Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0948265 (metabolic syndrome)
 24,271 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To elucidate molecular mechanisms of high fructose-induced metabolic derangements and the influence of peroxisome proliferator-activated receptor-alpha (PPARalpha) activation on them, we examined the expression of sterol regulatory element binding protein-1 (SREBP-1) and PPARalpha as well as its nuclear activation and target gene expressions in the liver of high fructose-fed rats with or without treatment of fenofibrate. After 8-wk feeding of a diet high in fructose, the mRNA contents of PPARalpha protein and its activity and gene expressions of fatty acid oxidation enzymes were reduced. In contrast, the gene expressions of SREBP-1 and lipogenic enzymes in the liver were increased by high fructose feeding. Similar high fructose effects were also found in isolated hepatocytes exposed to 20 mM fructose in the media. The treatment of fenofibrate (30 mg.kg(-1).day(-1)) significantly improved high fructose-induced metabolic derangements such as insulin resistance, hypertension, hyperlipidemia, and fat accumulation in the liver. Consistently, the decreased PPARalpha protein content, its activity, and its target gene expressions found in high fructose-fed rats were all improved by fenofibrate treatment. Furthermore, we also found that the copy number of mitochondrial DNA, the expressions of mitochondrial transcription factor A, ATPase-6 subunit, and uncoupling protein-3 were increased by fenofibrate treatment. These findings suggest that the metabolic syndrome in high fructose-fed rats is reversed by fenofibrate treatment, which is associated with the induction of enzyme expression related to beta-oxidation and the enhancement of mitochondrial gene expression.
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PMID:Amelioration of high fructose-induced metabolic derangements by activation of PPARalpha. 1193 85

The serum- and glucocorticoid-inducible kinase-1 (SGK1) is ubiquitously expressed and under genomic control by cell stress (including cell shrinkage) and hormones (including gluco- and mineralocorticoids). Similar to its isoforms SGK2 and SGK3, SGK1 is activated by insulin and growth factors via phosphatidylinositol 3-kinase and the 3-phosphoinositide-dependent kinase PDK1. SGKs activate ion channels (e.g., ENaC, TRPV5, ROMK, Kv1.3, KCNE1/KCNQ1, GluR1, GluR6), carriers (e.g., NHE3, GLUT1, SGLT1, EAAT1-5), and the Na+-K+-ATPase. They regulate the activity of enzymes (e.g., glycogen synthase kinase-3, ubiquitin ligase Nedd4-2, phosphomannose mutase-2) and transcription factors (e.g., forkhead transcription factor FKHRL1, beta-catenin, nuclear factor kappaB). SGKs participate in the regulation of transport, hormone release, neuroexcitability, cell proliferation, and apoptosis. SGK1 contributes to Na+ retention and K+ elimination of the kidney, mineralocorticoid stimulation of salt appetite, glucocorticoid stimulation of intestinal Na+/H+ exchanger and nutrient transport, insulin-dependent salt sensitivity of blood pressure and salt sensitivity of peripheral glucose uptake, memory consolidation, and cardiac repolarization. A common ( approximately 5% prevalence) SGK1 gene variant is associated with increased blood pressure and body weight. SGK1 may thus contribute to metabolic syndrome. SGK1 may further participate in tumor growth, neurodegeneration, fibrosing disease, and the sequelae of ischemia. SGK3 is required for adequate hair growth and maintenance of intestinal nutrient transport and influences locomotive behavior. In conclusion, the SGKs cover a wide variety of physiological functions and may play an active role in a multitude of pathophysiological conditions. There is little doubt that further targets will be identified that are modulated by the SGK isoforms and that further SGK-dependent in vivo physiological functions and pathophysiological conditions will be defined.
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PMID:(Patho)physiological significance of the serum- and glucocorticoid-inducible kinase isoforms. 1701 87

In spite of a progressive fall in the incidence of traditional risk factors of cardiovascular morbidity (cigarette smoking, high blood pressure, and hyperlipidemia), there is an upward trend in the prevalence of obesity and chronic kidney disease (CKD). Furthermore, there is a strong correlation between body mass indices and the relative risk of progression of CKD. The close biophysiological interaction between obesity and CKD is evident by a similar occurrence of comorbidities including insulin resistance, hyperlipidermia, endothelial dysfunction, and sleep disorders. Truncal obesity is a primary component of metabolic syndrome; unlike peripheral fat, the visceral adipocytes are more resistant to insulin. In addition, lipolysis results in a release of free fatty acid and TG, whereas hypertriglycedemia is potentiated by uremic activation of fatty acid synthase. Hypertriglycedemia and low HDL cholesterol increase the relative risk of progression of CKD. Furthermore, endothelial inflammation and premature atherosclerosis are promoted by hyperhomocysteinemia and oxidation of LDL, both of which are commonly observed in CKD and obesity. Predominance of oxidative stress in both obesity and azotemia stimulate synthesis of angiotensin II, which in turn increases TGF-B and plasminogen activator inhibitor-1, thereby propagating glomerular fibrosis. Furthermore, local synthesis of angiotensinogen by adipocytes, leptin activation of sympathetic nervous system, and hyperinsulinemia contribute to the development of hypertension in obesity and CKD. In addition, increased renal tubular expression of Na-K-ATPase and a blunted response to natiuretic hormones in obesity promote salt and water retention. Glomerular hyperfiltration from systemic volume load and hypertension results in mesangial cellular proliferation and progressive renal fibrosis. In addition, maternal nutritional deprivation increases the incidence of obesity, hypertension, and diabetes in adulthood. Reduced fetal protein synthesis contributes to oxidative glomerular injury and impairment of renal morphogenesis. Thus, kidneys are poorly equipped to handle physiologic stress that may result from the rapid body growth and programmed metabolic dysfunction later in life. Finally, in order to minimize morbidity of obesity-related kidney disease, preventive strategy must include optimal maternal health care, promotion of healthy nutrition and routine physical exercise, and early detection of CKD.
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PMID:The role of obesity and its bioclinical correlates in the progression of chronic kidney disease. 1704 21

Skeletal muscle contains one of the largest pools of Na,K-ATPase in the body, and therefore plays a central role in the clearance of [K(+)] from the blood during the ingestion or infusion of K(+). In the case of major hyperkalaemia (i.e. pathological increase of plasma [K(+)]), skeletal muscle can rapidly accumulate significant amounts (up to 50%) of extracellular K(+). Thus, skeletal muscle is an important temporary storage for K(+). Hyperkalaemia and impaired K(+)-tolerance frequently occurs in people who present features of the metabolic syndrome, concomitant with impaired activity of the sodium pump and decreased expression of the Na,K-ATPase subunits. These pathological conditions may lead to membrane depolarization in excitable tissues and to the development of cardiac arrhythmia or other cardiovascular complications that are a major consequence of metabolic syndrome. Thus, increasing Na,K-ATPase activity in skeletal muscle may protect from these complications.
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PMID:Regulation of the Na,K-ATPase: Special implications for cardiovascular complications of metabolic syndrome. 1797 97

We examined the role of epidermal growth factor (EGF) receptor in the pathogenesis of leptin-induced hypertension in the rat. Leptin, administered in increasing doses (0.1-0.5 mg/kg/day) for 10 days, increased phosphorylation levels of non-receptor tyrosine kinase, c-Src, EGF receptor and extracellular signal-regulated kinases (ERK) in aorta and kidney, which was accompanied by the increase in plasma concentration and urinary excretion of isoprostanes and H2O2. Blood pressure and renal Na+,K+-ATPase activity were higher, whereas urinary sodium excretion was lower in animals receiving leptin. The effects of leptin on renal Na+,K+-ATPase, natriuresis and blood pressure were abolished by NADPH oxidase inhibitor, apocynin, Src kinase inhibitor, PP2, EGF receptor inhibitor, AG1478, protein farnesyltransferase inhibitor, manumycin A, and ERK inhibitor, PD98059. In contrast, inhibitors of insulin-like growth factor-1 and platelet-derived growth factor receptors, AG1024 and AG1295, respectively, only slightly reduced ERK phosphorylation and had no effect on blood pressure in rats receiving leptin. These data indicate that: (1) experimental hyperleptinemia is associated with oxidative stress and c-Src-dependent transactivation of the EGF receptor, which stimulates ERK in vascular wall and the kidney, (2) overactivity of EGF receptor-ERK pathway contributes to leptin-induced hypertension by stimulating renal Na+,K+-ATPase and reducing sodium excretion, (3) inhibitors of c-Src, EGF receptor and ERK may be considered as a novel therapy for hypertension associated with hyperleptinemia, e.g. in patients with obesity and metabolic syndrome.
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PMID:Transactivation of epidermal growth factor receptor in vascular and renal systems in rats with experimental hyperleptinemia: role in leptin-induced hypertension. 1828 56

The skeletal muscle sodium pump plays a major role in the removal of K(+) ions from the circulation postprandial, or after a physical activity bout, thereby preventing the development of hyperkalemia and fatigue. Insulin and muscle contractions stimulate Na(+)-K(+)-ATPase activity in skeletal muscle, at least partially via translocation of sodium pump units to the plasma membrane from intracellular stores. The molecular mechanism of this phenomenon is poorly understood. Due to the contradictory reports in the literature, the very existence of the translocation of Na(+)-K(+)-ATPase to the skeletal muscle cell surface is questionable. This review summarizes more than 30 years work on the skeletal muscle sodium pump translocation paradigm. Furthermore, the methodological caveats of major approaches to study the sodium pump translocation in skeletal muscle are discussed. An understanding of the molecular regulation of Na(+)-K(+)-ATPase in skeletal muscle will have important clinical implications for the understanding of the development of complications associated with the metabolic syndrome, such as cardiovascular diseases or increased muscle fatigue in diabetic patients.
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PMID:Frontiers: skeletal muscle sodium pump regulation: a translocation paradigm. 1877 88

This study is to evaluate beta cell function and investigate the mechanism of impaired pancreatic islet beta cell function in monosodium glutamate (MSG) obese rat with insulin resistance, an animal model of metabolic syndrome. Insulin tolerance test was used to screen MSG obese rats with insulin resistance. Blood concentrations of glucose, triglyceride, total cholesterol and insulin were determined. Beta cell function was assessed with hyperglycemic clamp technique. The morphological alterations in pancreas and changes of islet beta cell mass were evaluated by hematoxylin-eosin (HE) and Gomori aldehyde fuchsin staining. Lipid, oxidative stress relevant factors, nitric oxide (NO) level and activity of ATPase in pancreas and pancreatic mitochondrial were tested. The MSG obese rats with insulin resistance could be validated as a typical metabolic syndrome animal model possessing increased fasting plasma triglycerides and insulin (P < 0. 001), markedly decreased weight indices of pancreas and impaired glucose-stimulated insulin secretion. Hematoxylin-eosin (HE) and Gomori aldehyde fuchsin staining showed increased adipocytes and fibroplasia deposition in pancreas and reduced beta cell mass. The increased contents of triglyceride and NO level, the decreased SOD levels and activities of total ATPase (P < 0.001), Na+-K+-ATPase (P < 0.001) and Ca2+-Mg2+-ATPase (P < 0.01) were observed in pancreas and its mitochondria versus normal rat. The study demonstrates that accumulation of lipids in pancreas could lead to increased systemic indicators of inflammation, such as NO, which may influence the activities of several kinds of ATPase in cell membranes and interfere the ion transport, substance metabolism and energy production in pancreas. Finally the MSG obese rats characterized with metabolic syndrome displayed an impairment of beta cell function.
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PMID:[A preliminary study on the mechanism of impaired beta cell function in monosodium glutamate obese rat with insulin resistance]. 1923 28

Sodium is the main determinant of body fluid distribution. Sodium accumulation causes water retention and, often, high blood pressure. At the cellular level, the concentration and active transport of sodium is handled by the enzyme Na(+),K(+)-ATPase, whose appearance enabled evolving primitive cells to cope with osmotic stress and contributed to the complexity of mammalian organisms. Na(+),K(+)-ATPase is a platform at the hub of many cellular signaling pathways related to sensing intracellular sodium and dealing with its detrimental excess. One of these pathways relies on an intracellular sodium-sensor network with the salt-inducible kinase 1 (SIK1) at its core. When intracellular sodium levels rise, and after the activation of calcium-related signals, this network activates the Na(+),K(+)-ATPase and expel the excess of sodium from the cytosol. The SIK1 network also mediates sodium-independent signals that modulate the activity of the Na(+),K(+)-ATPase, like dopamine and angiotensin, which are relevant per se in the development of high blood pressure. Animal models of high blood pressure, with identified mutations in components of multiple pathways, also have alterations in the SIK1 network. The introduction of some of these mutants into normal cells causes changes in SIK1 activity as well. Some cellular processes related to the metabolic syndrome, such as insulin effects on the kidney and other tissues, also appear to involve the SIK1. Therefore, it is likely that this protein, by modulating active sodium transport and numerous hormonal responses, represents a "crossroad" in the development and adaptation to high blood pressure and associated diseases.
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PMID:Intracellular sodium sensing: SIK1 network, hormone action and high blood pressure. 2034 66

Hypertension is a common complication of type 2 diabetes mellitus (T2DM), and is the main cause for T2DM-associated mortality. Although the stringent control of blood pressure is known to be beneficial in reducing the cardiovascular mortality of T2DM patients, drugs with both anti-hypertensive and anti-hyperglycemic effects are seldom reported. The traditional Chinese medicine danshen has long been used for lowering both blood pressure and blood glucose in T2DM patients, shedding lights on the development of such medication. However, the molecular mechanism and active component remain unclear. Here, we report that the lipophilic component, 15,16-dihydrotanshinone I (DHTH) from danshen potently antagonized both mineralocorticoid and glucocorticoid receptors, and efficiently inhibited the expression of their target genes like Na(+)/K(+) ATPase, glucose 6-phosphatase (G6Pase), and phosphoenolpyruvate carboxykinase (PEPCK). In addition, DHTH increased AMPKalpha phosphorylation and regulated its downstream pathways, including increasing acetyl-CoA carboxylase (ACC) phosphorylation, inhibiting transducer of regulated CREB activity 2 (TORC2) translocation and promoting glucose uptake. Such discovered multi-target effects of DHTH are expected to have provided additional understandings on the molecular basis of the therapeutic effects of danshen against the metabolic syndrome.
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PMID:Danshen extract 15,16-dihydrotanshinone I functions as a potential modulator against metabolic syndrome through multi-target pathways. 2038 Aug 78

Serum- and glucocorticoid-inducible kinase 1 (SGK1) is expressed following cell stress and exposure to a variety of hormones including glucocorticoids and mineralocorticoids. It is activated by insulin and growth factors via phosphatidylinositol-3-kinase and the 3-phosphoinositide-dependent kinase PDK1. SGK1 enhances the activity of a variety of ion channels such as ENaC, TRPV5, ROMK, KCNE1/KCNQ1 and ClCKb; carriers such as NHE3, NKCC2, NCC and SGLT1; as well as the Na+/K+-ATPase. SGK1 contributes to Na+ retention and K+ elimination of the kidney as well as mineralocorticoid stimulation of salt appetite. A certain SGK1 gene variant (combined polymorphisms in intron 6 [I6CC] and in exon 8 [E8CC/CT]) is associated with moderately enhanced blood pressure. The SGK1 gene variant has been shown to affect 3%-5% of whites and some 10% of Africans. The gene variant sensitizes the carriers to the hypertensive effects of hyperinsulinemia. Moreover, the SGK1 gene variant is associated with increased body mass index, presumably a result of enhanced SGLT1 activity with accelerated intestinal glucose absorption. Obesity predisposes the carriers of the gene variant to development of type 2 diabetes. Moreover, SGK1 stimulates coagulation. Thus, SGK1 may participate in the pathogenesis of metabolic syndrome or syndrome X, a condition characterized by the coincidence of essential hypertension, procoagulant state, obesity, insulin resistance and hyperinsulinemia.
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PMID:SGK, renal function and hypertension. 2117 Aug 69


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