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)

Overweight and obesity lead to an increased risk for metabolic disorders such as impaired glucose regulation/insulin resistance, dyslipidemia, and hypertension. Several molecular drug targets with potential to prevent or treat metabolic disorders have been revealed. Interestingly, the activation of peroxisome proliferator-activated receptor (PPAR), which belongs to the nuclear receptor superfamily, has many beneficial clinical effects. PPAR directly modulates gene expression by binding to a specific ligand. All PPAR subtypes (alpha, gamma, and sigma) are involved in glucose metabolism, lipid metabolism, and energy balance. PPAR agonists play an important role in therapeutic aspects of metabolic disorders. However, undesired effects of the existing PPAR agonists have been reported. A great deal of recent research has focused on the discovery of new PPAR modulators with more beneficial effects and more safety without producing undesired side effects. Herein, we briefly review the roles of PPAR in metabolic disorders, the effects of PPAR modulators in metabolic disorders, and the technologies with which to discover new PPAR modulators.
PPAR Res 2008
PMID:Peroxisome Proliferators-Activated Receptor (PPAR) Modulators and Metabolic Disorders. 1856 91

Therapeutic use of certain peroxisome proliferator-activated receptor (PPAR) alpha agonists (fibrates) for the treatment of dyslipidemia has infrequently been associated with the untoward side effect of myopathy. With interest in PPAR-delta as a therapeutic target, this study assessed whether a PPAR-delta agonist induced similar hepatic and skeletal muscle alterations as noted with some fibrates. PPAR-alpha null (KO) and corresponding wild-type (WT) mice were administered toxicological dosages of a potent PPAR-delta agonist tool ligand (GW0742; which also has weak PPAR-alpha agonist activity) or a potent PPAR-alpha agonist (WY-14,643) for 10 days. Increases in liver weights and clinical chemistry indicators of skeletal muscle damage and/or liver injury were more pronounced in WT mice compared with KO mice administered the PPAR-delta agonist. Likewise, the incidence and severity of skeletal myopathy were greater in WT mice given GW0742 compared with KO mice. Ultrastructural and immunohistochemical analyses revealed significant peroxisome proliferation in muscle and liver of WT mice treated with each agonist; however, KO animals showed little or no evidence of hepatic and muscle peroxisome proliferation. PMP-70 protein expression in liver was consistent with these results. The hepatomegaly, hepatic and skeletal muscle peroxisome proliferation, and skeletal myopathy induced by this PPAR-delta ligand was predominantly mediated by its cross-activation of PPAR-alpha, though PPAR-delta agonism contributed slightly to these effects.
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PMID:PPAR alpha, more than PPAR delta, mediates the hepatic and skeletal muscle alterations induced by the PPAR agonist GW0742. 1859 27

Hypertriglyceridemia is an independent risk factor for coronary artery disease. Because apolipoprotein (Apo)A5 regulates plasma triglyceride levels, we investigated the impact of human (h)ApoA5 on atherogenesis. The influence of hApoA5 transgenic expression was studied in the ApoE2 knock-in mouse model of mixed dyslipidemia. Our results demonstrate that hApoA5 lowers plasma triglyceride levels in Western diet-fed ApoE2 knock-in mice. Moreover, atherosclerotic lesion development was significantly decreased in the hApoA5 transgenic mice. Finally, pharmacologic activation of hApoA5 expression by the peroxisome proliferator-activated receptor-alpha agonist fenofibrate resulted in an enhanced atheroprotection. These results identify an atheroprotective role of hApoA5 in a mouse model of mixed dyslipidemia.
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PMID:Atheroprotective effect of human apolipoprotein A5 in a mouse model of mixed dyslipidemia. 1865 49

Hypertriglyceridemia is observed in many metabolic diseases such as the metabolic syndrome, diabetes mellitus, or mixed dyslipidemia frequently leading to premature coronary heart disease (CHD). Additionally, several studies have shown that postprandial hypertriglyceridemia is pronounced in patients with CHD, metabolic syndrome, hypertension, and other pathologic conditions. The triglyceride-rich lipoprotein remnants accumulating in the postprandial state seem to be involved in atherogenesis and in events leading to thrombosis. Since abnormal postprandial lipemia is associated with pathologic conditions, its treatment is of clinical importance.Fibrates are of significant help in managing hypertriglyceridemia. This review summarizes the effect of fibric acid derivatives on postprandial lipemia. Fibrates decrease the production of and enhance the catabolism of triglyceride-rich lipoproteins through the activation of peroxisome proliferator-activated receptor-alpha. Results of clinical studies with fibrates have confirmed their action in decreasing postprandial triglyceride levels by increasing lipoprotein lipase activity, decreasing apolipoprotein CIII production, and by increasing fatty acid oxidation in the liver.It is concluded that fibrates are effective agents in lowering the postprandial increase in remnant lipoprotein particles and retinyl palmitate. Furthermore, fibrates can also affect the postprandial lipid profile by increasing hepatic lipase levels and in some cases, by reducing cholesterol ester transfer protein activity. The main target of fibrate therapy is to improve fasting hypertriglyceridemia, which is an essential component associated with improving postprandial lipemia. Fibrates are well tolerated by patients and adverse effects have been reported rarely after their administration.
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PMID:Therapeutic effects of fibrates in postprandial lipemia. 1869 Jul 58

We investigated the antidiabetic effects of E3030, which is a potent dual activator of peroxisome proliferator-activated receptor (PPAR) alpha and PPARgamma, in an animal model of diabetes, C57BL/KsJ-db/db mice (db/db mice), and the lipidemic effects of E3030 in beagle dogs, whose PPARalpha and PPARgamma transactivation responses to E3030 were similar to those of humans. E3030 activated human PPARalpha, mouse PPARalpha, dog PPARalpha, human PPARgamma, mouse PPARgamma, and dog PPARgamma with EC(50) values of 65, 920, 87, 34, 73, and 34 nM, respectively, in the chimeric GAL4-PPAR receptor transactivation reporter assay. In db/db mice orally administered E3030 decreased blood glucose, triglyceride (TG), non-esterified fatty acids (NEFA), and insulin levels and increased blood adiponectin levels during a 14-day experimental period. Significant effects on blood glucose and adiponectin levels were observed at a dose of 3 mg/kg or greater. Furthermore, significant effects on blood TG, NEFA, and insulin levels were observed at doses of 1 mg/kg or more. An oral glucose tolerance test (OGTT) performed on Day 15 showed that E3030 at 3 mg/kg improved glucose tolerance in this model. Fourteen days of oral treatment with E3030 at a dose of 0.03 mg/kg or greater showed remarkable TG- and non high-density lipoprotein (non-HDL) cholesterol-lowering effects in beagle dogs. These results were similar to those observed for the PPARalpha agonist fenofibrate. E3030 also reduced apo C-III levels on Days 7 and 14, and elevated lipoprotein lipase (LPL) levels on Day 15. These results indicate that the TG- and non-HDL cholesterol-lowering actions of E3030 involve combined effects on reduction of apo C-III and elevation of LPL, resulting in increased lipolysis. The experimental results in animals suggest that E3030 has potential for use in the treatment of various aspects of metabolic dysfunction in type 2 diabetes, including dyslipidemia, hyperglycemia, hyperinsulinemia, and impaired glucose disposal.
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PMID:Antidiabetic and hypolipidemic effects of a novel dual peroxisome proliferator-activated receptor (PPAR) alpha/gamma agonist, E3030, in db/db mice and beagle dogs. 1877 9

Atrial fibrillation (AF) is the most common disorder of cardiac rhythm and is responsible for substantial morbidity and mortality in general population. A recent community-based observational study revealed that diabetes and/or hypertension were associated with the development of AF. However, there is no definite evidence to show that patients with type 1 diabetes have an increased risk for the development of AF. These findings suggest that hyperglycemia per se may not explain the positive association between diabetes and AF. Growing body of evidence supports the presence of insulin resistance as the fundamental pathophysiological disturbance responsible for the metabolic syndrome, a constellation of metabolic disorders such as hypertension, dyslipidemia, and obesity that raise the risk for diabetes mellitus and cardiovascular diseases. Further, several clinical trials have shown that the renin-angiotensin system (RAS) plays an important role in the pathogenesis of insulin resistance. These observations suggest that insulin resistance could account for the increased risk for AF in the patients with diabetes and/or hypertension and that the interruption of the RAS may be a promising therapeutic strategy for preventing the development of AF. In the first part of this paper, we review clinical studies to support the concept that angiotensin II type 1 receptor blockers (ARBs) could prevent the development of AF in insulin resistant patients and discuss the possible underlying mechanisms. In the second part, we discuss the potential utility of telmisartan, a unique ARB with peroxisome proliferator-activated receptor-gamma (PPAR-gamma)-modulating activity, for blocking the development of AF in patients with insulin resistance.
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PMID:Possible molecular mechanisms by which angiotensin II type 1 receptor blockers (ARBs) prevent the development of atrial fibrillation in insulin resistant patients. 1879 76

Adiposity-associated inflammation and insulin resistance are strongly implicated in the development of type 2 diabetes and atherosclerotic cardiovascular disease. This article reviews the mechanisms of adipose inflammation, because these may represent therapeutic targets for insulin resistance and for prevention of metabolic and cardiovascular consequences of obesity. The initial insult in adipose inflammation and insulin resistance, mediated by macrophage recruitment and endogenous ligand activation of Toll-like receptors, is perpetuated through chemokine secretion, adipose retention of macrophages, and elaboration of pro-inflammatory adipocytokines. Activation of various kinases modulates adipocyte transcription factors, including peroxisome proliferator-activated receptor-gamma and NFkappaB, attenuating insulin signaling and increasing adipocytokine and free fatty acid secretion. Inflammation retards adipocyte differentiation and further exacerbates adipose dysfunction and inflammation. Paracrine and endocrine adipose inflammatory events induce a local and systemic inflammatory, insulin-resistant state promoting meta-bolic dyslipidemia, type 2 diabetes, and cardiovascular disease. Developing therapeutic strategies that target both adipose inflammation and insulin resistance may help to prevent type 2 diabetes and cardiovascular disease in the emerging epidemic of obesity.
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PMID:Adipose inflammation, insulin resistance, and cardiovascular disease. 1897 44

The aim of present study was to identify the visceral adipose tissue genes differentially expressed in a well-characterized rat model of high-fat diet (HFD)-induced obesity. Male Sprague-Dawley rats were fed either the HFD (17 g lard + 3 g corn oil/100 g) or the normal diet (5 g corn oil/100 g) for 9 weeks. The HFD rats weighed 55% more and accumulated 85% to 133% greater visceral fats than did the normal-diet rats (P < .05). Animals given the HFD for 9 weeks acquired dyslipidemia, fatty liver, insulin resistance, and hyperleptinemia along with the overexpression of several obesity-related genes, such as leptin, tumor necrosis factor alpha, resistin, peroxisome proliferator-activated receptor gamma2, CCAAT/enhancer-binding protein alpha, and sterol regulatory element-binding protein-1c, in the epididymal adipose tissue. The differential gene expression profile obtained from the cDNA microarray analysis followed by the real-time polymerase chain reaction confirmation led to a recruitment of several uncharacterized adipose tissue genes responding to the HFD. We report herein, for the first time, that a series of genes which might be implicated in the insulin-stimulated glucose transporter 4 translocation, such as protein phosphatase 2 (formerly 2A), cell division cycle 42-interacting protein 4, syntaxin 6, linker of T-cell receptor pathways 10, as well as the genes which might be involved in cancer development, such as heat shock 10-kd protein 1, and ras-related C3 botulinum toxin substrate 1, were differentially expressed in the epididymal adipose tissue of rats rendered obese by an HFD.
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PMID:Genes are differentially expressed in the epididymal fat of rats rendered obese by a high-fat diet. 1908 40

Clinical guidelines highlight the importance of managing atherogenic mixed dyslipidemia to reduce the risk of premature cardiovascular disease in type 2 diabetes mellitus and metabolic syndrome. The lipid-modifying activity of fenofibrate, as demonstrated in clinical studies, indicates its effectiveness in treating dyslipidemia characteristic of these conditions. Fenofibrate also has a favorable impact on a number of nonlipid residual risk factors associated with type 2 diabetes and metabolic syndrome, mediated by peroxisome proliferator-activated receptor-alpha. In patients with type 2 diabetes, fenofibrate is effective in reducing the progression of coronary artery disease, as demonstrated by the Diabetes Atherosclerosis Intervention Study (DAIS). In the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study, the primary end point (major coronary events) was not significantly reduced by fenofibrate treatment. However, other findings from this study suggest that fenofibrate reduces cardiovascular risk. Both DAIS and the FIELD study also indicate that fenofibrate may offer additional vascular benefits, specifically affecting the progression of diabetes-related microvascular disease.
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PMID:Fenofibrate for cardiovascular disease prevention in metabolic syndrome and type 2 diabetes mellitus. 1908 87

Fenofibrate is a peroxisome proliferator-activated receptor-alpha (PPARalpha) activator that has been clinically used to treat dyslipidemia and insulin resistance. To better understand the molecular mechanisms underlying fenofibrate action, we investigated whether fenofibrate affects serum levels of retinol-binding protein-4 (RBP4), an adipocytokine that has recently been shown to link obesity and insulin resistance. Fenofibrate treatment significantly decreased serum RBP4 levels of dyslipidemic patients, which correlated with reduced body weight and increased insulin sensitivity. To elucidate the biochemical mechanisms of fenofibrate action, we investigated the effect of fenofibrate on RBP4 expression in obese rats. Fenofibrate greatly decreased RBP4 mRNA levels in adipose tissue but not in the liver, which correlated with decreased serum RBP4 levels and increased insulin sensitivity in obese rats. Consistent with a direct effect on RBP4 expression, fenofibrate treatment significantly reduced the mRNA expression levels of RPB4 in 3T3-L1 adipocytes. Together, our results demonstrate for the first time that fenofibrate inhibits RPB4 expression in dyslipidemic human subjects and suggest that inhibition of RBP4 expression in adipocytes may provide a mechanism by which fenofibrate improves insulin sensitivity in dyslipidemic patients.
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PMID:Fenofibrate reduces serum retinol-binding protein-4 by suppressing its expression in adipose tissue. 1908 57


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