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 PPAR (peroxisome proliferator activated receptor) transcription factors are ligand-activated receptors which regulate genes involved in lipid metabolism and homeostasis. PPARalpha is preferentially expressed in the liver and PPARgamma preferentially in adipose tissue. Activation of PPARalpha leads to peroxisome proliferation in rodents and increased beta-oxidation of fatty acids. PPARgamma-activation leads to adipocyte differentiation and improved insulin signaling of mature adipocytes. Both of these PPAR receptors are potential targets for treatment of dyslipidemia in man. Studies by others using a proteomics approach have characterized the effects of PPARalpha agonists in livers from lean healthy mice. However, we wanted to map the effects of a therapeutic dose of a PPARalpha agonist in a disease model of insulin resistance and diabetes, the obese diabetic ob/ob mouse, by proteomics. Therefore, ob/ob mice, which have highly elevated levels of plasma triglycerides, glucose and insulin, were treated for one week with WY14,643 (180 micromol/kg/day), a well-characterized selective PPARalpha agonist. Plasma triglycerides, glucose and insulin levels were determined and we found significant therapeutic effects on triglycerides and glucose levels. The liver protein compositions were investigated by high-resolution two-dimensional gel electrophoresis which showed that WY14,643 produced up-regulation of at least 16 spots. These were identified by mass spectrometry and 14 spots were found to be components of the peroxisomal fatty acid metabolism. Thus, WY14,643 at a therapeutic dose, caused induction of peroxisomal fatty acid beta-oxidation in obese diabetic mice.
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PMID:A proteome analysis of livers from obese (ob/ob) mice treated with the peroxisome proliferator WY14,643. 1034 69

The peroxisome proliferator-activated receptors (PPARalpha, gamma, delta) are members of the nuclear receptor superfamily of ligand-activated transcription factors that have central roles in the storage and catabolism of fatty acids. Although the three PPAR subtypes are closely related and bind to similar DNA response elements as heterodimers with the 9-cis retinoic acid receptor RXR, each subserves a distinct physiology. PPARalpha (NR1C1) is the receptor for the fibrate drugs, which are widely used to lower triglycerides and raise high-density lipoprotein cholesterol levels in the treatment and prevention of coronary artery disease. In rodents, PPARalpha agonists induce hepatomegaly and stimulate a dramatic proliferation of peroxisomes as part of a coordinated physiological response to lipid overload. PPARgamma (NR1C3) plays a critical role in adipocyte differentiation and serves as the receptor for the glitazone class of insulin-sensitizing drugs used in the treatment of type 2 diabetes. In contrast to PPARalpha and PPARgamma, relatively little is known about the biology of PPARdelta (NR1C2), although recent findings suggest that this subtype also has a role in lipid homeostasis. All three PPARs are activated by naturally occurring fatty acids and fatty acid metabolites, indicating that they function as the body's fatty acid sensors. Three-dimensional crystal structures reveal that the ligand-binding pockets of the PPARs are much larger and more accessible than those of other nuclear receptors, providing a molecular basis for the promiscuous ligand-binding properties of these receptors. Given the fundamental roles that the PPARs play in energy balance, drugs that modulate PPAR activity are likely to be useful for treating a wide range of metabolic disorders, including atherosclerosis, dyslipidemia, obesity, and type 2 diabetes.
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PMID:Peroxisome proliferator-activated receptors: from genes to physiology. 1123 16

Using solid-phase, parallel-array synthesis, a series of urea-substituted thioisobutyric acids was synthesized and assayed for activity on the human PPAR subtypes. GW7647 (3) was identified as a potent human PPARalpha agonist with approximately 200-fold selectivity over PPARgamma and PPARdelta, and potent lipid-lowering activity in animal models of dyslipidemia. GW7647 (3) will be a valuable chemical tool for studying the biology of PPARalpha in human cells and animal models of disease.
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PMID:Identification of a subtype selective human PPARalpha agonist through parallel-array synthesis. 1135 82

(-)DRF 2725 (6) is a phenoxazine analogue of phenyl propanoic acid. Compound 6 showed interesting dual activation of PPAR alpha and PPAR gamma. In insulin resistant db/db mice, 6 showed better reduction of plasma glucose and triglyceride levels as compared to rosiglitazone. Compound 6 has also shown good oral bioavailability and impressive pharmacokinetic characteristics. Our study indicates that 6 has great potential as a drug for diabetes and dyslipidemia.
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PMID:(-)3-[4-[2-(Phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid [(-)DRF 2725]: a dual PPAR agonist with potent antihyperglycemic and lipid modulating activity. 1147 21

The accrued evidence that lipid-lowering therapy limits the progression of atherosclerosis and reduces CAD events is overwhelming. The focus has been on LDL-C reduction with statins, but recent evidence also stresses the importance of raising HDL-C and reducing triglyceride-rich lipoproteins (TRL). Treatment should take into account the type of dyslipidemia, combination therapy, drug interactions and pleiotropic effects of drugs (multiple effects in different systems). Statins and fibrates are the most widely prescribed. Fibrates have a major impact on plasma TRL and HDL-C levels. They enhance lipoprotein lipase, apoAI and apoAII transcription and reduce that of apoCIII. The discovery that their multiple actions are in large part mediated by the PPAR alpha pathway is a breakthrough. Fibrates also lower plasma fibrinogen and plasma viscosity but their ability to inhibit smooth muscle cell activation is one of their most promising pleiotropic effects. Statins are safe and potent LDL-C-lowering agents but also lower TRL and raise HDL. Their pleiotropic effects are numerous, and include vasodilatory, anti-thrombotic, antioxidant, anti-proliferative, anti-inflammatory and plaque stabilizing properties. Many findings make a case for their early use in CAD to improve myocardial perfusion after a myocardial infarction, and they are indicated in heart transplant recipients to improve survival and reduce graft rejection. Fibrates and statins have complementary lipid modifying and pleiotropic effects so that their combination, carried out with caution to avoid potential untoward effects, should provide the highest cardiovascular benefit. This hypothesis is currently being tested in the Lipid in Diabetes Study (LDS), an outcome trial comparing monotherapy with fenofibrate and cerivastatin to combination therapy conducted in England.
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PMID:Advances in lipid-lowering therapy in atherosclerosis. 1190 Apr 1

New agents are being developed to address the underlying endocrinopathies and metabolic disturbances of type 2 diabetes. Stimulants of the nuclear peroxisome proliferator-activated receptor gamma (PPAR gamma) are being identified to selectively improve insulin actions, and dual agonists of PPAR gamma and PPAR alpha are being evaluated for enhanced control of hyperglycemia and dyslipidemia. Novel activators of insulin receptor phosphorylation and inhibitors of receptor dephosphorylation are offering encouraging leads for new agents. Analogues of glucagon-like peptide-1 that increase glucose-induced insulin secretion may additionally increase beta-cell neogenesis from progenitor duct cells. The amylin analogue pramlintide, which suppresses glucagon secretion and reduces weight, is advancing in clinical trial. Direct stimulants of glucose utilization and partial inhibitors of gluconeogenesis are providing useful new drug templates. Thus, new pharmacologic approaches are emerging to treat the multiple lesions of type 2 diabetes.
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PMID:New pharmacologic agents for diabetes. 1264 7

Substituted phenylpropanoic acid derivatives were prepared as part of a search for subtype-selective human peroxisome proliferator activated receptor alpha (PPARalpha) activators. Structure-activity relationship studies indicated that the nature and the stereochemistry of the substituent at the alpha-position of the head part containing the carboxyl group, the distance between the carboxyl group and the central benzene ring, the linking group between the central benzene ring and the distal benzene ring, and the substituent at the distal hydrophobic tail part of the molecule all play key roles in determining the potency and selectivity of PPAR subtype transactivation. This study has led to the identification of potent and human PPARalpha selective optically active alpha-alkylphenylpropanoic acid derivatives, which will be useful not only as pharmacological tools to investigate the physiology and pathophysiology of PPARalpha but also as candidate drugs for the treatment of altered metabolic homeostasis, such as dyslipidemia, obesity, and diabetes.
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PMID:Design, synthesis, and evaluation of substituted phenylpropanoic acid derivatives as human peroxisome proliferator activated receptor activators. Discovery of potent and human peroxisome proliferator activated receptor alpha subtype-selective activators. 1290 63

Dietary fat has a dual role in human physiology: a) it functions as a source of energy and structural components for cells; b) it functions as a regulator of gene expression that impacts lipid, carbohydrate, and protein metabolism, as well as cell growth and differentiation. Fatty acid effects on gene expression are cell-specific and influenced by fatty acid structure and metabolism. Fatty acids interact with the genome through several mechanisms. They regulate the activity or nuclear abundance of several transcription factors, including PPAR, LXR, HNF-4, NFkappaB, and SREBP. Fatty acids or their metabolites bind directly to specific transcription factors to regulate gene transcription. Alternatively, fatty acids indirectly act on gene expression through their effects on a) specific enzyme-mediated pathways, such as cyclooxygenase, lipoxygenase, protein kinase C, or sphingomyelinase signal transduction pathways; or b) pathways that involve changes in membrane lipid/lipid raft composition that affect G-protein receptor or tyrosine kinase-linked receptor signaling. Further definition of these fatty acid-regulated pathways will provide insight into the role dietary fat plays in human health and the onset and progression of several chronic diseases, like coronary artery disease and atherosclerosis, dyslipidemia and inflammation, obesity and diabetes, cancer, major depressive disorders, and schizophrenia.
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PMID:Fatty acid regulation of gene transcription. 1507 23

The design and synthesis of the dual peroxisome proliferator activated receptor (PPAR) alpha/gamma agonist (S)-2-methyl-3-[4-[2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)ethoxy]phenyl]-2-phenoxypropionic acid (2) for the treatment of type 2 diabetes and associated dyslipidemia are described. 2 possesses a potent dual hPPAR alpha/gamma agonist profile (IC(50) = 28 and 10 nM; EC(50) = 9 and 4 nM, respectively, for hPPARalpha and hPPARgamma). In preclinical models, 2 substantially improves insulin sensitivity and potently reverses diabetic hyperglycemia while significantly improving overall lipid homeostasis.
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PMID:Design and synthesis of alpha-aryloxy-alpha-methylhydrocinnamic acids: a novel class of dual peroxisome proliferator-activated receptor alpha/gamma agonists. 1511 85

Metabolic syndrome is a pathophysiological state in which risks for atherosclerosis are clustered. Etiology of metabolic syndrome is multi-factorial. Excess energy intake causes imbalance of energy transcription factors such as PPARs and SREBP-1c, which are deeply involved in lipid and carbohydrate metabolism, leading to insulin resistance and dyslipidemia. Especially hepatic SREBP-1c could be involved in production of remnant lipoproteins, fatty liver, and hepatic insulin resistance. Meanwhile, currently, therapeutic trend is activation of energy expenditure, in which PPAR alpha, delta, and AMP kinase are current targets of treatment. Proinflammatory agents should also be involved and adipocytokines could play an important role in peripheral insulin resistance.
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PMID:[Pathophysiology of metabolic syndrome]. 1520 38


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