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)

Peroxisome Proliferator-Activate Receptors (PPARs) are transcription factors belonging to the nuclear receptor superfamily. The three PPARs (alpha, beta/delta, and gamma) are distributed differently in the different organs. PPARalpha is most common in the liver, but also found in kidney, gut, skeletal muscle and adipose tissue, while PPARbeta/delta, is fairly ubiquitous; it may be found in body tissues and brain (for myelination process and lipid metabolism in the brain). PPARgamma has 3 isoforms, such as PPARgamma 1, PPARgamma 2, and PPARgamma 3. The syndrome-X was firstly coined by Reaven in 1988 and then to be provided in 1999 by the name : the metabolic syndrome-X. This metabolic syndrome represents a "Cluster" of metabolic disorders and cardiovascular risk factors which has been collected and summarized by the author and such a cluster includes: insulin resistance/hyperinsulinemia, central obesity, glucose intolerance/DM, atherogenic dyslipidemia (increase TG, decrease HDL-cholesterol, increase Apo-B, increase small dense LDL), hypertension, prothrombotic state (increase PAI-1, increase F-VII, increase fibrinogen, increase vWF, increase adhesion molecules), endothelial dysfunction, hyperuricemia, and increased hsC-RP and cytokines. The metabolic syndrome-X may lead to the development of T2DM and coronary heart disease (CHD); insulin resistance plays pivotal roles in the progression of such a syndrome and cardiovascular diseases. Improvement of Insulin Resistance, therefore, is most likely to reduce the high cardiovascular event rate in T2DM. It has been generally accepted that Insulin Resistance (detected by HOMA-R) and Acute Insulin Response = AIR (by HOMA-B) are both usually present in T2DM. The Thiazolidinedions (TZDs) are Insulin Sensitizers (e.g Rosiglitazone = ROS, Pioglitazone = PIO) introduced into clinical practice in 1997; clinical evidence data showed that TZDs improved both HOMA-R, and HOMA-B. PPARgamma can be activated by TZDs and it appears to be fundamental to the pathophysiology of diabetes mellitus i.e increase GLUT-4, increase glucokinase, decrease PEPCK, increase GLUT-4, and decreases production by fat cell of several mediators that may cause insulin resistance, such as TNFalpha and resistin. PPARgamma also mediates increased production of Adiponectin and the insulin signaling intermediate PI3K, and both actions lead to increase insulin sensitivity. A "dual PPARgamma-PPARalpha agonists" (e.g PIO, but ROS poorly activate PPARalpha) might lower glucose and modulate lipids. Thus, PIO, as a stronger "dual PPARgamma-PPARalpha agonists", shows an important therapeutic pathway in diabetes mellitus and cardiovascular diseases, even in metabolic syndrome. Current evidence suggests a close relationship between activation of PPARgamma and restoration of insulin sensitivity by reductions in TNFalpha and FFAs, and the enhancement of insulin stimulation of PI3-K Pathway and also increase adiponectin & decrease resistin.
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PMID:New approach in the treatment of T2DM and metabolic syndrome (focus on a novel insulin sensitizer). 1711 68

The three peroxisome-proliferator-activated receptor (PPAR) subtypes PPAR-alpha, PPAR-gamma, and PPAR-delta are ligand-activated transcription factors of the nuclear receptor family. PPARs form obligate heterodimers with the retinoid X receptor, which bind to peroxisome-proliferator-response elements (PPREs). PPAR-alpha is expressed mainly in liver, brown fat, kidney, heart, and skeletal muscle; PPAR-gamma in intestine and adipose tissue; PPAR-alpha and PPAR-gamma are both expressed in vascular endothelium, smooth muscle cells, macrophages, and foam cells; PPAR-delta in skeletal muscle, human embryonic kidney, intestine, heart, adipose tissue, developing brain, and keratinocytes. Intense interest in the development of drugs with new mechanisms of action for the metabolic syndrome has focused attention on nuclear receptors, such as PPARs that function as regulators of energy homeostasis. Agonists of PPAR-alpha and PPAR-gamma are currently used to treat diabetic dyslipidemia and type 2 diabetes. Dual PPAR-alpha/gamma agonists and PPAR-alpha/gamma/delta pan-agonists are under investigation for treatment of cardiovascular disease and the metabolic syndrome. Selective PPAR modulators (SPPARMs) are PPAR ligands that possess desirable efficacy and improved tolerance. Efforts are being made to identify novel partial agonists or antagonists for PPAR-gamma in order to combine their antidiabetic and antiobesity effects. Glucocorticoids are major mediators of the stress response and could be the link between stress and PPAR activator signaling and thus may affect the downstream metabolic pathways involved in fuel homeostasis.
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PMID:Targeting components of the stress system as potential therapies for the metabolic syndrome: the peroxisome-proliferator-activated receptors. 1714 46

Peroxisome proliferator-activated receptor (PPAR)alpha is a nuclear receptor activated by natural ligands such as fatty acids as well as by synthetic ligands such as fibrates currently used to treat dyslipidemia. PPARalpha regulates the expression of genes encoding proteins that are involved in lipid metabolism, fatty acid oxidation, and glucose homeostasis, thereby improving markers for atherosclerosis and insulin resistance. In addition, PPARalpha exerts anti-inflammatory effects both in the vascular wall and the liver. Here we provide an overview of the mechanisms through which PPARalpha affects the initiation and progression of atherosclerosis, with emphasis on the modulation of atherosclerosis-associated inflammatory responses. PPARalpha activation interferes with early steps in atherosclerosis by reducing leukocyte adhesion to activated endothelial cells of the arterial vessel wall and inhibiting subsequent transendothelial leukocyte migration. In later stages of atherosclerosis, evidence suggests activation of PPARalpha inhibits the formation of macrophage foam cells by regulating expression of genes involved in reverse cholesterol transport, formation of reactive oxygen species (ROS), and associated lipoprotein oxidative modification among others. Furthermore, PPARalpha may increase the stability of atherosclerotic plaques and limit plaque thrombogenicity. These various effects may be linked to the generation of PPARalpha ligands by endogenous mechanisms of lipoprotein metabolism. In spite of this dataset, other reports implicate PPARalpha in responses such as hypertension and diabetic cardiomyopathy. Although some clinical trials data with fibrates suggest that fibrates may decrease cardiovascular events, other studies have been less clear, in terms of benefit. Independent of the clinical effects of currently used drugs purported to achieve PPARalpha, extensive data establish the importance of PPARalpha in the transcriptional regulation of lipid metabolism, atherosclerosis, and inflammation.
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PMID:PPARalpha in atherosclerosis and inflammation. 1763 13

Normal physiological processes are under control of circadian rhythms. Moreover, certain pathological events, such as cardiovascular accidents (myocardial infarction, stroke) occur more frequently at specific times of the day. Recent observations demonstrate a causal relationship between alterations in circadian rhythmicity and metabolic disorders. Disruption of clock genes results in dyslipidemia, insulin resistance and obesity, all predisposing to atherosclerosis. The nuclear receptor Rev-erb alpha is part of the clock circuitry and plays an important role in keeping proper timing of the clock. Rev-erb alpha also regulates lipid metabolism, adipogenesis and vascular inflammation. Interestingly, Rev-erb alpha also cross-talks with several other nuclear receptors involved in energy homeostasis. Therefore Rev-erb alpha may serve to couple metabolic and circadian signals.
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PMID:Rev-erb alpha gives a time cue to metabolism. 1776 29

Despite the success of existing therapies, new therapies targeted toward dyslipidemia are still needed. Liver X receptor (LXR) and farnesoid X receptor (FXR) represent 2 very different attractive targets for new therapeutic development. LXR is a nuclear receptor that primarily acts to rid cells and the body of excess cholesterol. LXR agonists have been shown to reduce atherosclerosis in animals and are therefore of great interest as a therapeutic approach. Despite some increases in hepatic fat and low-density lipoprotein (LDL) cholesterol in preclinical models, LXR remains an important new target. FXR is a nuclear receptor that primarily acts to protect hepatocytes against the effects of elevated bile acids. FXR agonists also have triglyceride-lowering properties and could be useful in treating certain types of dyslipidemia. FXR modulators or antagonists could potentially lower LDL cholesterol levels and even modulate high-density lipoprotein metabolism. FXR is a complicated but fascinating target for the development of new therapeutic approaches.
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PMID:Liver X receptor and farnesoid X receptor as therapeutic targets. 1804 47

The metabolic syndrome (MetS) is defined by a set of metabolic risk factors, including insulin resistance, central obesity, dyslipidemia, hyperglycemia, and hypertension for type 2 diabetes and cardiovascular disease. Although both retrospective and prospective clinical studies have revealed that MetS is associated with chronic renal disease, even with a nondiabetic cause, the cellular and molecular mechanisms in this association remain largely uncharacterized. Recently, increasing evidence suggests that peroxisome proliferator-activated receptors (PPARs), a subgroup of the nuclear hormone receptor superfamily of ligand-activated transcription factors, may play an important role in the pathogenesis of MetS. All three members of the PPAR nuclear receptor subfamily, PPARalpha, -beta/delta, and -gamma, are critical in regulating insulin sensitivity, adipogenesis, lipid metabolism, inflammation, and blood pressure. PPARs have also been implicated in many renal pathophysiological conditions, including diabetic nephropathy and glomerulosclerosis. Ligands for PPARs such as hypolipidemic PPARalpha activators, and antidiabetic thiazolidinedione PPARgamma agonists affect not only diverse aspects of MetS but also renal disease progression. Emerging data suggest that PPARs may be potential therapeutic targets for MetS and its related renal complications. This review focuses on current knowledge of the role of PPARs in MetS and discusses the potential therapeutic utility of PPAR modulators in the treatment of kidney diseases associated with MetS.
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PMID:PPARs and the kidney in metabolic syndrome. 1823 57

Nuclear receptors function as ligand-inducible transcription factors that regulate various physiological functions such as development, reproduction, and metabolism. Dysregulation of the metabolism of cholesterol, triglyceride, and glucose leads to the metabolic syndrome including type 2 diabetes mellitus, obesity, dyslipidemia, and atherosclerosis. Studies of nuclear receptors promise to provide discoveries of therapeutic agents against the metabolic syndrome. Farnesoid X receptor (FXR) is a member of the nuclear receptor superfamily and is activated by bile acids. FXR regulates the metabolism of not only bile acid but also cholesterol, lipoprotein, triglyceride, and glucose, and is considered a potential therapeutic target for the metabolic syndrome because of these functions. Nuclear receptors have two regions for transactivation, a constitutive activation function (AF-1) and a ligand-dependent activation function (AF-2). AF-1 and AF-2 seem to require interactions with coactivators for the activation function and both work synergistically to give full transactivation of nuclear receptors. However, coactivators for AF-1 activity are poorly understood, whereas coactivators required for AF-2 activity have been well studied. To understand the molecular mechanism of AF-1 in FXR, we isolated proteins associated with AF-1 by GST pull-down assay using the N-terminal region of FXR and nuclear extracts from HeLa cells. This review focuses on the roles of FXR and our new findings regarding FXR-associated factors.
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PMID:[Functional analysis of nuclear receptor FXR controlling metabolism of cholesterol]. 1831 Oct 53

Alagille syndrome (AGS) is a rare hereditary disorder exhibiting fluctuating cholestasis and dyslipidemia. Farnesoid X receptor (FXR) and liver X receptor (LXR) are hepatic nuclear receptors that regulate bile acid and lipoprotein metabolism. To investigate whether cholestasis is related to dyslipidemia and hepatic nuclear receptor expression in AGS patients, we determined the blood levels of total bile acid (TBA) and lipoprotein parameters, and examined hepatic nuclear receptor expression in three AGS children and their three incomplete AGS parents repeatedly over several years. In the AGS children, TBA level showed significant positive correlations with low-density lipoprotein-cholesterol, apolipoprotein E (apoE)-rich high-density lipoprotein-cholesterol (HDL-C), apoA-I, apoE, and cholesteryl ester transfer protein (CETP) concentrations, but negative correlation with apoE-poor HDL-C concentration. Western blot analysis of liver biopsy specimens revealed that FXR and LXR expression increased in parallel with TBA level. CETP- and ATP-binding cassette transporter A1 expression also increased with TBA level, while scavenger receptor class B type-I expression showed the opposite response. However, apoA-I expression was similar to the control level at any TBA level. In the incomplete AGS parents, TBA and lipoprotein parameters showed little fluctuation. In summary, cholestasis is closely related to dyslipidemia and hepatic nuclear receptor expression in AGS patients.
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PMID:Fluctuation of lipoprotein metabolism linked with bile acid-activated liver nuclear receptors in Alagille syndrome. 1843 Apr 27

Although a change in lifestyle is the first choice in controlling cardiovascular risk, lipid-lowering drugs are effective in normalizing different forms of atherogenic dyslipidemia. Although statins are a class of drugs which primarily lower low-density lipoprotein cholesterol, fibrates decrease triglycerides, normalize the low-density lipoprotein cholesterol profile, and increase high-density lipoprotein cholesterol. As lipids are important determinants for cardiovascular diseases, these drugs reduce cardiovascular morbidity. However, a number of recent studies indicate that, in addition to their lipid-normalizing activities, statins and fibrates exhibit pleiotropic actions, such as inhibit inflammation, improve endothelial function, suppress the production of reactive oxygen species, etc. Statins are competitive inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase, the rate-limiting enzyme of cholesterol synthesis, whereas fibrates are activators of the nuclear receptor peroxisome proliferator-activated receptor alpha (PPARalpha). The similarity between the pleiotropic effects of statins and fibrates is remarkable and suggests a mechanistic link between these two classes of drugs. Here we discuss recent data on the cross-talk between statins and PPARalpha agonists and the mechanisms behind these actions.
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PMID:Cross-talk between statins and PPARalpha in cardiovascular diseases: clinical evidence and basic mechanisms. 1843 44

The Peroxisome Proliferator-Activated Receptors-PPAR alpha, PPAR gamma, and PPAR delta--are members of the nuclear receptor gene family that have emerged as therapeutic targets for the development of drugs to treat human metabolic diseases. The discovery of high affinity, subtype-selective agonists for each of the three PPAR subtypes has allowed elucidation of the pharmacology of these receptors and development of first-generation therapeutic agents for the treatment of diabetes and dyslipidemia. However, despite proven therapeutic benefits of selective PPAR agonists, safety concerns and dose-limiting side effects have been observed, and a number of late-stage development failures have been reported. Scientists have continued to explore ligand-based activation of PPARs in hopes of developing safer and more effective drugs. This review highlights recent efforts on two newer approaches, the simultaneous activation of all three PPAR receptors with a single ligand (PPAR pan agonists) and the selective modulation of a single PPAR receptor in a cell or tissue specific manner (selective PPAR modulator or SPPARM) in order to induce a subset of target genes and affect a restricted number of metabolic pathways.
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PMID:PPAR modulators and PPAR pan agonists for metabolic diseases: the next generation of drugs targeting peroxisome proliferator-activated receptors? 1853 85


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