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: UMLS:C0242339 (dyslipidemia)
13,927 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The current study examined the relationship between skeletal muscle levels of adiponectin and parameters of insulin sensitivity. A high fat/sucrose diet (HFD) for 20 weeks resulted in significant increases in body weight, serum insulin, triglycerides (TG), and free fatty acids (FFA) (all p < 0.01). Interestingly, this diet leads to a slight increase in serum adiponectin, but significant decreases in gastrocnemius muscle and white adipose adiponectin (all p < 0.05). HFD for 4 weeks also resulted in a significant decrease in muscle adiponectin, which correlated with serum insulin, TG, and FFA (all p < 0.05). Treatment of the 4-week HFD rats with a PPARgamma agonist GI262570 ameliorated the diet-induced hyperinsulinemia and dyslipidemia, and effectively restored muscle adiponectin (all p < 0.05). This study demonstrated that HFD-induced hyperinsulinemia and dyslipidemia appeared without changes in serum adiponectin, but were associated with decreased tissue adiponectin. This provides the first evidence for a connection between tissue adiponectin and diet-induced hyperinsulinemia and dyslipidemia.
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PMID:Changes of skeletal muscle adiponectin content in diet-induced insulin resistant rats. 1641 18

Significant attention has focused on the role of low-density lipoprotein (LDL) in the pathogenesis of atherosclerosis. However, recent advances have identified triglyceride-rich lipoproteins [e.g., very LDL (VLDL)] as independent risk predictors for this disease. We have previously demonstrated peroxisome proliferator-activated receptor (PPAR)delta, but not PPARgamma, is the major nuclear VLDL sensor in the macrophage, which is a crucial component of the atherosclerotic lesion. Here, we show that, in addition to beta-oxidation and energy dissipation, activation of PPARdelta by VLDL particles induces key genes involved in carnitine biosynthesis and lipid mobilization mediated by a recently identified TG lipase, transport secretion protein 2 (also named desnutrin, iPLA2zeta, and adipose triglyceride lipase), resulting in increased fatty acid catabolism. Unexpectedly, deletion of PPARdelta results in derepression of target gene expression, a phenotype similar to that of ligand activation, suggesting that unliganded PPARdelta suppresses fatty acid utilization through active repression, which is reversed upon ligand binding. This unique transcriptional mechanism assures a tight control of the homeostasis of VLDL-derived fatty acid and provides a therapeutic target for other lipid-related disorders, including dyslipidemia and diabetes, in addition to coronary artery disease.
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PMID:Peroxisome proliferator-activated receptor delta promotes very low-density lipoprotein-derived fatty acid catabolism in the macrophage. 1646 50

Obesity is a growing threat to global health by virtue of its association with insulin resistance, glucose intolerance, hypertension, and dyslipidemia, collectively known as the metabolic syndrome or syndrome X. The nuclear receptors PPARalpha and PPARgamma are therapeutic targets for hypertriglyceridemia and insulin resistance, respectively, and drugs that modulate these receptors are currently in clinical use. More recent work on the less-described PPAR isotype PPARdelta has uncovered a dual benefit for both hypertriglyceridemia and insulin resistance, highlighting the broad potential of PPARdelta in the treatment of metabolic disease. PPARdelta enhances fatty acid catabolism and energy uncoupling in adipose tissue and muscle, and it suppresses macrophage-derived inflammation. Its combined activities in these and other tissues make it a multifaceted therapeutic target for the metabolic syndrome with the potential to control weight gain, enhance physical endurance, improve insulin sensitivity, and ameliorate atherosclerosis.
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PMID:PPAR delta: a dagger in the heart of the metabolic syndrome. 1651 91

The metabolic syndrome consists of a combination of cardiovascular risk factors that include hyperglycemia with or without type 2 diabetes mellitus, visceral obesity, elevated blood pressure, and atherogenic dyslipidemia. These interrelated disorders and their associated lipotoxicity, oxidative stress, and inflammatory state predispose to a constellation of cardiovascular conditions leading to high risk of heart attack, stroke, renal failure, blindness, and lower extremity amputation. Visceral obesity, a prime risk factor for type 2 diabetes and a major component of the metabolic syndrome, potentiates atherogenesis, atherosclerosis, organ lipotoxicity, and oxidative tissue damage.Peroxisome proliferator-activated receptors (PPARs) are relatively recently discovered nuclear transcription factors that are modulated by dietary fatty acids, including the essential polyunsaturated fatty acids, arachidonic acid and its metabolites, and are essential to the control of energy metabolism. Of the three PPAR isoforms (alpha, gamma, and delta), synthetic pharmaceutical ligands that activate PPARalpha (the antidyslipidemic fibric acid derivatives ['fibrates']) and PPARgamma (the antidiabetic thiazolidinediones) have been studied extensively. Recently developed dual PPARalpha/gamma agonists may combine the therapeutic effects of these drugs, creating the expectation of greater efficacy, and perhaps other advantages in the treatment of type 2 diabetes and the metabolic syndrome. However, thiazolidinediones are hampered by adverse effects related to increased weight gain and fluid overload. It remains to be seen whether the dual PPARalpha/gamma agonists currently under development have similar limitations. Nevertheless, existing clinical data imply that the combined effects of thiazolidinediones and fibrates are likely to be emulated by dual PPARalpha/gamma agonists, providing superior efficacy to these classes for the treatment of type 2 diabetes, the metabolic syndrome, and their cardiovascular and other end-organ complications.
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PMID:Dual Peroxisome Proliferator-Activated Receptor-alpha/gamma Agonists : In the Treatment of Type 2 Diabetes Mellitus and the Metabolic Syndrome. 1654 49

Compounds that target the peroxisome proliferator-activated receptors PPARalpha and PPARgamma are used to correct dyslipidemia and to restore glycemic balance, respectively. Because the majority of diabetic patients suffer from atherogenic lipid abnormalities, in addition to insulin resistance, ligands are required that can activate both PPARalpha and PPARgamma. In this study, we used chimeric PPARalpha/gamma reporter-gene bioassays to screen herbal extracts with purported antidiabetic properties. Extracts of Astragalus membranaceus and Pueraria thomsonii significantly activated PPARalpha and PPARgamma. Bioassay-guided fractionation resulted in the isolation of the isoflavones, formononetin, and calycosin from Astragalus membranaceus, and daidzein from Pueraria thomsonii as the PPAR-activating compounds. We investigated the effects of these and 2 common isoflavones, genistein and biochanin A, using chimeric and full-length PPAR constructs in vitro. Biochanin A and formononectin were potent activators of both PPAR receptors (EC50 = 1-4 micromol/L) with PPARalpha/PPARgamma activity ratios of 1:3 in the chimeric and almost 1:1 in the full-length assay, comparable to those observed for synthetic dual PPAR-activating compounds under pharmaceutical development. There was a subtle hierarchy of PPARalpha/gamma activities, indicating that biochanin A, formononetin, and genistein were more potent than calycosin and daidzein in chimeric as well as full-length receptor assays. At low doses, only biochanin A and formononetin, but not genistein, calycosin, or daidzein, activated PPARgamma-driven reporter-gene activity and induced differentiation of 3T3-L1 preadipocytes. Our data suggest the potential value of isoflavones, especially biochanin A and their parent botanicals, as antidiabetic agents and for use in regulating lipid metabolism.
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PMID:Differential effects of isoflavones, from Astragalus membranaceus and Pueraria thomsonii, on the activation of PPARalpha, PPARgamma, and adipocyte differentiation in vitro. 1654 48

The metabolic syndrome is characterized by the clustering of insulin resistance, dyslipidemia, and hypertension and is associated with increased risk of cardiovascular disease and type 2 diabetes mellitus. However, older antihypertensive agents such as thiazide diuretics and beta-blockers have potentially adverse effects on glucose and lipid metabolism and may even the exacerbate the metabolic syndrome and increase risk of type 2 diabetes. Recent clinical trials have suggested that antihypertensive agents that inhibit the renin-angiotensin system may reduce risk for new-onset type 2 diabetes, but only a few of these studies were placebo controlled, and in most cases, the absolute antidiabetic effects were relatively modest. Evidence is accumulating that telmisartan, in addition to blocking the angiotensin II type 1 receptor, activates the peroxisome proliferator-activated receptor (PPAR)-gamma a well-known target for treatment of the metabolic syndrome and diabetes. By contrast, other angiotensin-receptor blockers are largely devoid of activity on PPAR-gamma. Telmisartan is a partial agonist of PPAR-gamma and has a superior tolerability profile without causing the fluid retention and edema associated with full agonists of PPAR-gamma such as pioglitazone and rosiglitazone. Recent studies have indicated that in addition to antidiabetic properties, PPAR-gamma activators may also provide protection against atherosclerosis and coronary events. Thus, the ability of telmisartan both to activate PPAR-gamma and to block the angiotensin receptor may provide added value not only in the treatment of the metabolic syndrome and prevention of type 2 diabetes but also in prevention and treatment of atherosclerotic cardiovascular disease.
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PMID:New treatment strategies for patients with hypertension and insulin resistance. 1656 44

While glycemic control remains the cornerstone of clinical management for patients with type 2 diabetes, the importance of a more comprehensive approach that addresses the multiple metabolic abnormalities seen in this population is now widely recognized. Abnormal lipid metabolism resulting in dyslipidemia contributes greatly to the markedly increased risks of cardiovascular disease observed in diabetic patients and in prediabetic patients with signs of insulin resistance. The peroxisome proliferator-activated receptors (PPARs) play a key role in the regulation of energy homeostasis and the coordination of inflammatory responses. As such, they are interesting targets for addressing both the glucose and lipid abnormalities associated with insulin resistance. The thiazolidinediones (TZDs), which activate PPARgamma, appear to improve glycemic control primarily by increasing peripheral insulin sensitivity and reducing hepatic glucose production, thereby helping to preserve beta-cell function. They have also demonstrated modest beneficial effects on some lipid parameters. The fibrate drugs, which activate PPARalpha, produce robust improvements in dyslipidemia, decrease atherosclerotic lesions and may have an effect on cardiovascular events, but do not affect glycemia. Theoretically, a compound targeting both the alpha and gamma PPARs simultaneously might combine the benefits of TZDs and fibrates. Tesaglitazar is a dual-acting PPARalpha/gamma agonist currently being investigated in phase III clinical trials as an alternative treatment for insulin resistance and the characteristic dyslypidemia of type 2 diabetes. This article reviews the available data on the clinical efficacy and safety of tesaglitazar in patients with type 2 diabetes and in individuals without diabetes but with insulin resistance.
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PMID:Tesaglitazar: a promising approach in type 2 diabetes. 1662 56

HM74A is a G protein-coupled receptor for nicotinic acid (niacin), which has been used clinically to treat dyslipidemia for decades. The molecular mechanisms whereby niacin exerts its pleiotropic effects on lipid metabolism remain largely unknown. In addition, the most common side effect in niacin therapy is skin flushing that is caused by prostaglandin release, suggesting that the phospholipase A(2) (PLA(2))/arachidonic acid (AA) pathway is involved. Various eicosanoids have been shown to activate peroxisome-proliferator activated receptors (PPAR) that play a diverse array of roles in lipid metabolism. To further elucidate the potential roles of HM74A in mediating the therapeutic effects and/or side effects of niacin, we sought to explore the signaling events upon HM74A activation. Here we demonstrated that HM74A synergistically enhanced UTP- and bradykinin-mediated AA release in a pertussis toxin-sensitive manner in A431 cells. Activation of HM74A also led to Ca(2+)-mobilization and enhanced bradykinin-promoted Ca(2+)-mobilization through Gi protein. While HM74A increased ERK1/2 activation by the bradykinin receptor, it had no effects on UTP-promoted ERK1/2 activation.Furthermore, UTP- and bradykinin-mediated AA release was significantly decreased in the presence of both MAPK kinase inhibitor PD 098059 and PKC inhibitor GF 109203X. However, the synergistic effects of HM74A were not dramatically affected by co-treatment with both inhibitors, indicating the cross-talk occurred at the receptor level. Finally, stimulation of A431 cells transiently transfected with PPRE-luciferase with AA significantly induced luciferase activity, mimicking the effects of PPARgamma agonist rosiglitazone, suggesting that alteration of AA signaling pathway can regulate gene expression via endogenous PPARs.
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PMID:Enhancement of arachidonic acid signaling pathway by nicotinic acid receptor HM74A. 1667 24

In the quest for novel PPARalpha/gamma co-agonists as putative drugs for the treatment of type 2 diabetes and dyslipidemia, we have used a structure-based design approach to identify propionic acids with a 1,5-disubstituted indole scaffold as potent PPARalpha/gamma activators. Compounds 13, 24, and 28 are examples of submicromolar dual agonists with different alpha/gamma EC50 ratios that are selective against the delta-isoform. Analysis of the X-ray complex structure of PPARgamma with the indole propionic acid 13 provides a rationalization for some of the observed SAR.
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PMID:Structure-based design of indole propionic acids as novel PPARalpha/gamma co-agonists. 1673 14

1. The aim of this study was to investigate the capacity of chiglitazar to improve insulin resistance and dyslipidemia in monosodium L-glutamate (MSG) obese rats and to determine whether its lipid-lowering effect is mediated through its activation of PPARalpha. 2. Chiglitazar is a PPARalpha/gamma dual agonist. 3. The compound improved impaired insulin and glucose tolerance; decreased plasma insulin level and increased the insulin sensitivity index and decreased HOMA index. Euglycemic hyperinsulinemic clamp studies showed chiglitazar increased the glucose infusion rate in MSG obese rats. 4. Chiglitazar inhibited alanine gluconeogenesis, lowered the hepatic glycogen level in MSG obese rats. Like rosiglitazone, chiglitazar promoted the differentiation of adipocytes and decreased the maximal diameter of adipocytes. In addition, chiglitazar decreased the fibrosis and lipid accumulation in the islets and increased the size of islets. 5. Chiglitazar reduced plasma triglyceride, total cholesterol (TCHO), nonesterified fatty acids (NEFA) and low density lipoprotein-cholesterol levels; lowered hepatic triglyceride and TCHO contents; decreased muscular NEFA level. Unlike rosiglitazone, chiglitazar showed significant increase of mRNA expression of PPARalpha, CPT1, BIFEZ, ACO and CYP4A10 in the liver of MSG obese rats. 6. These data suggest that PPARalpha/gamma coagonist, such as chiglitazar, affect lipid homeostasis with different mechanisms from rosiglitazone, chiglitazar may have better effects on lipid homeostasis in diabetic patients than selective PPARgamma agonists.
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PMID:The PPARalpha/gamma dual agonist chiglitazar improves insulin resistance and dyslipidemia in MSG obese rats. 1675 99


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