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- December 1, 2008 |
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| Presentation |
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"Nuclear Receptor Diseases Mechanisms"Dr. Mitchell Lazar (biography)
English - 2002-10-28 - 47 minutes
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Summary :
Nuclear receptors are important mediators of disease in general. In this talk Dr Lazar focuses on two mechanistic aspects, showing how these receptors may be targeted for disease. Nuclear hormone receptors are transcription factors that are found in the nucleus of cells, and bind to ligands. Classical members of the nuclear receptor family are thyroid hormone, the steroid hormones, and vitamins A and D. Recently several ligands have been discovered which bind nuclear receptors, including fatty acids which bind PPARγ receptors. Whether or not the receptor is mutated here, the signaling mechanism can be used by drugs called thiazolidinediones (TZDs), to improve the disease condition of type 2 diabetes. Dr Lazar first explains the molecular basis of nuclear receptor action in Myeloid leukemias, and how HDAC inhibitors can be used to target some leukemias. Switching to the endocrinological topic of type 2 diabetes, he then explains that PPARγ is the critical receptor here. This receptor is highly expressed in fat cells and adipose tissue, and is not usually mutated. Interestingly, the drugs called thiazolidinediones act as ligands to this receptor, and are able to produce clinically antidiabetic effects. Thiazolidinediones change the gene program in fat cells, leading to increased fatty acid and triglyceride uptake and storage. The gene regulation of adipocyte-secreted polypeptides is also affected: for example, the insulin resistance factor resistin is downregulated, and adiponectin which increases insulin action is upregulated. These last two effects lead to amelioration of the diabetic state. Finally Dr Lazar shares new insights on the effects of TZDs on metabolism, including effects on the enzyme glycerol kinase.
Learning objectives :
Nuclear recptors are ligand-activated transcription factors, and their mechanisms of action can be understood to develop ways to treat some diseases, for example type 2 diabetes.
The drugs called thiazolidinediones (TZDs) act as ligands to the PPARγ nuclear recptors, thereby downregulating the insulin resistance molecule resistin, and upregulating adiponectin which increases insulin action. These produce clinically antidiabetic effects, thus making TZDs a treatment option for type 2 diabetes.
TZDs also promote fat uptake and storage, and have recently been found to affect the enzyme glycerol kinase in this process.
Bibliographic references :
Thiazolidinedione activation of peroxisome proliferator-activated receptor gamma can enhance mitochondrial potential and promote cell survival.
Wang YL, Frauwirth KA, Rangwala SM, Lazar MA, Thompson CB.
Abramson Family Cancer Research Institute, Department of Cancer Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19104-6160, USA.
Thiazolidinediones (TZDs) are widely used for treatment of type 2 diabetes mellitus. Peroxisome proliferator-activated receptor gamma (PPAR gamma) is the molecular target of TZDs and is believed to mediate the apoptotic effects of this class of drugs in a variety of cell types, including B and T lymphocytes. The finding that TZDs induce lymphocyte death has raised concerns regarding whether TZDs might further impair immune functions in diabetics. To address this issue, we investigated the roles of PPAR gamma and TZDs in lymphocyte survival. PPAR gamma was up-regulated upon T cell activation. As previously reported, PPAR gamma agonists induced T cell death in a dose-dependent manner. However, the concentrations of TZD needed to cause T cell death were above those needed to induce PPAR gamma-dependent transcription. Surprisingly, at concentrations that induce optimal transcriptional activation, TZD activation of PPAR gamma protected cells from apoptosis following growth factor withdrawal. The survival-enhancing effects depended on both the presence and activation of PPAR gamma. Measurements of mitochondrial potential revealed that PPAR gamma activation enhanced the ability of cells to maintain their mitochondrial potential. These data indicate that activation of PPAR gamma with TZDs can promote cell survival and suggest that PPAR gamma activation may potentially augment the immune responses of diabetic patients.
J Biol Chem 2002 Aug 30;277(35):31781-8
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