Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.7.49 (reverse transcriptase)
31,746 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Phytanic acid, a metabolite of the chlorophyll molecule, is part of the human diet and is present in normal human serum at low micromolar concentrations. It was previously shown to be a ligand of the 9-cis-retinoic acid receptor and peroxisome proliferator-activated receptor (PPAR) a. PPAR agonists are widely used in the treatment of type 2 diabetes. Here, we report that phytanic acid is not only a transactivator of PPARa, but it also acts via PPARb and PPARg in CV-1 cells that have been cotransfected with the respective full-length receptor and an acyl-CoA oxidase-PPAR-responsive element-luciferase construct. We observed that, in contrast to other fatty acids, phytanic acid at physiological concentrations enhances uptake of 2-deoxy-D-glucose in rat primary hepatocytes. This result could be explained by the increase in mRNA expression of glucose transporters-1 and -2 and glucokinase, as determined by quantitative real-time reverse transcriptase-polymerase chain reaction. Compared with the PPARg-specific agonist ciglitazone, phytanic acid exerts only minor effects on the differentiation of C3H10T1/2 cells into mature adipocytes. These results clearly demonstrate that phytanic acid acts via different PPAR isoforms to modulate expression of genes involved in glucose metabolism, thus suggesting a potential role of phytanic acid in the management of insulin resistance.
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PMID:Phytanic acid, a natural peroxisome proliferator-activated receptor (PPAR) agonist, regulates glucose metabolism in rat primary hepatocytes. 1192 21

Visceral fat accumulation is accompanied by several metabolic disorders. Here, we investigate the improvement of visceral fat accumulation in the early phase of diet. Hyperlipidemic obese patients received a low-calorie diet (1000 kcal/day) for 14 days. Visceral and subcutaneous fat accumulation was analyzed using ultrasonography. After 14 days of the diet, the average visceral fat of obese patients obviously decreased (P < 0.05), as well as the visceral fat-related secreted proteins, whereas subcutaneous fat did not decrease in these patients. These results show that visceral fat is reduced significantly in the early phase of diet therapy in humans. Therefore, to clarify its mechanism, we analyzed the expression of lipid metabolism-related genes in visceral and subcutaneous fat using obese rats. The Long-Evans Tokushima Otsuka (LETO) rats, as an obese model, were divided into two groups: fasting and non-fasting. The gene expressions in visceral and subcutaneous fat were measured by reverse transcriptase-polymerase chain reaction (RT-PCR). The expression of beta(3)-adrenergic receptor (AR), hormone sensitive lipase (HSL), peroxisome proliferator-activated receptor (PPAR)-gamma, and uncoupling protein (UCP)-2 genes increased by 3.2-, 2.3-, 2.2-, and 2-fold in visceral fat (P < 0.01), but remained almost unchanged in subcutaneous fat. Taken together, the responsiveness of lipid metabolism-related genes to fasting is more sensitive in visceral fat than in subcutaneous fat in rats, suggesting that the different responsiveness to calorie restriction in fat tissues is due to the different induction of metabolism-related gene expression.
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PMID:Visceral fat: higher responsiveness of fat mass and gene expression to calorie restriction than subcutaneous fat. 1461 Feb 49

A serious metabolic syndrome combining insulin-resistance, dyslipidemia, central adiposity, and peripheral lipoatrophy has arisen in HIV-infected patients receiving highly active antiretroviral therapy. The aim of this work was to examine the effects of the nonnucleoside reverse transcriptase inhibitor (NNRTI) efavirenz on adipocyte differentiation and metabolism. When induced to differentiate in the presence of efavirenz (5-50 microm), 3T3-F442A preadipocytes failed to accumulate cytoplasmic triacylglycerol droplets. This phenomenon was rapidly reversible and was also readily detectable in the 3T3-L1 preadipose cell line and in primary cultures of human preadipocytes. When applied to mature 3T3-F442A adipocytes, efavirenz induced a delayed and moderate reduction in cell triglyceride content. Measurement of [(3)H]deoxyglucose uptake, basal and agonist-stimulated lipolysis, and cell viability indicated that these pathways are not involved in efavirenz effects on triacylglycerol accumulation. By contrast, we found that the NNRTI induced a dramatic dose- and time-dependent decrease in gene and protein expression of the lipogenic transcription factor sterol regulatory element-binding protein-1c (SREBP-1c). Adipose conversion was only altered at the highest efavirenz concentrations, as suggested by the mild reduction in peroxisome proliferator-activated receptor-gamma and CCAAT/enhancer-binding protein-alpha. CCAAT/enhancer-binding protein-beta remained unchanged. The inhibition of SREBP-1c expression was accompanied by a sharp reduction in the expression of SREBP-1c target genes and in the adipocyte lipogenic activity in efavirenz-treated cells. Finally, the inhibitory effect of efavirenz on cell triglyceride accumulation was prevented by directly providing free fatty acids to the cells and was reversed by overexpression of a dominant positive form of SREBP-1c, reinforcing the implication of this transcription factor in the antilipogenic effect of the drug. When considered together, these results demonstrate for the first time that the NNRTI efavirenz induces a strong inhibition of the SREBP-1c-dependent lipogenic pathway that might contribute to adipose tissue atrophy.
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PMID:In vitro suppression of the lipogenic pathway by the nonnucleoside reverse transcriptase inhibitor efavirenz in 3T3 and human preadipocytes or adipocytes. 1472 61

15-Lipoxygenase-2 (15-LOX-2) synthesizes 15-S-hydroxyeicosatetraenoic acid (15-S-HETE), an endogenous ligand for the nuclear receptor, peroxisome proliferator-activated receptor-gamma (PPAR-gamma). Several studies have described an inverse relationship between 15-LOX-2 and PPAR-gamma expression in normal versus tumor samples. To systematically determine if this is a ubiquitous phenomenon, we used a variety of epithelial and nonepithelial cells and some tissues to further evaluate the extent of this inverse relationship. The levels of mRNA or protein were measured by reverse transcriptase polymerase chain reaction or Western gray level intensity, whereas distribution was determined by in situ hybridization or immunofluorescence. 15-S-HETE was measured by liquid chromatography/tandem mass spectrometry. Normal epithelial cells/samples generally expressed high levels of 15-LOX-2 along with the enzyme product 15-S-HETE, but both levels were reduced in cancer cells/samples. In contrast, most cancer cells expressed high levels of PPAR-gamma mRNA and protein, which were absent from normal epithelial cells. Overall, the inverse relationship between these two genes was primarily restricted to epithelial samples. Forced expression of PPAR-gamma reduced 15-LOX-2 protein levels in normal cells, whereas forced expression of 15-LOX-2 in tumor cells suppressed PPAR-gamma protein levels. These results suggest that feedback mechanisms may contribute to the loss of 15-LOX-2 pathway components, which coincide with an increase in PPAR-gamma in many epithelial cancers.
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PMID:Inverse relationship between 15-lipoxygenase-2 and PPAR-gamma gene expression in normal epithelia compared with tumor epithelia. 1579 28

Ochratoxin A (OTA), a mycotoxin and widespread food contaminant, is known for its patent nephrotoxicity and potential neurotoxicity. Previous observations in vitro showed that in the CNS, glial cells were particularly sensitive to OTA. In the search for the molecular mechanisms underlying OTA neurotoxicity, we investigated the relationship between OTA toxicity and glial reactivity, in serum-free aggregating brain cell cultures. Using quantitative reverse transcriptase-polymerase chain reaction to analyze changes in gene expression, we found that in astrocytes, non cytotoxic concentrations of OTA down-regulated glial fibrillary acidic protein, while it up-regulated vimentin and the peroxisome proliferator-activated receptor-gamma expression. OTA also up-regulated the inducible nitric oxide synthase and the heme oxygenase-1. These OTA-induced alterations in gene expression were more pronounced in cultures at an advanced stage of maturation. The natural peroxisome proliferator-activated receptor-gamma ligand, 15-deoxy-delta(12,14) prostaglandin J2, and the cyclic AMP analog, bromo cyclic AMP, significantly attenuated the strong induction of peroxisome proliferator-activated receptor-gamma and inducible nitric oxide synthase, while they partially reversed the inhibitory effect of OTA on glial fibrillary acidic protein. The present results show that OTA affects the cytoskeletal integrity of astrocytes as well as the expression of genes pertaining to the brain inflammatory response system, and suggest that a relationship exists between the inflammatory events and the cytoskeletal changes induced by OTA. Furthermore, these results suggest that, by inducing an atypical glial reactivity, OTA may severely affect the neuroprotective capacity of glial cells.
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PMID:Unusual astrocyte reactivity caused by the food mycotoxin ochratoxin A in aggregating rat brain cell cultures. 1599 20

Impairment of peroxisome proliferator-activated receptor-gamma (PPAR-gamma) function through a dominant negative PAX-8/PPAR-gamma fusion gene or other events resulting in wild-type PPAR-gamma downregulation has been implicated in malignant thyroid cell transformation. The aim of our study was to perform a systematic evaluation of PPAR-gamma mRNA and protein expression in normal thyroid tissue as opposed to benign thyroid pathologies of different functional status and thyroid malignancy, to gain further insights into a putative physiological role of PPAR-gamma in the thyroid and to define whether PPAR-gamma could serve as a marker of thyroid cell differentiation. Ten cold benign (CTN) and 10 toxic (TTN) thyroid nodules and corresponding normal thyroid tissues, 10 follicular thyroid cancers (FTC), 10 papillary thyroid cancers (PTC) and 8 Graves' disease (GD) thyroids were studied by real-time polymerase chain reaction (PCR), immunohistochemistry and reverse transcriptase (RT)-PCR (PAX-8/PPAR-gamma fusion gene). PPAR-gamma mRNA expression was demonstrated in all samples. When comparing benign nodular and normal thyroid tissue of the same patient no significant difference in PPAR-gamma mRNA expression was observed. PPAR-gamma mRNA levels were similar in CTN and FTC. In contrast, PPAR-gamma mRNA expression was downregulated in 9 of 10 PTC and all GD samples, whereby at least 4 fold downregulation (compared with normal and benign nodular thyroid tissues) was observed in the latter. Immunohistochemistry showed an increased, patchy PPAR-gamma nuclear staining in CTNs and TTNs and only faint staining in the corresponding normal thyroid tissues. A diffuse and weak PPAR-gamma staining pattern was observed in all GD samples. No PAX-8/PPAR-gamma rearrangements were detected in any of the 68 thyroid tissue samples. In conclusion PPAR-gamma mRNA and protein expression levels are not concordant in benign thyroid nodular disease. Furthermore there is no clear-cut association of PPAR-gamma mRNA expression with follicular thyroid tumorigenesis. Absence of a PAX-8/PPAR-gamma fusion gene in the series of 68 thyroid samples is in agreement with the suggestion of PAX-8/PPAR-gamma rearrangement being restricted to a subset of follicular thyroid cancers. The marked downregulation of PPAR-gamma in GD warrants further investigation and could be linked, for example, with changes in apoptosis.
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PMID:Evaluation of peroxisome proliferator-activated receptor-gamma expression in benign and malignant thyroid pathologies. 1618 7

Agonists of the nuclear receptors peroxisome proliferator-activated receptor (PPAR) gamma, PPARalpha, and liver X receptors (LXRs) reduce blood glucose in type 2 diabetic patients and comparable mouse models. Since the capacity of these drugs to normalize hepatic gene expression is not known, we compared groups of obese diabetic db/db mice treated with agonists for PPARgamma [rosiglitazone (Rosi); 10 mg/kg/day], PPARalpha [Wy 14643 (Wy; 4-chloro-6-(2,3-xylidino)-2-pyrimidinyl)thioacetic acid); 30 mg/kg/day], and LXR [T0901317 (T09; N-(2,2,2-trifluoroethyl)-N-[4-[2,2,2-trifluoro-1-hydroxy-1(trifluoromethyl)-ethyl]phenyl]-benzenesulfonamide); 40 mg/kg/day] and from untreated nondiabetic litter mates (db/+) by oligonucleotide microarrays and quantitative reverse transcriptase-polymerase chain reaction. The 10-day treatment period of db/db mice with Rosi, Wy, and T09 altered expression of 300, 620, and 735 genes including agonist-specific target genes, respectively. However, from the 337 genes differentially regulated in untreated db/+ versus db/db animals, only 34 (10%), 51 (15%), and 82 (24%) were regulated in the direction of the db/+ group by Rosi, Wy, and T09, respectively. Gene expression normalization by drug treatment involved glucose homeostasis, lipid homeostasis, and local glucocorticoid activation. In addition, our data pointed to hitherto unknown interference of these nuclear receptors with growth hormone receptor gene expression and endoplasmic reticulum stress. However, many diabetes-associated gene alterations remained unaffected or were even aggravated by nuclear receptor agonist treatment. These results suggest that diabetes-induced gene expression is minimally reversed by potent blood glucose-lowering nuclear receptor agonists.
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PMID:Blood glucose-lowering nuclear receptor agonists only partially normalize hepatic gene expression in db/db mice. 1626 May 81

Fat depots vary in size, function, and potential contribution to disease. Since fat tissue turns over throughout life, preadipocyte characteristics could contribute to this regional variation. To address whether preadipocytes from different depots are distinct, we produced preadipocyte strains from single abdominal subcutaneous, mesenteric, and omental human preadipocytes by stably expressing human telomere reverse transcriptase (hTERT). These strains could be subcultured repeatedly and retained capacity for differentiation, while primary preadipocyte adipogenesis and replication declined with subculturing. Primary omental preadipocytes, in which telomeres were longest, replicated more slowly than mesenteric or abdominal subcutaneous preadipocytes. Even after 40 population doublings, replication, abundance of the rapidly replicating preadipocyte subtype, and resistance to tumor necrosis factor alpha-induced apoptosis were highest in subcutaneous, intermediate in mesenteric, and lowest in omental hTERT-expressing strains, as in primary preadipocytes. Subcutaneous hTERT-expressing strains accumulated more lipid and expressed more adipocyte fatty acid-binding protein (aP2), peroxisome proliferator-activated receptor gamma2, and CCAAT/enhancer-binding protein alpha than omental cells, as in primary preadipocytes, while hTERT abundance was similar. Thus, despite dividing 40 population doublings, hTERT strains derived from single preadipocytes retained fat depot-specific cell dynamic characteristics, consistent with heritable processes contributing to regional variation in fat tissue function.
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PMID:Fat depot-specific characteristics are retained in strains derived from single human preadipocytes. 1693 6

A proteomic analysis of procyanidin B(2) isolated from cocoa against oxidized low-density lipoprotein-induced lipid-laden macrophage formation was performed. Of approximately 400 detected proteins, 12 were differentially expressed as a result of B(2) treatment. They were subsequently identified by liquid chromatography-electrospray ionization-tandem mass spectrometry and the SWISS-PROT database. Further reverse transcriptase-polymerase chain reaction and Western blot analysis revealed that B(2) strongly inhibited arachidonic acid inflammatory reactions, apoptosis, and their coupled mitogen-activated protein kinase and NF-kappaB pathways. To highlight proteins or genes with similar expressed patterns and similarly biological function induced by B(2) in lipid-laden macrophages, a cluster and Kyoto Encyclopedia of Genes and Genomes pathway analysis were performed. The data were mapped to multiple pathways. Further validation of the bioinformatic results revealed that activation of Wnt signaling may contribute to the cardioprotection of B(2). The differentially expressed genes and proteins mentioned above induced by B(2) are through regulating nuclear transcription factors, activating peroxisome proliferator-activated receptor-gamma and inhibiting AP-1 mRNA expressions. These in vitro data help to interpret the beneficial effects of B(2) in reducing the risk of atherosclerosis after consumption of flavonoid-rich foods. Many differentially expressed genes induced by B(2) help to uncover novel targets and may help to target disease interactions in atherosclerosis in the future.
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PMID:Inhibitory effects of procyanidin B(2) dimer on lipid-laden macrophage formation. 1695 22

The transcription factor peroxisome proliferator-activated receptor (PPAR) alpha plays an important role in lipid homeostasis. In this study, we examined whether the down-regulation of PPAR-alpha gene expression is associated with dyslipidemia in a rat model of chronic renal failure (CRF). Rats with laboratory-induced uremia by 5/6 nephrectomy were bled at 2 weeks and 10 weeks after the nephrectomy to produce conditions. For the sake of convenience, the rats observed at postoperative week 2 were defined as acute renal failure (ARF) and those observed at week 10 were defined as CRF. Lipids in lipoprotein fractions were measured by high-performance liquid chromatography. The abundance of PPAR-alpha messenger RNA (mRNA) in the liver was measured by reverse transcriptase-polymerase chain reaction. Serum creatinine and blood urea nitrogen levels rose with the progression of renal failure, but the total protein levels remained constant. Serum triglyceride in ARF rats remained unchanged from the level in sham-operated control rats, whereas that in CRF rats was 66% higher than the control level. Serum cholesterol was elevated 1.5-fold in ARF rats and 2-fold in CRF rats compared with the sham-operated counterparts. As with triglyceride, very low-density lipoprotein remained unchanged in ARF rats but rose substantially in CRF rats. All of the major lipoprotein fractions were elevated in CRF rats. These lipid and lipoprotein changes were significantly associated with creatinine and blood urea nitrogen levels. The PPAR-alpha mRNA expression in the liver was unchanged in ARF rats but was 44% lower in CRF rats. The PPAR-alpha mRNA expression was inversely correlated with serum creatinine and lipids in the overall rats. Our results indicate that PPAR-alpha mRNA expression is down-regulated in the liver of CRF rats and that this down-regulation may play a crucial role in the development of dyslipidemia.
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PMID:Decreased peroxisome proliferator-activated receptor alpha gene expression is associated with dyslipidemia in a rat model of chronic renal failure. 1799 26


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