBP-1 but not activity of SREBP-2 for E-boxes. These data demonstrate the different specificity and affinity of nuclear SREBP-1 and -2 for different target DNAs, explaining a part of the mechanism behind the differential in vivo regulation of cholesterogenic and lipogenic enzymes by SREBP-1 and -2, respectively.
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23 MeSH Terms
Sterol regulatory element-binding protein-1 is regulated by glucose at the transcriptional level.
Hasty AH, Shimano H, Yahagi N, Amemiya-Kudo M, Perrey S, Yoshikawa T, Osuga J, Okazaki H, Tamura Y, Iizuka Y, Shionoiri F, Ohashi K, Harada K, Gotoda T, Nagai R, Ishibashi S, Yamada N
(2000) J Biol Chem 275: 31069-77
MeSH Terms: Animals, Antimetabolites, Antineoplastic, Azaserine, Blotting, Northern, CCAAT-Enhancer-Binding Proteins, Cell Differentiation, Cell Line, Cell Membrane, Cell Nucleus, Chromones, Colforsin, DNA-Binding Proteins, Dose-Response Relationship, Drug, Enzyme Inhibitors, Fatty Acid Synthases, Fructose, Fructosephosphates, Galactose, Genes, Reporter, Glucose, Immunoblotting, Liver, Mice, Morpholines, Phosphoinositide-3 Kinase Inhibitors, Protein Isoforms, RNA, Messenger, Ribonucleases, Sterol Regulatory Element Binding Protein 1, Sterol Regulatory Element Binding Protein 2, Temperature, Time Factors, Transcription Factors, Transcription, Genetic, Transfection, Up-Regulation, Xylose
Show Abstract · Added March 27, 2013
In vivo studies suggest that sterol regulatory element-binding protein (SREBP)-1 plays a key role in the up-regulation of lipogenic genes in the livers of animals that have consumed excess amounts of carbohydrates. In light of this, we sought to use an established mouse hepatocyte cell line, H2-35, to further define the mechanism by which glucose regulates nuclear SREBP-1 levels. First, we show that these cells transcribe high levels of SREBP-1c that are increased 4-fold upon differentiation from a prehepatocyte to a hepatocyte phenotype, making them an ideal cell culture model for the study of SREBP-1c induction. Second, we demonstrate that the presence of precursor and mature forms of SREBP-1 protein are positively regulated by medium glucose concentrations ranging from 5. 5 to 25 mm and are also regulated by insulin, with the amount of insulin in the fetal bovine serum being sufficient for maximal stimulation of SREBP-1 expression. Third, we show that the increase in SREBP-1 protein is due to an increase in SREBP-1 mRNA. Reporter gene analysis of the SREBP-1c promoter demonstrated a glucose-dependent induction of transcription. In contrast, expression of a fixed amount of the precursor form of SREBP-1c protein showed that glucose does not influence its cleavage. Fourth, we demonstrate that the glucose induction of SREBP could not be reproduced by fructose, xylose, or galactose nor by glucose analogs 2-deoxy glucose and 3-O-methyl glucopyranose. These data provide strong evidence for the induction of SREBP-1c mRNA by glucose leading to increased mature protein in the nucleus, thus providing a potential mechanism for the up-regulation of lipogenic genes by glucose in vivo.
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37 MeSH Terms
Sterol regulatory element-binding protein-1 as a key transcription factor for nutritional induction of lipogenic enzyme genes.
Shimano H, Yahagi N, Amemiya-Kudo M, Hasty AH, Osuga J, Tamura Y, Shionoiri F, Iizuka Y, Ohashi K, Harada K, Gotoda T, Ishibashi S, Yamada N
(1999) J Biol Chem 274: 35832-9
MeSH Terms: Acetyl-CoA Carboxylase, Animal Nutritional Physiological Phenomena, Animals, CCAAT-Enhancer-Binding Proteins, Cholesterol, DNA-Binding Proteins, Diet, Eating, Enzyme Induction, Fasting, Fatty Acid Synthases, Fatty Acids, Nonesterified, Female, Gene Expression Regulation, Gene Expression Regulation, Enzymologic, Hydroxymethylglutaryl CoA Reductases, Hydroxymethylglutaryl-CoA Synthase, Liver, Mice, Mice, Knockout, Nuclear Proteins, RNA, Messenger, Stearoyl-CoA Desaturase, Sterol Regulatory Element Binding Protein 1, Sterol Regulatory Element Binding Protein 2, Transcription Factors, Triglycerides
Show Abstract · Added March 27, 2013
To elucidate the physiological role of sterol regulatory element-binding protein-1 (SREBP-1), the hepatic mRNA levels of genes encoding various lipogenic enzymes were estimated in SREBP-1 gene knockout mice after a fasting-refeeding treatment, which is an established dietary manipulation for the induction of lipogenic enzymes. In the fasted state, the mRNA levels of all lipogenic enzymes were consistently low in both wild-type and SREBP-1(-/-) mice. However, the absence of SREBP-1 severely impaired the marked induction of hepatic mRNAs of fatty acid synthetic genes, such as acetyl-CoA carboxylase, fatty acid synthase, and stearoyl-CoA desaturase, that was observed upon refeeding in the wild-type mice. Furthermore, the refeeding responses of other lipogenic enzymes, glycerol-3-phosphate acyltransferase, ATP citrate lyase, malic enzyme, glucose-6-phosphate dehydrogenase, and S14 mRNAs, were completely abolished in SREBP-1(-/-) mice. In contrast, mRNA levels for cholesterol biosynthetic genes were elevated in the refed SREBP-1(-/-) livers accompanied by an increase in nuclear SREBP-2 protein. When fed a high carbohydrate diet for 14 days, the mRNA levels for these lipogenic enzymes were also strikingly lower in SREBP-1(-/-) mice than those in wild-type mice. These data demonstrate that SREBP-1 plays a crucial role in the induction of lipogenesis but not cholesterol biosynthesis in liver when excess energy by carbohydrates is consumed.
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27 MeSH Terms