Peroxisome Proliferator-activated Receptor Modulators Research Articles

Peroxisome Proliferator-Activated Receptor Family and Its Relationship to Renal Complications of the Metabolic Syndrome

Peroxisome proliferator-activated receptors (PPAR) are members of the nuclear hormone receptor superfamily of ligand-activated transcription factors. Three PPAR isoforms, designated PPARalpha, -beta/delta, and -gamma, have been identified and attracted enormous attention as a result of the key role that these receptors play in regulating adipogenesis, lipid metabolism, insulin sensitivity, inflammation, and BP. Growing evidence points to a causative relationship between PPAR activity and the metabolic syndrome, including insulin resistance, glucose intolerance or type 2 diabetes, obesity, dyslipidemia, hypertension, atherosclerosis, and albuminuria. Importantly, both PPAR-alpha activators, such as the fibric acid class of hypolipidemic drugs, and PPAR-gamma agonists, including antidiabetic thiazolidinediones, have been proved to be effective for improving diverse aspects of the metabolic syndrome. All three PPAR isoforms seem to play important roles in the development of diabetic nephropathy in type 2 diabetes. Accumulating data suggesting that PPAR may serve as potential therapeutic targets for treating the metabolic syndrome and its related renal complications have begun to emerge. This article reviews the literature pertaining to the action, ligand selectivity, and physiologic role of PPAR. Particular emphasis is placed on their pathogenic roles in the metabolic syndrome and the therapeutic utility of PPAR modulators in the treatment of diabetic nephropathy.

Modulation of PPAR in Aging, Inflammation, and Calorie Restriction

Peroxisome proliferator-activated receptors (PPARs), members of the nuclear hormone receptor superfamily of transcription factors, are key regulators in various pathophysiological processes related to energy metabolism including lipid, carbohydrate metabolism, and inflammation. At present, little information is on the effect of age and calorie restriction (CR) on PPARs. In the present study, we investigated how age and CR (60% of the ad libitum intake) modulate PPARs in kidneys obtained from Fischer 344 rats, ages 13 and 25 months. Results showed that nuclear protein, mRNA level, and DNA binding activity of PPARs decreased with age, while CR blunted the reduction. Our findings were verified in separate experiments in which rats were injected with lipopolysaccharide, with the result of increased susceptibility to inflammation. Based on these findings, we conclude that the altered expression of PPARs may be due to increased oxidative stress with age, and that CR prevents these decreases through its antioxidative action.

A New Class of Peroxisome Proliferator-activated Receptor Agonists with a Novel Binding Epitope Shows Antidiabetic Effects

The peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors belonging to the NR1 subfamily of nuclear receptors. The PPARs play key roles in the control of glucose and lipid homeostasis, and the synthetic isoform-specific PPAR agonists are used clinically to improve insulin sensitivity and to lower serum triglyceride levels. All of the previously reported PPAR agonists form the same characteristic interactions with the receptor, which have been postulated to be important for the induction of agonistic activity. Here we describe a new class of PPARalpha/gamma modulators, the 5-substituted 2-benzoylaminobenzoic acids (2-BABAs). As shown by x-ray crystallography, the representative compounds BVT.13, BVT.762, and BVT.763, utilize a novel binding epitope and lack the agonist-characteristic interactions. Despite this, some compounds within the 2-BABA family are potent agonists in a cell-based reporter gene assay. Furthermore, BVT.13 displays antidiabetic effects in ob/ob mice. We concluded that the 2-BABA binding mode can be used to design isoform-specific PPAR modulators with biological activity in vivo.

Impaired glucose metabolism in patients with heart failure: pathophysiology and possible treatment strategies.

The firm association of diabetes mellitus with congestive heart failure (CHF) has been undoubtedly established. Recent reports support the presence of the reciprocal interrelationships between CHF and glucose abnormalities. The present review provides an overview of some aspects of the multifactorial interrelationships between heart failure and diabetes mellitus. Patients with heart failure are generally at higher risk of developing type 2 diabetes mellitus. Several factors may be involved, such as a lack of physical activity, hypermetabolic state, intracellular metabolic defects, poor muscle perfusion, and poor nutrition. Serum levels of inflammatory cytokines and leptin are elevated in patients with heart failure. Activation of the sympathetic system in CHF not only increases insulin resistance but also decreases the release of insulin from the pancreatic beta cells, increases hepatic glucose production by stimulating both gluconeogenesis and glycogenolysis, and increases glucagon production and lipolysis. People who develop type 2 diabetes mellitus usually pass through the phases of nuclear peroxisome proliferator-activated receptor modulation, insulin resistance, hyperinsulinemia, pancreatic beta-cell stress and damage leading to progressively decreasing insulin secretion, and impaired fasting and postprandial blood glucose levels. Once hyperglycemia ensues, the risk of metabolic and cardiovascular complications also increases. It is possible that the cornerstone of diabetes mellitus prevention in patients with CHF could be controlled by increased physical activity in a cardiac rehabilitation framework. Pharmacologic interventions by some medications (metformin, orlistat, ramipril and acarbose) can also effectively delay progression to type 2 diabetes mellitus in general high risk populations, but the magnitude of the benefit in patients with CHF is unknown. In patients with CHF and overt diabetes mellitus, ACE inhibitors may provide a special advantage and should be the first-line agent. Recent reports have suggested that angiotensin receptor antagonists (angiotensin receptor blockers), similar to ACE inhibitors, provide beneficial effects in patients with diabetes mellitus and should be the second-line agent if ACE inhibitors are contraindicated. Treatment with HMG-CoA reductase inhibitors should probably now be considered routinely for all diabetic patients with CHF, irrespective of their initial serum cholesterol levels, unless there is a contraindication.

The role of peroxisome proliferator-activated receptor gamma in colon cancer and inflammatory bowel disease.

Review the role and therapeutic potential of peroxisome proliferator-activated receptor (PPAR) gamma in colonic disorders. Recent peer-reviewed scientific literature focusing on PPAR gamma in the colon. Research reports using animal models, cultured cell lines, and clinical material were examined for content related to the role of PPAR gamma in normal colon cell function, colon cancer, and inflammatory bowel disease. Issues concerned with potential therapeutic use were also considered. Key points pertaining to PPAR function and involvement in colon pathology were extracted and noted. Potential compromises to therapeutic utility are identified. The emerging important role of PPAR gamma in normal tissue homeostasis and pathologic outcomes suggests this receptor is a good candidate as a drug target. Several potential problems with this approach will require further investigation prior to widespread recommendations for modulation of PPAR as an efficacious therapy for cancer, chemoprevention of colon cancer, or treatment of inflammatory bowel disease. The widespread use of PPAR gamma ligands for management of type 2 diabetes (such as the glitazone class of drugs including rosiglitazone and pioglitazone) may provide a fortuitous assessment of the efficacy of long-term PPAR modulation.

Synthesis and pharmacological evaluation of a new class of peroxisome proliferator-activated receptor modulators

A series of 5-substituted 2-benzoylaminobenzoic acids has been synthesized and assayed for PPARα/γ activity. Both dual activators and selective PPARγ agonists have been identified. This class of compounds was shown to activate the PPARγ receptor through interaction with a novel binding site.

Agent identification and preclinical testing.

This chapter provides an overview of the preclinical screening assays and animal efficacy testing models currently utilized by the drug discovery and development program of the Division of Cancer Prevention (DCP), National Cancer Institute (NCI) to identify chemical agents or natural biological products which may be efficacious in preventing human cancers. The first step of the drug discovery process involves subjecting candidate agents to a sequential series of mechanism-based assays which target specific biochemical and molecular pathways known to be involved in carcinogenesis. Thesein vitromechanistic assays provide quantitative data used to establish chemopreventive efficacy and also to assist in classifying and prioritizing agents for further evaluation in whole animal models. Major classes of chemopreventive agents identified thus far include, for example, signal transduction modulators, such as Ras farnesyl transferase inhibitors; retinoids; protein tyrosine kinase inhibitors (PTK), such as epidermal growth factor receptor (EGFR) inhibitors; peroxisome proliferator-activated receptor (PPAR) modulators; hormone modulatory agents, such as anti-androgens, anti-estrogens, and aromatase inhibitors; antiinflammatories including NSAIDs, cyclooxygenase (COX-2), and lipoxygenase (LOX) inhibitors; antimutagens, such as phase II enzyme inducers; antioxidants, such as selenium and vitamin E; and angiogenesis inhibitors, including collagenase and matrix metalloproteinase blocking agents. In the second step promising chemopreventive compounds or combinations of agents possessing pleiotropic activities are subsequently developed both in carcinogen-induced and genetically manipulated animal tumor models, including models of colon, lung, bladder, mammary, prostate, and skin cancer, as well as in batteries of toxicity and pharmacokinetic tests. Development of chemopreventive drugs using this targeted approach affords a strategic framework for evaluating agents according to defined criteria and not only provides evidence of agent efficacy but also serves to generate dose-response, toxicity, and pharmacokinetic data needed to consider Phase 1 clinical safety and pharmacokinetic evaluations.

Transcriptional modulation of hepatocyte nuclear factor 4a (HNF-4a) and/or peroxisome proliferator-activated receptor a (PPARa)-controlled genes by low molecular weight compounds

Transcriptional modulation of hepatocyte nuclear factor 4a (HNF-4a) and/or peroxisome proliferator-activated receptor a (PPARa)-controlled genes by low molecular weight compounds