Linking Induction and Transrepression of PPARβ/δ with Cellular Function

The copyrights of all papers published in this journal are retained by the respective authors as per the 'Creative Commons Attribution License' (http://creativecommons.org/licenses/by/3.0/).Peroxisome proliferator activated receptors (PPARs) are ligand-activated transcription factors and members of the nuclear hormone receptor superfamily. PPARβ/δ is ubiquitously expressed and has a central role in homeostasis, and has been suggested as a therapeutic target for a number of metabolic and cardiovascular disorders. This important nuclear receptor controls transcription under different modes of molecular activity which directly control the cellular function and fate of tissues. This complex activity of induction and transrepression of gene expression (with and without exogenous ligands) is poorly understood and yet understanding this molecular control through novel drug development would led to control over a key molecular switch in all cells. This review outlines the main molecular mechanisms of PPARβ/δ, and links the modes of activity to the signalling pathways in inflammation, proliferation and senescence, with the goal to understand how this will translate into novel drug design to control the PPARβ/δ molecular switch.Peer reviewe

Metabolic interactions between vitamin A and conjugated linoleic acid

Lipid-soluble molecules share several aspects of their physiology due to their common adaptations to a hydrophilic environment, and may interact to regulate their action in a tissue-specific manner. Dietary conjugated linoleic acid (CLA) is a fatty acid with a conjugated diene structure that is found in low concentrations in ruminant products and available as a nutritional supplement. CLA has been shown to increase tissue levels of retinol (vitamin A alcohol) and its sole specific circulating carrier protein retinol-binding protein (RBP or RBP4). However, the precise mechanism of this action has not been elucidated yet. Here, we provide a summary of the current knowledge in this specific area of research and speculate that retinol and CLA may compete for catabolic pathways modulated by the activity of PPAR- and RXR heterodimer. We also present preliminary data that may position PPAR- at the crossroads between the metabolism of lipids and vitamin

A role for peroxisome proliferator-activated receptors in the immunopathology of schistosomiasis?

Peroxisome proliferator-activated receptors (PPARs) have been demonstrated to have a role in immune regulation. In general, they are anti-inflammatory and promote Th2 type responses, and they are associated with the alternative activation of macrophages. Interestingly, helminth infections, such as the schistosome blood flukes that cause schistosomiasis, are characterised by a Th2 response and the accumulation of alternative activated macrophages. This would suggest that at some level, PPARs could have a role in the modulation of the immune response in schistosomiasis. This paper discusses possible areas where PPARs could have a role in this disease

The Role of PPARgamma in the Cyclooxygenase Pathway in Lung Cancer.

Decreased expression of peroxisome proliferator activated receptor-gamma (PPARgamma) and high levels of the proinflammatory enzyme cyclooxygenase-2 (COX-2) have been observed in many tumor types. Both reduced (PPARgamma) expression and elevated COX-2 within the tumor are associated with poor prognosis in lung cancer patients, and recent work has indicated that these signaling pathways may be interrelated. Synthetic (PPARgamma) agonists such as the thiazolidinedione (TZD) class of anti-diabetic drugs can decrease COX-2 levels, inhibit growth of non-small-cell lung cancer (NSCLC) cells in vitro, and block tumor progression in xenograft models. TZDs alter the expression of COX-2 and consequent production of the protumorigenic inflammatory molecule prostaglandin E2 (PGE2) through both (PPARgamma) dependent and independent mechanisms. Certain TZDs also reduce expression of PGE2 receptors or upregulate the PGE2 catabolic enzyme 15-prostaglandin dehydrogenase. As several COX-2 enzymatic products have antitumor properties and specific COX-2 inhibition has been associated with increased risk of adverse cardiac events, directly reducing the effects or concentration of PGE2 may provide a more safe and effective strategy for lung cancer treatment. Understanding the mechanisms underlying these effects may be helpful for designing anticancer therapies. This article summarizes recent research on the relationship between (PPARgamma), TZDs, and the COX-2/PGE2 pathways in lung cancer

Estrogen-related receptor α (ERRα) : a novel target in type 2 diabetes

Recent studies have shown that reduced mitochondrial content and function in skeletal muscle are common features of type 2 diabetes. Here, we review the molecular mechanisms involved in the regulation of mitochondrial genes in skeletal muscle, focusing on a key transcriptional network consisting of ERRα and PGC-1α. We describe how knowledge of this transcriptional circuit can be translated to the development of novel therapies for type 2 diabetes

The effect of neuronal conditional knock-out of peroxisome proliferator-activated receptors in the MPTP mouse model of Parkinson's disease

This study was supported by Parkinson’s Disease Foundation (IRGP 09-11 (P.T.)), the Royal Society (2006/R1 (P.T.)), the Wellcome Trust (WT080782MF (P.T.)), the Biotechnology and Biological Sciences Research Council (P.T. and H.L.M.), the National Institutes of Health (DK057978) (R.M.E.), and by grants from the Leona M. and Harry B. Helmsley Charitable Trust (R.M.E.), the Glenn Foundation for Medical Research (R.M.E.), and the Ellison Medical Foundation (R.M.E.). R.M.E. is an investigator at the Howard Hughes Medical Institute and March of Dimes Chair in Molecular and Developmental Biology at the Salk Institute. The authors would like to thank Lynne J. Hocking, University of Aberdeen, for her assistance with the statistics. We are grateful to the staff of the Medical Research Facility for their help with the animal care and the microscopy core facility at the University of Aberdeen for the use of microscopy equipment.Peer reviewedPublisher PD

The anti-atherogenic effects of thiazolidinediones

The thiazolidinediones (TZDs) rosiglitazone (ROS) and pioglitazone (PIO) are insulin-sensitising agents widely used to treat patients with type 2 diabetes mellitus (T2DM). Thiazolidinediones significantly improve glycaemic control in diabetics by reduced fasting glucose, insulin and glycated haemoglobin and they delay the progression of insulin resistance/impaired glucose tolerance into T2DM. It is well recognized that adequate glycaemic control and subsequent amelioration of hyperinsulinaemia and hyperglycaemia can delay the onset of vascular complications. TZDs, however, also have a number of anti-atherogenic effects independent of their influences on glucose and insulin metabolism. They improve lipid profiles, lower blood pressure, have anti-inflammatory properties, improve endothelial function and increase large artery compliance in patients with type 2 diabetes mellitus. When compared to rosiglitazone, pioglitazone has more favourable effects on the lipid profiles of patients with T2DM. The disease preventive actions of TZDs may be the result of their agonistic effects on peroxisome proliferator-activated receptors (PPARs), ligand-activated transcription factors that regulate the expression of numerous genes and affect metabolism and vascular parameters. Thiazolidinediones, provide an effective treatment for populations with insulin resistance which is at high risk of developing cardiovascular disease. This paper discusses the differences between ROS and PIO and explores their anti-atherogenic effects with particular focus on post-menopausal women with type 2 diabetes mellitus

PPAR-alpha: a novel target in pancreatic cancer

Background: Current targeted therapies in pancreatic cancer have been ineffective. The tumor stroma, including intra- and peri-tumoral inflammation and fibrosis, is increasingly implicated in pancreatic cancer. Pancreatic cancer is characterized by a highly fibrotic tumor environment resulting in stromal resistance to chemotherapy. Peroxisome proliferator-activated receptor-alpha (PPARα), a ligand-activated nuclear receptor/transcription factor, is a negative regulator of inflammation. In PPARα deficient mice, stromal processes inhibit tumor growth, resulting in dormant tumors. The presence of PPARα in the tumor cells as well as in the host is necessary for unabated tumor growth. Objective: We hypothesized that blocking the PPARα pathway with a small molecule PPARα antagonist (NXT) may prevent pancreatic cancer progression by targeting tumor cells as well as non-neoplastic cells in the tumor microenvironment. Methods: Growth inhibitory activity of the PPARα antagonist was assessed in murine as well as human pancreatic tumor cell lines (Panc0H7 and BxPC3) and in a murine macrophage cell line (RAW 264.7). Cell viability was determined by trypan blue exclusion assay. AKT, P-AKT, PCNA, BAX, and p27 levels were analyzed by western blot analysis. Cell cycle changes were detected by flow cytometry. Cellular senescence was determined by senescence-associated β-gal (SA-β-gal) staining. Results: The PPARα antagonist inhibited cell growth in macrophages and in pancreatic tumor cells as confirmed by reduced protein level expression of PCNA and activated AKT. Treatment of the PPARα antagonist was non-cytotoxic to tumor cells. Inhibition of PPARα induced cell cycle arrest at G0/G1 in tumor cells and macrophages. The induction of cellular senescence was observed in pancreatic cancer cells. Interestingly, we observed a reduction in protein level expression of BAX, a marker for apoptosis, and p27, an inhibitor of the cell cycle. Conclusion: We now demonstrate that a PPARα antagonist exerts its anti-growth activity by inducing G0/G1 cell cycle arrest, thereby inducing cellular senescence without cell death. These findings provide a mechanism for the anti-tumorigenic activity of PPARα inhibition, and the rationale to use PPARα antagonists as a novel therapeutic approach to pancreatic cancer.2016-11-03T00:00:00

Regulation of genes involved in carnitine homeostasis by PPARa across different species (rat, mouse, pig, cattle, chicken, and human)

Recent studies in rodents convincingly demonstrated that PPAR-alpha is a key regulator of genes involved in carnitine homeostasis, which serves as a reasonable explanation for the phenomenon that energy deprivation and fibrate treatment, both of which cause activation of hepatic PPAR-alpha, causes a strong increase of hepatic carnitine concentration in rats. The present paper aimed to comprehensively analyse available data from genetic and animal studies with mice, rats, pigs, cows, and laying hens and from human studies in order to compare the regulation of genes involved in carnitine homeostasis by PPAR-alpha across different species. Overall, our comparative analysis indicates that the role of PPAR-alpha as a regulator of carnitine homeostasis is well conserved across different species. However, despite demonstrating a well-conserved role of PPAR-alpha as a key regulator of carnitine homeostasis in general, our comprehensive analysis shows that this assumption particularly applies to the regulation by PPAR-alpha of carnitine uptake which is obviously highly conserved across species, whereas regulation by PPAR-alpha of carnitine biosynthesis appears less well conserved across species