Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0242339 (dyslipidemia)
 13,927 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Because of their wide range of actions on glucose homeostasis, lipid metabolism and vascular inflammation, peroxisome proliferator-activated receptors (PPARs) are promising targets for the development of new drugs for the treatment of metabolic disorders such as diabetes, dyslipidemia and atherosclerosis. In clinical practice, PPARalpha agonists, such as the already available fibrates, improve dyslipidemia, while PPARgamma agonists, such as thiazolidinediones, improve insulin resistance and diabetes. The complementary action of simultaneous activation of each PPAR in patients suffering from metabolic syndrome and type 2 diabetes has led to new pharmacological strategies focused on the development of agonists targeting more than one receptor such as the dual PPARalpha/gamma agonists. However, despite the proven benefits of targeting PPARs, safety concerns have recently led to late stage development failures of various PPAR agonists including novel specific PPARgamma agonists and dual PPARalpha/gamma agonists. These safety concerns include potential carcinogenicity in rodents, signs of myopathy and rhabdomyolysis, increase in plasma creatinine and homocysteine, weight gain, fluid retention, peripheral edema and potential increased risk of cardiac failure. Although the discontinued compounds shared common side effects, the reason for discontinuation was always compound specific and the toxicological or adverse effects which have motivated the discontinuation could be either due to the activation of PPARgamma, PPARalpha or both (class effect) or due to a PPAR unrelated effect. Thus, the risk evaluation of each adverse effect should be viewed on a case by case basis considering both the PPAR profile of the drug, its absorption/distribution profile, the nature of the side effect and the putative PPAR-related mechanism of action. This review mainly focuses on the preclinical and clinical adverse events of PPAR agonists that could be of concern when considering the development of new PPAR agonists. The selective modulation of PPAR activities is a promising approach to develop new drugs with preserved efficacy but diminished adverse effects.
 ...
PMID:Safety issues and prospects for future generations of PPAR modulators. 1742 30

The three isotypes of peroxisome proliferator-activated receptors (PPARs) are currently perceived as major regulatory nodes (or hubs) of metabolic pathway networks, linking most prevalent diseases including Type 2 diabetes, obesity, dyslipidemia and atherosclerosis. The integrative functions of PPARs are also reflected in their ecogenetic profile, when the variants underlying pharmacogenetic interactions were also shown to modulate the effect of lifestyle factors. Despite their extensive clinical use, there are many outstanding issues, especially concerning their safety. Critical pharmacogenomic assessment is warranted for the new potent ligands of multiple PPAR isoforms as many have displayed serious side-effects in a limited number of treated subjects. Nevertheless, the advent of genomic, transcriptomic and system biology-level approaches, integrating knowledge from model systems and human biology, should greatly facilitate the transition to individualized PPAR-based therapies.
 ...
PMID:Peroxisome proliferator-activated receptors as molecular targets in relation to obesity and type 2 diabetes. 1755 48

A well-worn medical aphorism states that "when you hear hoof beats, think of a horse and not a zebra." When applying this principle to the cardiometabolic syndrome (CMS), the horse would be represented by the prevalent CMS phenotype that affects approximately 30% of individuals in Westernized societies, while the zebra is represented by very rare conditions--such as lipodystrophy syndromes--that share some features with the more prevalent CMS. For instance, familial partial lipodystrophy types 2 and 3 result from heterozygous mutations in LMNA, encoding nuclear lamin A/C, and in PPARG, encoding peroxisome proliferator-activated receptor (PPAR)-gamma, respectively. Patients with either subtype of partial lipodystrophy exhibit an increased ratio of central to peripheral fat stores, dysglycemia, dyslipidemia, and hypertension, with predisposition for developing insulin-resistant diabetes and atherosclerosis end points. Sometimes, however, the zebra serves as a model that can help us understand the horse, so that the rare partial lipodystrophies might offer some insight into pathogenesis and treatment of the more prevalent CMS.
 ...
PMID:Genetic forms of the cardiometabolic syndrome: what can they tell the clinician? 1768 46

Atherosclerosis is a chronic inflammatory condition initiated in the endothelium in response to injury and maintained through the interactions between modified lipoproteins, macrophages, and arterial wall constituents. Risk for macrovascular disease is substantially increased in patients with type 2 diabetes mellitus. Factors underlying the link between insulin resistance/type 2 diabetes and macrovascular disease include reduced adiponectin concentration, increased expression of vascular cell adhesion molecule-1 and consequent adhesion of T-lymphocytes to the coronary endothelium, procoagulability with increased expression of plasminogen activator inhibitor-1 (PAI)-1, and instability of atherosclerotic plaques resulting from increased expression by macrophages of matrix metalloproteinases (MMPs). Thiazolidinediones (TZDs) are agonists of peroxisome proliferator-activated receptor (PPAR)-gamma and increase adiponectin. TZD therapy is associated with decreases in hepatic fat content and glycosylated hemoglobin and an increase in hepatic glucose disposal. TZDs lower circulating free fatty acid concentration and triglyceride content in the liver, but not in skeletal muscle. Effects of PPAR-gamma agonists in vitro and in animal models provide evidence for additional potential antiatherosclerotic benefits in patients with diabetes beyond the treatment of hyperglycemia and dyslipidemia, including the reduction of expression of macrophage MMPs and scavenger receptor-1, and indirect reduction of PAI-1 and inhibition of vascular smooth muscle cell proliferation, via suppression of type 1 angiotensin-2 receptor expression. Dual PPAR-alpha/gamma agonists, retinoid receptor agonists, and, to a lesser extent, TZDs, also stimulate cholesterol efflux from macrophages in vitro.
 ...
PMID:Diabetes mellitus and macrovascular disease: mechanisms and mediators. 1782 41

Cardiovascular events in patients with type 2 diabetes mellitus are a major problem in clinical practice, and patients with diabetes have derived less benefit from advances in preventive and interventional cardiology. Tighter goals for metabolic management and attention to nontraditional risk factors may be needed in this patient group. Insulin resistance rather than hyperinsulinemia is thought to underlie cardiovascular disease in patients with diabetes. Insulin resistance is associated with cardiovascular events and a wide range of traditional and nontraditional risk factors for cardiovascular disease (e.g., endothelial dysfunction, dyslipidemia, inflammation, vascular wall abnormalities). Therapy with lifestyle modifications, metformin, or thiazolidinediones (TZDs) corrects many of the abnormalities associated with diabetes in addition to lowering blood glucose and correcting diabetic dyslipidemia. TZDs, acting via the peroxisome proliferator-activated receptor-gamma, affect a number of mediators involved in the development of the cardiovascular complications of diabetes, including lipid profiles, vascular changes, and inflammatory mediators. TZDs decrease plasminogen activator-1 and C-reactive protein levels. They also reduce the extent of thickening of the carotid artery and reduce hyperplasia after coronary stent implantation. Insulin-sensitizing therapy with TZDs is a promising intervention for patients with diabetes at risk for adverse cardiovascular outcomes.
 ...
PMID:Rationale for the use of insulin sensitizers to prevent cardiovascular events in type 2 diabetes mellitus. 1782 42

In the present study, the polyherbal preparation diabegon, containing 18 plant extracts with hypoglycemic activity, was evaluated for its preventive effect during progression of type 2 diabetes in high-fructose-diet-fed rats. Oral administration of diabegon (100 mg/kg body weight) delayed development of glucose intolerance for 4 weeks in comparison with the diabetic control group, and the effect of diabegon was compared to that of the standard insulin sensitizer drug rosiglitazone. Diabegon treatment also ameliorated the elevation of glycosylated haemoglobin, liver glycogen content, plasma insulin, homeostasis model assessment, free fatty acids, triglycerides, total cholesterol, LDL-cholesterol, and VLDL-cholesterol, whereas it increased HDL-cholesterol after 56 days of treatment (P<0.05). The mechanism of action by which diabegon attenuates insulin resistance and dyslipidemia may be through induction of peroxisome proliferator-activated receptor-gamma and lipoprotein lipase activity in peripheral tissues (muscles). Moreover, diabegon administration for 56 days also produced no alteration in liver and kidney function tests, which seems to indicate its non-toxicity during treatment. Our present results suggest that diabegon may be included in diabetes mellitus treatment regimens, as a drug with good antidiabetic actions but no toxic manifestations.
 ...
PMID:Preventive effect of diabegon, a polyherbal preparation, during progression of diabetes induced by high-fructose feeding in rats. 1787 7

Improvements in our understanding of the functions of peroxisome proliferator-activated receptor (PPAR) subtypes as master regulators of many biological functions have made it possible to develop novel PPAR ligands with characteristic subtype selectivity as biochemical tools and/or candidate drugs for the treatment of PPAR-dependent diseases such as metabolic syndrome, which includes type II diabetes, dyslipidemia, obesity, hypertension, and inflammation. Based on the findings that the glitazone-class antidiabetic agents, and fibrate-class antidyslipidemic agents are ligands of PPARgamma and PPARalpha respectively, much research interest has been focused on these two subtypes as therapeutic targets for the treatment of type II diabetes and dyslipidemia. In contrast, research interest in PPARdelta has been limited. However, since 2001, the availability of PPARdelta knockout animals and selective ligands has led to the uncovering of possible roles of PPARdelta in fatty acid metabolism, insulin resistance, reverse cholesterol transport, inflammation, and so on. It has become clear that ligands able to modulate PPARdelta-mediated pathways are candidates for the treatment of altered metabolic function. This review focuses on recent medicinal chemical studies to identify PPARdelta-selective agonists.
 ...
PMID:Design, synthesis, and structure-activity relationship study of peroxisome proliferator-activated receptor (PPAR) delta-selective ligands. 1789 82

Individuals with metabolic syndrome typically have atherogenic dyslipidemia, characterized by increased concentrations of triglycerides, reduced concentrations of high-density lipoprotein cholesterol, and increased concentrations of small dense low-density lipoprotein particles. Statins have been shown to improve atherogenic dyslipidemia in patients with metabolic syndrome in a number of studies. Fibrates and niacin have also been shown to be effective therapy in these patients. Post hoc analyses suggest that lipid-regulating therapy reduces cardiovascular risk in patients with metabolic syndrome. Other approaches to the treatment of atherogenic dyslipidemia in these patients include targeting insulin resistance and adipose tissue. Agents such as the peroxisome proliferator-activated receptor-gamma agonist pioglitazone and the CB1 receptor antagonist rimonabant improve insulin resistance as well as atherogenic dyslipidemia. Weight loss has also been shown to improve risk factors associated with metabolic syndrome.
 ...
PMID:Treatment of dyslipidemia to reduce cardiovascular risk in patients with multiple risk factors. 1794 62

The transcription factor peroxisome proliferator-activated receptor (PPAR) alpha plays an important role in lipid homeostasis. In this study, we examined whether the down-regulation of PPAR-alpha gene expression is associated with dyslipidemia in a rat model of chronic renal failure (CRF). Rats with laboratory-induced uremia by 5/6 nephrectomy were bled at 2 weeks and 10 weeks after the nephrectomy to produce conditions. For the sake of convenience, the rats observed at postoperative week 2 were defined as acute renal failure (ARF) and those observed at week 10 were defined as CRF. Lipids in lipoprotein fractions were measured by high-performance liquid chromatography. The abundance of PPAR-alpha messenger RNA (mRNA) in the liver was measured by reverse transcriptase-polymerase chain reaction. Serum creatinine and blood urea nitrogen levels rose with the progression of renal failure, but the total protein levels remained constant. Serum triglyceride in ARF rats remained unchanged from the level in sham-operated control rats, whereas that in CRF rats was 66% higher than the control level. Serum cholesterol was elevated 1.5-fold in ARF rats and 2-fold in CRF rats compared with the sham-operated counterparts. As with triglyceride, very low-density lipoprotein remained unchanged in ARF rats but rose substantially in CRF rats. All of the major lipoprotein fractions were elevated in CRF rats. These lipid and lipoprotein changes were significantly associated with creatinine and blood urea nitrogen levels. The PPAR-alpha mRNA expression in the liver was unchanged in ARF rats but was 44% lower in CRF rats. The PPAR-alpha mRNA expression was inversely correlated with serum creatinine and lipids in the overall rats. Our results indicate that PPAR-alpha mRNA expression is down-regulated in the liver of CRF rats and that this down-regulation may play a crucial role in the development of dyslipidemia.
 ...
PMID:Decreased peroxisome proliferator-activated receptor alpha gene expression is associated with dyslipidemia in a rat model of chronic renal failure. 1799 26

Patients with type-2 diabetes mellitus (T2DM) are considered to be at particularly high risk for cardiovascular disease. Over the last decade, the members of the peroxisome proliferator-activated receptor (PPAR) subfamily of nuclear receptors have emerged as valuable pharmacological targets whose activation can normalize metabolic dysfunctions and reduce some cardiovascular risk factors associated with T2DM. PPARalpha agonists, such as the fibrates, can correct dyslipidemia. PPARgamma agonists, such as the thiazolidinediones, act as insulin sensitizers and improve insulin resistance in patients with T2DM. Because of restricted potency and certain side-effects of PPAR agonists, as well as the increasingly epidemic incidence of T2DM, there is a real need for the development of selective PPAR agonists with improved clinical efficacy. This chapter focuses on the PPAR agonists currently used in the clinic, as well as on the discovery and development of the next generation of PPAR agonists.
 ...
PMID:PPAR agonists: multimodal drugs for the treatment of type-2 diabetes. 1805 42


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>