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)

Both 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) as well as peroxisome proliferator-activated receptor (PPAR)alpha activators (fibrates) proved to be effective in the primary and secondary prevention of cardiovascular diseases. The benefits of hypolipemic therapy in cardiovascular diseases cannot be explained only by the lipid-lowering potential of these agents. The aim of this study was to clarify the effect of hypolipemic agents on proinflammatory cytokine release from human monocytes in relationship with their action on plasma levels of sensitive systemic marker of low-grade vascular inflammation. Plasma lipid and high-sensitivity C-reactive protein (hsCRP) levels, and the release of tumor necrosis factor-alpha (TNFalpha) and interleukin-1beta from monocytes were assessed at baseline and 30 and 90 days following randomization of IIa dyslipidemic patients into fluvastatin or simvastatin groups and randomization of type IIb dyslipidemic patients to the micronized form of either ciprofibrate or fenofibrate. Lipopolysaccharide-stimulated monocytes from dyslipidemic patients released significantly more TNFalpha (types IIa and IIb dyslipidemias) and interleukin-1beta (type IIa dyslipidemia) in comparison with monocytes in 59 age-, sex-, and weight-matched control subjects. Their baseline hsCRP levels were also higher. Both statins and fibrates reduced the release of TNFalpha and interleukin-1beta, and lowered plasma hsCRP levels. The effects of hypolipemic agents on cytokine release and plasma hsCRP were unrelated to their lipid-lowering action. Our results have demonstrated that type IIa and IIb dyslipidemic patients exhibit the abnormal pattern of TNFalpha and interleukin-1beta production by activated monocytes. Both HMG-CoA reductase inhibitors and PPARalpha activators normalize monocytic secretion of these cytokines, and this action may partially contribute to the systemic antiinflammatory effect of hypolipemic agents. The statin- and fibrate-induced suppression of proinflammatory cytokine release from monocytes seems to play a role in their beneficial effect on the incidence of cardiovascular events.
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PMID:Monocyte release of tumor necrosis factor-alpha and interleukin-1beta in primary type IIa and IIb dyslipidemic patients treated with statins or fibrates. 1611 45

There are three peroxisome proliferator-activated receptors (PPARs) subtypes which are commonly designated PPAR alpha, PPAR gamma and PPAR beta/delta. PPAR alpha activation increases high density lipoprotein (HDL) cholesterol synthesis, stimulates "reverse" cholesterol transport and reduces triglycerides. PPAR gamma activation results in insulin sensitization and antidiabetic action. Until recently, the biological role of PPAR beta/delta remained unclear. However, treatment of obese animals by specific PPAR delta agonists results in normalization of metabolic parameters and reduction of adiposity. Combined treatments with PPAR gamma and alpha agonists may potentially improve insulin resistance and alleviate atherogenic dyslipidemia, whereas PPAR delta properties may prevent the development of overweight which typically accompanies "pure" PPAR gamma ligands. The new generation of dual-action PPARs--the glitazars, which target PPAR-gamma and PPAR-alpha (like muraglitazar and tesaglitazar) are on deck in late-stage clinical trials and may be effective in reducing cardiovascular risk, but their long-term clinical effects are still unknown. A number of glitazars have presented problems at a late stage of clinical trials because of serious side-effects (including ragaglitazar and farglitazar). The old and well known lipid-lowering fibric acid derivative bezafibrate is the first clinically tested pan--(alpha, beta/delta, gamma) PPAR activator. It is the only pan-PPAR activator with more than a quarter of a century of therapeutic experience with a good safety profile. Therefore, bezafibrate could be considered (indeed, as a "post hoc" understanding) as an "archetype" of a clinically tested pan-PPAR ligand. Bezafibrate leads to considerable raising of HDL cholesterol and reduces triglycerides, improves insulin sensitivity and reduces blood glucose level, significantly lowering the incidence of cardiovascular events and new diabetes in patients with features of metabolic syndrome. Clinical evidences obtained from bezafibrate-based studies strongly support the concept of pan-PPAR therapeutic approach to conditions which comprise the metabolic syndrome. However, from a biochemical point of view, bezafibrate is a PPAR ligand with a relatively low potency. More powerful new compounds with pan-PPAR activity and proven long-term safety should be highly effective in a clinical setting of patients with coexisting relevant lipid and glucose metabolism disorders.
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PMID:Dual and pan-peroxisome proliferator-activated receptors (PPAR) co-agonism: the bezafibrate lessons. 1616 52

Metabolism, in part, is regulated by the peroxisome proliferator-activated receptors (PPARs). The PPARs act as nutritional lipid sensors and three mammalian PPAR subtypes designated PPARalpha (NR1C1), PPARgamma (NR1C3) and PPARdelta (NR1C2) have been identified. This subgroup of nuclear hormone receptors binds DNA and controls gene expression at the nexus of pathways that regulate lipid and glucose homeostasis, energy storage and expenditure in an organ-specific manner. Recent evidence has demonstrated activation of PPARdelta in the major mass peripheral tissue (ie, adipose and skeletal muscle). It enhances glucose tolerance, insulin-stimulated glucose disposal, lipid catabolism, energy expenditure, cholesterol efflux and oxygen consumption. These effects positively influence the blood-lipid profile. Furthermore, PPARdelta activation produces a predominant type I/slow twitch/oxidative muscle fiber phenotype that leads to increased endurance, insulin sensitivity and resistance to obesity. PPARdelta has rapidly emerged as a potential target in the battle against dyslipidemia, insulin insensitivity, type II diabetes and obesity, with therapeutic efficacy in the treatment of cardiovascular disease risk factors. GW-501516 is currently undergoing phase II safety and efficacy trials in human volunteers for the treatment of dyslipidemia. The outcome of these clinical trials are eagerly awaited against a background of conflicting reports about cancer risks in genetically predisposed animal models. This review focuses on the potential pharmacological utility of selective PPARdelta agonists in the context of risk factors associated with metabolic and cardiovascular disease.
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PMID:Cardiovascular disease and PPARdelta: targeting the risk factors. 1618 88

Lipids are essential components of biological membranes, fuel molecules and metabolic regulators that control cellular functions, metabolism and homeostasis. The liver plays a central role in regulating lipid metabolism and whole body lipid homeostasis. Sterols, bile acids and fatty acids are the endogenous ligands of the liver orphan receptor, farnesoid X receptor, peroxisome proliferator-activated receptor, vitamin D receptor, constitutive androstane receptor and pregnane X receptor. These metabolic receptors coordinately regulate lipid, glucose, energy and drug metabolism. Alteration of lipid homeostasis causes dyslipidemia, which is a major risk factor contributing to atherosclerotic cardiovascular diseases, diabetes, obesity and liver diseases. Advances in the understanding of the mechanisms of nuclear receptor regulation of lipid homeostasis have provided an opportunity to investigate potential therapeutic drugs targeted to nuclear receptors. This could be useful for the treatment of diabetes, and cardiovascular and chronic liver diseases.
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PMID:Nuclear receptor regulation of lipid metabolism: potential therapeutics for dyslipidemia, diabetes, and chronic heart and liver diseases. 1625 20

Many studies indicate that postprandial metabolic abnormalities, such as hyperglycemia and dyslipidemia, which are exaggerated and prolonged in type 2 diabetes, are important risk factors for cardiovascular disease. Different pharmacotherapies have been developed to specifically target these risk factors associated with type 2 diabetes. The peroxisome proliferator-activated receptor (PPAR) agonists, which are potent insulin sensitizers, have been the focus of much research during the past decade. Since their development, PPAR agonists have emerged as an important target for the treatment of insulin resistance and dyslipidemia. The more recent development of agonists that selectively target both the alpha and gamma PPARs has provided a potential treatment of global risk in patients with the metabolic syndrome or type 2 diabetes. Muraglitazar is a non-thiazolidinedione, oxybenzylglycine dual PPARalpha/gamma agonist that is in advanced clinical development for the treatment of type 2 diabetes and its associated dyslipidemia. This article summarizes the available clinical data on the efficacy and safety of muraglitazar in patients with type 2 diabetes.
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PMID:Muraglitazar: an agent for the treatment of type 2 diabetes and associated dyslipidemia. 1634 Dec 89

Dyslipidemia is the sine qua non of atherosclerosis, but it is also strongly associated with the metabolic syndrome, obesity, diabetes, and fatty liver disease. The molecular basis for future therapies requires understanding the pivotal role of nuclear hormone receptors in lipid and inflammatory homeostasis. This review summarizes evidence that the liver X receptor (LXR) and peroxisome proliferator-activated receptor (PPAR) are key transcriptional regulators in lipid metabolism. Additionally, their effects on glucose homeostasis and inflammation make LXR and PPAR signaling networks attractive molecular targets for managing lipid-related diseases.
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PMID:Nuclear receptors in lipid metabolism: targeting the heart of dyslipidemia. 1640 52

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

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

Fibrate peroxisome proliferator-activated receptor (PPAR)-alpha ligands are mainly used as hypolipidemic drugs. But this commentary highlights their potential in treating insulin resistance, dyslipidemia, and hypertension and in preventing diabetic nephropathy, inflammation, and cardiovascular disease. Because diabetes is a major contributor to chronic kidney disease and cardiovascular disease, PPAR-alpha agonists may provide greater opportunities for hitting multiple targets in this complex metabolic disease.
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PMID:The PPARalpha ligand fenofibrate: meeting multiple targets in diabetic nephropathy. 1667 21

Consumption of trans fatty acids (TFA) predicts higher risk of coronary heart disease, sudden death, and possibly diabetes mellitus. These associations are greater than would be predicted by effects of TFA on serum lipoproteins alone. Systemic inflammation and endothelial dysfunction may be involved in the pathogenesis of atherosclerosis, acute coronary syndromes, sudden death, insulin resistance, dyslipidemia, and heart failure. Evidence from both observational and experimental studies indicates that TFA are pro-inflammatory. Limited evidence suggests that pro-inflammatory effects may be stronger for trans isomers of linoleic acid (trans-C18:2) and oleic acid (trans-C18:1), rather than of palmitoleic acid (trans-C16:1), but further study of potential isomer-specific effects is needed. TFA also appear to induce endothelial dysfunction. The mechanisms underlying these effects are not well-established, but may involve TFA incorporation into endothelial cell, monocyte/macrophage, or adipocyte cell membranes (affecting membrane signaling pathway relating to inflammation) or ligand-dependent effects on peroxisome proliferator-activated receptor (PPAR) or retinoid X receptor (RXR) pathways. Activation of inflammatory responses and endothelial dysfunction may represent important mediating pathways between TFA consumption and risk of coronary heart disease, sudden death, and diabetes. Further study is indicated to define these effects of TFA and the implications of such effects for cardiovascular health.
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PMID:Trans fatty acids - effects on systemic inflammation and endothelial function. 1671 93


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