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)

Leptin has properties of a profibrogenic cytokine. In liver, the activated hepatic stellate cell (HSC) is responsible for a net production of extracellular matrix. A key molecule synthesized is the tissue inhibitor of metalloproteinase I (TIMP-1), which acts to inhibit the activity of matrix metalloproteinases. The purpose of the present study was to determine how leptin, a gp130 cytokine, orchestrates the regulation of TIMP-1 gene activation and expression. Transient transfection of primary HSCs revealed that leptin significantly increased luciferase activity of a 229-bp TIMP-1 promoter construct (TIMP-1-229). An EMSA revealed that leptin enhanced specificity protein 1 (Sp1) binding. Site-directed mutagenesis for Sp1 reduced the enhancing effect of leptin on TIMP-1 transcriptional activation, and this effect was dose dependent on the number of Sp1 sites mutated. Chromatin immunoprecipitation revealed that leptin enhanced binding of Sp1; however, inhibition of signal transducer and activator of transcription (STAT) 3 phosphorylation by AG490 also blocked Sp1 phosphorylation and significantly reduced leptin-associated TIMP-1-229 promoter activity, indicating that one mechanism for leptin-increased transcriptional activity is via phosphorylation of Sp1 and subsequent promoter binding. Finally, we demonstrate that leptin also results in intranuclear pSTAT3 binding to Sp1. We propose a novel mechanism whereby leptin-mediated TIMP-1 transcription employs a Sp1/pSTAT3-dependent mechanism, one of which is a noncanonical association between Sp1 and pSTAT3. These data provide a new molecular mechanism whereby the adipocytokine leptin plays a role in complications of the metabolic syndrome.
Mol Endocrinol 2006 Dec
PMID:Leptin increases tissue inhibitor of metalloproteinase I (TIMP-1) gene expression by a specificity protein 1/signal transducer and activator of transcription 3 mechanism. 1693 73

Carbon monoxide (CO) is an endogenously derived gas formed from the breakdown of heme by the enzyme heme oxygenase. Although long considered an insignificant and potentially toxic waste product of heme catabolism, CO is now recognized as a key signaling molecule that regulates numerous cardiovascular functions. Interestingly, alterations in CO synthesis are associated with many cardiovascular disorders, including atherosclerosis, septic shock, hypertension, metabolic syndrome, and ischemia-reperfusion injury. Significantly, restoration of physiologic CO levels exerts a beneficial effect in many of these settings, suggesting a crucial role for CO in maintaining cardiovascular homeostasis. In this review, we outline the actions of CO in the cardiovascular system and highlight this gas as a potential therapeutic target in treating a multitude of cardiovascular disorders.
J Cell Mol Med
PMID:Role of carbon monoxide in cardiovascular function. 1698 27

Metabolic syndrome (MS) is characterized by the presence of at least three of the following alterations: enlargement of the waist diameter, higher levels of arterial pressure, low density lipoprotein cholesterol and glycemia, and reduction of high density lipoprotein cholesterol. The prevalence of MS reaches 23% in young adults, a percentage that increases with age. People with MS have a greater risk of suffering from cardiovascular disease (CVD). The physiopathologic alterations now found to exist in MS are diverse; among them is endothelial dysfunction, which triggers atherogenic lesions and hypercoagulability characterized by alterations of the coagulation factors and the regulatory proteins of fibrinolysis such as the plasminogen activator inhibitor (PAI-1). The increase in oxidative stress and/or the reactive oxygen species in patients with MS is partially related to the oxidation state of the lipoproteins, especially of the low density lipoproteins. This fact favors atherogenesis. Moreover, the oxidative stress produces alterations in the production of adipokines, cytokines secreted by the adipose tissues. The abnormality in the transport of lipoprotein diminishes the catabolism of the very low density lipoprotein (VLDL) and increases the catabolism of the high density lipoprotein (HDL), which creates insulin resistance. This process is associated with a lower concentration of adiponectin that in turn regulates the catabolism of VLDL and HDL; consequently increasing the flow of fatty acids from the adipose tissue to the liver and muscles. The proinflammatory cytokines, among them tumor necrosis factor alpha (TNF-alpha), are of great importance in MS regulating different processes and molecules such as PAI-1. PAI-1 is controlled by the group of transcription factors peroxisome proliferator-activated receptor (PPAR), especially by PPAR gamma and alpha ligands. In summary, MS includes multiple alterations related to insulin resistance at several levels: hepatic, muscular, adipose and vascular tissue (endothelium). The exact mechanism that underlies the relationship between MS and CVD are not sufficiently known yet; pathogenic explanations are lacking for the mechanisms relating metabolic factors to insulin resistance and the association with the development of atherosclerosis and thrombosis. MS alterations and the main aspects related to homeostasis alterations are examined in this report.
Int J Mol Med 2006 Nov
PMID:Hemostasis alterations in metabolic syndrome (review). 1701 29

Adiponectin, a protein exclusively secreted by adipose tissue but present at low levels in obesity, is now widely recognised as a key determinant of insulin sensitivity and of protection against obesity-associated metabolic syndrome. In this review we explain how genetic findings have contributed to a better understanding of the physiological role of adiponectin in humans. The adiponectin-encoding gene, ADIPOQ (ACDC), is very polymorphic: many frequent exonic synonymous, intronic and promoter single-nucleotide polymorphisms (SNPs) have been identified, as well as a few rare exonic amino acid substitutions. Several of these variations additively contribute to the modulation of adiponectin level and function, and associate with insulin sensitivity, type 2 diabetes and vascular complications of obesity.
Expert Rev Mol Med 2006 Nov 20
PMID:Adiponectin, type 2 diabetes and the metabolic syndrome: lessons from human genetic studies. 1711 91

Elevated plasma interleukin-6 (IL-6) is associated with coronary heart disease (CHD), impaired glucose tolerance (IGT), and type 2 diabetes (T2DM). We and others have described an association between the human interleukin-6 -174G>C gene variant and body mass index (BMI). Within our previous sample of subjects with T2DM, we measured plasma IL-6 and grouped subjects by the WHO-defined metabolic syndrome, in order to study the association between the -174G>C gene variant, plasma IL-6 and the metabolic syndrome (and component parts). Genotype was obtained in 571 Caucasian subjects with plasma IL-6 measures. There was a significant association between genotype and plasma IL-6 (GG vs GC vs CC: 3.23+/-0.93 pg/ml vs 3.42+/-0.95 pg/ml vs 4.16+/-1.18 pg/ml, p=0.02; for GG/GC vs CC p=0.008). No interactions were observed between genotype and the individual components of the metabolic syndrome in determining plasma IL-6. Increased plasma IL-6 was also associated with the number of components (none vs 1 vs 2 vs > or =3: 2.67+/-0.71 pg/ml vs 2.97+/-0.94 pg/ml vs 4.07+/-1.13 pg/ml, p<0.0001). Within the sample, 76% of CC compared to 56% of GG subjects had the metabolic syndrome (p=0.007). Further analysis of association between the genotype and the components of the metabolic syndrome revealed no further associations than that with BMI previously described. The association of this gene variant with the metabolic syndrome is intimately linked with obesity per se. Further prospective work is required to explore the effect of this gene variant in relation to obesity, the metabolic syndrome and 'prediabetes'.
Mol Genet Metab 2007 Apr
PMID:Association between plasma IL-6, the IL6 -174G>C gene variant and the metabolic syndrome in type 2 diabetes mellitus. 1712 52

Definitions of the metabolic syndrome (MetS) include obesity, dyslipidemia, elevated levels of fasting blood glucose, and blood pressure as criteria, but it is also known that the MetS is associated with chronic, subclinical inflammation. Hyperglycemia (fasting and postprandial) may be important in exacerbating this proinflammatory state. We aimed to assess the impact of oral glucose challenge and in vitro glucose-stimulation on gene expression and secretion of inflammatory parameters in peripheral blood leukocytes and to investigate whether presence of the MetS could "prime" leukocytes to up-regulate proinflammatory markers in response to glucose. Using quantitative real-time PCR, we could show that the expression of intercellular adhesion molecule 1 (ICAM-1), tumor necrosis factor alpha (TNF-alpha), and interleukin 6 (IL-6) significantly increased in peripheral blood leukocytes from "MetS" subjects (n=39) compared to "no MetS" subjects (n=35) 2 h after an oral glucose tolerance test (ICAM-1 +52%, TNF-alpha +107%, and IL-6 +38%) and also in vitro after 72 h cultivation in high-glucose medium (ICAM-1 +74%, TNF-alpha +71%, and IL-6 +44%). Using ELISA and Luminex technique, we further observed a trend towards increased immune mediator concentrations in the corresponding cell culture supernatants from MetS patients (ICAM-1 +21%, TNF-alpha +31%, and IL-6 +175%). Thus, the MetS may support peripheral inflammation by sensitizing leukocytes to up-regulate proinflammatory markers in response to glucose, which in turn increases the risk for type-2 diabetes mellitus and cardiovascular disease.
J Mol Med (Berl) 2007 Apr
PMID:The metabolic syndrome sensitizes leukocytes for glucose-induced immune gene expression. 1716 Jun 70

Adipose tissue is an endocrine organ involved in storage and release of energy but also in regulation of energy metabolism in other organs via secretion of peptide and protein hormones (adipokines). Especially visceral adipose tissue has been implicated in the development of metabolic syndrome and type 2 diabetes. Factors secreted by the stromal-vascular fraction contribute to the secretome and modulate adipokine secretion by adipocytes. Therefore, we aimed at the characterization of the adipose tissue secretome rather than the adipocyte cell secretome. The presence of serum proteins and intracellular proteins from damaged cells, released during culture, may dramatically influence the dynamic range of the sample and thereby identification of secreted proteins. Part of the study was therefore dedicated to the influence of the culture setup on the quality of the final sample. Visceral adipose tissue was cultured in five experimental setups, and the quality of resulting samples was evaluated in terms of protein concentration and protein composition. The best setup involved one wash after the 1st h in culture followed by two or three additional washes within an 8-h period, starting after overnight culture. Thereafter tissue was maintained in culture for an additional 48-114 h to obtain the final sample. For the secretome experiment, explants were cultured in media containing L-[(13)C(6),(15)N(2)]lysine to validate the origin of the identified proteins (adipose tissue- or serum-derived). In total, 259 proteins were identified with > or =99% confidence. 108 proteins contained a secretion signal peptide of which 70 incorporated the label and were considered secreted by adipose tissue. These proteins were classified into five categories according to function. This is the first study on the (human) adipose tissue secretome. The results of this study contribute to a better understanding of the role of adipose tissue in whole body energy metabolism and related diseases.
Mol Cell Proteomics 2007 Apr
PMID:Characterization of the human visceral adipose tissue secretome. 1725 83

Genes involved in carbohydrate and lipid metabolism are nutritionally regulated at the transcriptional level in a coordinated fashion. SREBP-1c is a bHLH transcription factor that controls lipogenesis and is induced during overnutrition to facilitate the conversion of glucose to fatty acids and triglycerides for the storage of the excess energy. Uncontrolled activation of nuclear SREBP-1c in the liver can cause hepatosteatosis, hypertriglyceridemia, and hepatic insulin resistance due to direct suppression of insulin signaling pathways, precipitating development of metabolic syndrome. Conversely, TFE3 is a novel bHLH transcription factor that strongly activates various insulin signaling molecules, protecting against the development of insulin resistance and the metabolic syndrome. Regulation of IRS-2 is the primary site where TFE3 in synergy with Foxo1, and SREBP-1c converge. Taken together, TFE3/Foxo1 and SREBP-1c reciprocally regulate IRS-2 expression and insulin sensitivity in the liver. This scenario provides a mechanistic explanation for the physiological link between glucose and lipid metabolism such as physiological switching of glycogen synthesis to lipogenesis. In addition, these two transcription factors may ultimately contribute to pathophysiological effects of overnutrition leading to the development of the metabolic syndrome and diabetes. In this review, I will discuss roles of SREBP-1c and TFE3 in homeostasis of energy metabolism and in metabolic disturbances, focusing on hepatic insulin sensitivity.
J Mol Med (Berl) 2007 May
PMID:SREBP-1c and TFE3, energy transcription factors that regulate hepatic insulin signaling. 1727 46

Insulin resistance is a defining feature of type 2 diabetes and the metabolic syndrome. While the molecular mechanisms of insulin resistance are multiple, recent evidence suggests that attenuation of insulin signaling by c-Jun N-terminal kinase (JNK) may be a central part of the pathobiology of insulin resistance. Here we demonstrate that the p85alpha regulatory subunit of phosphoinositide 3-kinase (PI3K), a key mediator of insulin's metabolic actions, is also required for the activation of JNK in states of insulin resistance, including high-fat diet-induced obesity and JNK1 overexpression. The requirement of the p85alpha regulatory subunit for JNK occurs independently of its role as a component of the PI3K heterodimer and occurs only in response to specific stimuli, namely, insulin and tunicamycin, a chemical that induces endoplasmic reticulum stress. We further show that insulin and p85 activate JNK by via cdc42 and MKK4. The activation of this cdc42/JNK pathway requires both an intact N terminus and functional SH2 domains within the C terminus of the p85alpha regulatory subunit. Thus, p85alpha plays a dual role in regulating insulin sensitivity and may mediate cross talk between the PI3K and stress kinase pathways.
Mol Cell Biol 2007 Apr
PMID:The p85alpha regulatory subunit of phosphoinositide 3-kinase potentiates c-Jun N-terminal kinase-mediated insulin resistance. 1728 57

The metabolic syndrome and diabetes are associated with bladder dysfunction in many people. Peroxisome proliferator-activated receptors (PPARs) may play a role in the effects of the metabolic syndrome on bladder smooth muscle (BSM). The purpose of this study was to determine if there are gender and genetic differences in PPAR levels in BSM. We measured PPAR levels using quantitative PCR in BSM from male Yucatan swine and male and female Ossabaw Island swine, which is a model for the metabolic syndrome. Male Ossabaw swine had 0.732 +/- 0.111 the amount of PPAR-alpha mRNA as male Yucatan swine (P < 0.05), suggesting a genetic difference in PPAR-alpha levels. This difference may possibly contribute to the incidence of metabolic syndrome in the Ossabaw model compared to the Yucatan model. PPAR-delta mRNA was 2-fold higher in male Ossabaw swine than in female Ossabaw swine, with no significant differences in PPAR-alpha levels. However, PPAR-gamma mRNA was 4.067 +/- 0.134 times higher in female Ossabaw swine than in their male counterparts (P < 0.001). Changing the percentage of calories derived from fat did not alter any PPAR mRNA levels. Thus, PPAR-delta and PPAR-gamma mRNA levels in male and female Ossabaw swine BSM are not only different, but may also result in gender differences in lipid metabolism in bladder smooth muscle. We conclude that PPAR profiles in BSM may contribute to the susceptibility of BSM to lipotoxicity in the metabolic syndrome.
Mol Cell Biochem 2007 Aug
PMID:Gender and genetic differences in bladder smooth muscle PPAR mRNA in a porcine model of the metabolic syndrome. 1731 6


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