Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The androgen-regulated enzyme fatty acid synthase (FAS), required for de novo lipogenesis, is overexpressed in several cancers including prostate carcinoma and has been associated with aggressive disease. FAS expression was assessed in 81 prostate carcinomas, both by immunohistochemistry in tissue microarrays and by Affymetrix Hu95Av2 oligonucleotide arrays. Both FAS mRNA and protein were significantly overexpressed in prostate carcinomas compared with the corresponding normal tissue. FAS mRNA and protein expression increased substantially from normal to prostatic intraepithelial neoplasia, to low grade, to high grade, and to androgen-independent bone metastases. A significant correlation between FAS mRNA and protein expression was found in two thirds of the cases. In 17% of the cases, FAS protein levels were high despite low mRNA levels, and these tumors exhibited a distinct molecular signature when compared with tumors that did not express FAS protein. Whereas the latter group of tumors expressed some proapoptotic genes, tumors with high FAS levels overexpressed, among other genes, its transcriptional regulator, steroid regulator binding protein, and apolipoprotein E. These data demonstrate (1) the consistent overexpression of FAS in prostate carcinoma compared with the adjacent normal tissue, (2) a strong association between FAS and prostate tumor initiation and progression, (3) the highest FAS expression occurring in androgen-independent bone metastases, (4) the transcriptional and posttranscriptional regulation of FAS in the majority and in a subset of prostate cancers, respectively, and (5) most importantly, the identification by FAS expression of prostate tumors with unique molecular signatures and potentially diverse biologic behavior.
Mol Cancer Res 2003 Aug
PMID:Fatty acid synthase expression defines distinct molecular signatures in prostate cancer. 1293 96

This study was conducted to examine the effects of dietary grape extracts on preneoplastic foci formation in rat hepatocarcinogenesis, and related hepatic enzymes. Male Sprague-Dawley rats were fed basal diet or grape diet containing 15% concentrated grape extracts (68 bricks). The grape diet groups were divided into whole-period grape diet group (DEN-GW; grape diet group fed throughout experimental period) and postinitiation grape diet group (DEN-GP; grape diet group fed from post initiation stage) according to the starting time point of the grape diet. Hepatocarcinogenesis was induced by diethylnitrosamine (DEN; 200 mg/kg bw) and 2/3 partial hepatectomy (DEN-B; DEN-treated basal diet group, DEN-GW, and DEN-GP groups), while the control group treated with saline and sham operation (Control group). The formation of placental glutathione (GSH) S-transferase positive (GST-P+) foci in DEN-GW group was moderately but significantly suppressed, however, not in DEN- GP group. Thiobarbituric acid reactive substances content of DEN-GW group was significantly lower than that of DEN-B group. The activity of fatty acid synthase (FAS) in the grape diet groups was decreased about 1/2 of the DEN-B group. The content of GSH and GSH peroxidase activity were increased by carcinogen treatment, but not modulated by grape diet. The activities of GSH S-transferase, p-nitrophenol hydroxylase, and catalase were not affected by diet or treatment. Conclusively, the grape diet-induced reduction of FAS activity that was expressed highly in neoplastic tissues, might be one of the contributing mechanisms of hepatic cancer prevention.
Exp Mol Med 2003 Oct 31
PMID:Grape extracts suppress the formation of preneoplastic foci and activity of fatty acid synthase in rat liver. 1464 90

Repeated dieting is one of the methods used for weight reduction; however, its effectiveness is questionable. We developed an experimental, rat model of repeated dieting, which mimics the dietary approach used in the treatment of obesity in humans. In this experimental model, despite the lower caloric intake, decreased body mass and reduced fat stores, the lipogenic potential of adipose tissue increased. We observed a substantial increase in fatty acid synthase (a key lipogenic enzyme) gene expression in rat adipose tissue accompanied by a 9-fold increase in the serum insulin level. Fatty acid synthase gene expression is controlled at the transcriptional level by SREBP-1. In this study, a remarkable increase (24-fold) in SREBP-1 protein amount, parallel to that in fatty acid synthase mRNA level, protein concentration and enzyme activity was observed after multiple cycles of fasting-refeeding. Although it is possible that the interactions between transcription factors are more complex, we propose that the pivotal role in the increase of the lipogenic potential of adipose tissue after repeated dieting may be played by SREBP-1.
Cell Mol Biol Lett 2003
PMID:Increased lipogenic potential of rat adipose tissue after repeated dieting--the role of SREBP-1 transcription factor. 1466 13

The primary purpose of this investigation was to determine whether adipose tissue glycerol 3-phosphate dehydrogenase activity is associated with human obesity. The data presented in this paper indicate that the glycerol 3-phosphate dehydrogenase activity in adipose tissue from morbidly obese subjects is approximately 2-fold higher than from lean individuals. Moreover, positive correlation between adipose tissue glycerol 3-phosphate dehydrogenase activity and body mass index (BMI) (r = 0.5; p < 0.01) was found. In contrast, the adipose tissue fatty acid synthase (FAS) and ATP-citrate lyase (ACL) activities in morbidly obese patients are significantly lower than in lean subjects. Furthermore, negative correlation between adipose tissue FAS activity and BMI (r = -0.3; p < 0.05) as well as between ACL activity and BMI (r = -0.3; p < 0.05) was found. These data indicate that elevated glycerol 3-phosphate dehydrogenase might contribute to the increase of triacylglycerol (TAG) synthesis in obese subjects, however, fatty acids necessary for glycerol 3-phosphate esterification must be derived (because of lower FAS and ACL activities) mainly from TAG in circulating lipoproteins formed in liver (VLDL), and/or from the intake with food (chylomicrons). The conclusion is, that the enhanced activity of glycerol 3-phosphate dehydrogenase, and hence the generation of more glycerol 3-phosphate in adipose tissue offers a novel explanation for increased TAG production in adipose tissue of obese subjects.
Mol Cell Biochem 2003 Dec
PMID:Enhanced glycerol 3-phosphate dehydrogenase activity in adipose tissue of obese humans. 1467 82

Hepatic genes crucial for carbohydrate and lipid homeostasis are regulated by insulin and glucose metabolism. However, the relative contributions of insulin and glucose to the regulation of metabolic gene expression are poorly defined in vivo. To address this issue, adenovirus-mediated hepatic overexpression of glucokinase was used to determine the effects of increased hepatic glucose metabolism on gene expression in fasted or ad libitum fed rats. In the fasted state, a 3 fold glucokinase overexpression was sufficient to mimic feeding-induced increases in pyruvate kinase and acetyl CoA carboxylase mRNA levels, demonstrating a primary role for glucose metabolism in the regulation of these genes in vivo. Conversely, glucokinase overexpression was unable to mimic feeding-induced alterations of fatty acid synthase, glucose-6-phosphate dehydrogenase, carnitine palmitoyl transferase I or PEPCK mRNAs, indicating insulin as the primary regulator of these genes. Interestingly, glucose-6-phosphatase mRNA was increased by glucokinase overexpression in both the fasted and fed states, providing evidence, under these conditions, for the dominance of glucose over insulin signaling for this gene in vivo. Importantly, glucokinase overexpression did not alter sterol regulatory element binding protein 1-c mRNA levels in vivo and glucose signaling did not alter the expression of this gene in primary hepatocytes. We conclude that a modest hepatic overexpression of glucokinase is sufficient to alter expression of metabolic genes without changing the expression of SREBP-1c.
Mol Cell Biochem 2003 Dec
PMID:A modest glucokinase overexpression in the liver promotes fed expression levels of glycolytic and lipogenic enzyme genes in the fasted state without altering SREBP-1c expression. 1467 13

New Zealand obese (NZO) mice exhibit severe insulin resistance of hepatic glucose metabolism. In order to define its biochemical basis, we studied the differential expression of genes involved in hepatic glucose and lipid metabolism by microarray analysis. NZOxF1 (SJLxNZO) backcross mice were generated in order to obtain populations with heterogeneous metabolism but comparable genetic background. In these backcross mice, groups of controls (normoglycemic/normoinsulinemic), insulin-resistant (normoglycemic/hyperinsulinemic) and diabetic (hyperglycemic/hypoinsulinemic) mice were identified. At 22 weeks, mRNA was isolated from liver, converted to cDNA, and used for screening of two types of cDNA arrays (high-density filter arrays and Affymetrix oligonucleotide microarrays). Differential gene expression was ascertained and assessed by Northern blotting. The data indicate that hyperinsulinemia in the NZO mouse is associated with: (i) increased mRNA levels of enzymes involved in lipid synthesis (fatty acid synthase, malic enzyme, stearoyl-CoA desaturase) or fatty acid oxidation (cytochrome P450 4A14, ketoacyl-CoA thiolase, acyl-CoA oxidase), (ii) induction of the key glycolytic enzyme pyruvate kinase, and (iii) increased mRNA levels of the gluconeogenic enzyme phosphoenolpyruvate carboxykinase. These effects were enhanced by a high-fat diet. In conclusion, the pattern of gene expression in insulin-resistant NZO mice appears to reflect a dissociation of the effects of insulin on genes involved in glucose and lipid metabolism. The data are consistent with a hypothetical scenario in which an insulin-resistant hepatic glucose production produces hyperinsulinemia, and an enhanced insulin- and substrate-driven lipogenesis further aggravates the deleterious insulin resistance of glucose metabolism.
J Mol Endocrinol 2004 Feb
PMID:Differential hepatic gene expression in a polygenic mouse model with insulin resistance and hyperglycemia: evidence for a combined transcriptional dysregulation of gluconeogenesis and fatty acid synthesis. 1476 2

Insulin promotes adipocyte differentiation via a complex signaling network involving multiple insulin receptor substrates (IRSs). In cultured brown preadipocytes, expression of IRS-1 and IRS-2 mRNAs and proteins was at relatively high levels before and after differentiation into mature fat cells, while IRS-3 transcript was not detectable in preadipocytes but increased during the course of differentiation, and IRS-4 mRNA was barely detected in both states. To determine more precisely the roles of various IRS proteins in adipogenesis, we established and characterized brown preadipocyte cell lines from wild-type and IRS knockout (KO) animals. While wild-type, IRS-2 KO, and IRS-4 KO cells fully differentiated into mature adipocytes, IRS-3 KO cells showed a moderate defect in differentiation and IRS-1 KO cells exhibited a severe defect in the process. Cells lacking both IRS-1 and IRS-3 completely failed to differentiate. Expression of the adipogenic markers peroxisome proliferator-activated receptor gamma (PPARgamma), CCAAT/enhancer-binding protein alpha, fatty acid synthase, glucose transporter 4, and the transcription factor signal transducer and activator of transcription 5, as well as the brown-fat-specific markers PPARgamma coactivator 1 alpha and uncoupling protein 1, mirrored the differentiation pattern. Reconstitution of the IRS-1 KO cells with IRS-1 and IRS-4, but not IRS-2 or IRS-3, compensated for the lack of differentiation in IRS-1 KO cells. A chimeric molecule containing the N terminus of IRS-1 and the C terminus of IRS-2, but not one with the N terminus of IRS-2 and the C terminus of IRS-1, also rescued differentiation. Expression of Wnt 10a, a molecule known to inhibit adipogenesis, was dramatically increased in the IRS-1 KO cells, and this could be reduced by overexpression of IRS-1 or IRS-4, which was correlated with restoration of differentiation. These data indicate that both IRS-1 and -3 play important roles in the differentiation of brown adipocytes and that the N terminus of IRS-1 is more important for this function of the molecule. Although IRS-4 is not essential for the process, overexpression of IRS-4 can compensate for the deficiency in differentiation in IRS-1 KO cells.
Mol Cell Biol 2004 Mar
PMID:Differential roles of insulin receptor substrates in brown adipocyte differentiation. 1496 73

Aspergillus nidulans produces the polyketide toxin sterigmatocystin (ST) of which the biosynthetic and pathway specific regulatory genes compose a stc gene cluster. A previous mutagenesis screen identified 23 mutants defective in production of ST. Five mutants constitute a single locus. Genetic complementation and sequencing analysis revealed the mutant locus to be mcsA encoding methylcitrate synthase that converts propionyl-CoA to methylcitrate. Feeding downstream products of methylcitrate synthase, methylcitrate and pyruvate, did not restore ST production in mcsA mutants, indicating that loss of methylcitrate cycle products is not the cause of the ST defect. However, propionate, a precursor for propionyl-CoA, inhibited ST production and induced transcription of mcsA in the wild type. Furthermore, propionate impaired formation of two polyketide spore pigments whereas overexpression of mcsA relieved inhibition of ST production by propionate. Transcription analyses revealed that disruption of mcsA did not affect expression of the specialized fatty acid synthase genes (stcJ and stcK) or polyketide synthase gene (stcA) required for formation of norsolorinic acid (NOR), the first stable intermediate in the ST biosynthetic pathway. Feeding studies showed that NOR but not hexanoic acid (the fatty acid produced by StcJ/StcK and primer unit of StcA) or malonate (source of the extender unit of StcA) restored ST production in the mcsA mutant. We hypothesize that excess buildup of propionyl-CoA in mcsA mutants interferes with polyketide synthase activity.
Mol Microbiol 2004 Apr
PMID:Blockage of methylcitrate cycle inhibits polyketide production in Aspergillus nidulans. 1506 39

Pulmonary surfactant is a lipoprotein complex that functions to reduce surface tension at the air liquid interface in the alveolus of the mature lung. In late gestation glycogen-laden type II cells shift their metabolic program toward the synthesis of surfactant, of which phosphatidylcholine (PC) is by far the most abundant lipid. To investigate the cellular site of surfactant PC synthesis in these cells we determined the subcellular localization of two key enzymes for PC biosynthesis, fatty acid synthase (FAS) and CTP:phosphocholine cytidylyltransferase-alpha (CCT-alpha), and compared their localization with that of surfactant storage organelles, the lamellar bodies (LBs), and surfactant proteins (SPs) in fetal mouse lung. Ultrastructural analysis showed that immature and mature LBs were present within the glycogen pools of fetal type II cells. Multivesicular bodies were noted only in the cytoplasm. Immunogold electron microscopy (EM) revealed that the glycogen pools were the prominent cellular sites for FAS and CCT-alpha. Energy-filtering EM demonstrated that CCT-alpha bound to phosphorus-rich (phospholipid) structures in the glycogen. SP-B and SP-C, but not SP-A, localized predominantly to the glycogen stores. Collectively, these data suggest that the glycogen stores in fetal type II cells are a cellular site for surfactant PC synthesis and LB formation/maturation consistent with the idea that the glycogen is a unique substrate for surfactant lipids.
Am J Physiol Lung Cell Mol Physiol 2004 Oct
PMID:Surfactant lipid synthesis and lamellar body formation in glycogen-laden type II cells. 1516 78

CCAAT/enhancer binding protein alpha (C/EBP alpha) is a critical factor in glucose metabolism in the neonate as revealed by conventional C/EBP alpha-null mice that do not survive beyond the first day after birth because of severe hypoglycemia and a deficiency in hepatic glycogen accumulation. To elucidate the function of C/EBP alpha in leptin-deficient mouse (ob/ob) liver, a C/EBP alpha-liver null mouse on an ob/ob background (ob/ob-C/EBP alpha/Cre(+)) was produced using a floxed C/EBP alpha allele and Cre recombinase under control of the albumin promoter (AlbCre). The C/EBP alpha-deficient liver in ob/ob mice had significantly decreased triglyceride content compared with equivalent mice lacking the AlbCre transgene (ob/ob-C/EBP alpha/Cre(-)). Expression of genes involved in lipogenesis including fatty acid synthase, acetyl-coenzyme A carboxylase, stearoyl-coenzyme A desaturase 1 and ATP-citrate lyase dramatically decreased in ob/ob-C/EBP alpha/Cre(+) mouse liver. Induction of these lipogenic genes by a high-carbohydrate diet caused an exacerbation in the development of fatty liver and an increase in liver size, hepatic triglyceride, and cholesterol contents in ob/ob-C/EBP alpha/Cre(-) mice but not in ob/ob-C/EBP alpha/Cre(+) mice. Deficiency in hepatic C/EBP alpha expression caused an exacerbation of hyperglycemia because of decreased insulin secretion. Taken together, these results indicate that hepatic C/EBP alpha plays a critical role in the acceleration of lipogenesis in ob/ob mice and in glucose homeostasis by the indirect regulation of insulin secretion.
Mol Endocrinol 2004 Nov
PMID:Hepatic CCAAT/enhancer binding protein alpha mediates induction of lipogenesis and regulation of glucose homeostasis in leptin-deficient mice. 1531 54


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