The PPAR: RXR heterodimer exists in both an active and inactive state. When inactive, it is bound to corepressors such as the NCOR (Nuclear Receptor Corepressor) or the SMRT (Silencing Mediator For Retinoid and Thyroid Hormone Receptor). In the presence of ligand for either PPAR or RXR, the corepressors dissociate so that the ligand can bind and activate co-activators, such as SRC1 (Steroid Receptor Coactivator1), CBP/p300 (CREB-Binding Protein), the Tuberous Sclerosis Gene-2 product, the PPAR binding protein, P-GammaC1, P-GammaC2 (PPAR-Gamma Coactivator 1 and 2), and Ara70 (Ref.3). The only known natural ligand for RXR is 9-cis Retinoic Acid. When the PPAR: RXR complex is activated, it binds to PPRE in the 5'region of target genes to induce transcription. PPAR-Alpha regulates the expression of genes involved in the peroxisomal and mitochondrial Beta-oxidation pathways such as Acyl-CoA oxidase, Enoyl-CoA hydratase/dehydrogenase multifunctional enzyme, Keto-Acyl-CoA thiolase, Malic enzyme, medium chain Acyl-CoA dehydrogenase, and mitochondrial hydroxy methylglutaryl-CoA synthase. PPAR-Alpha also regulates FATP (Fatty Acid Transport Protein), the FAT/CD36 (Fatty Acid Translocase), L-FABP (Liver Cytosolic Fatty Acid-Binding Protein) and UCP2 and UCP3 (Uncoupling Proteins-2 and 3). By altering transcription of these genes, activated PPAR-Alpha leads to increased breakdown of triglycerides and fatty acids, increased cellular fatty acid uptake, and reduced triglyceride and fatty acid synthesis. The expression of PPAR-Gamma is widespread and it is found at moderate levels in most tissues, with high levels of the protein found in the placenta and large intestine. The activity of PPAR-Alpha and PPAR-Gamma is also regulated by phosphorylation events. Specifically, the recruitment of adaptor molecules, including SHC (SH2 containing protein) and the GRB2 (Growth Factor Receptor-Bound Protein-2)-SOS complex by several growth factor receptors, which leads phosphorylation of Ras and Raf1 molecules. This in turn activates the MAPKs (Mitogen Activated Protein Kinases) of the ERK (Extracellular Signal Regulated Kinase) type, which occurs by sequential activation of TAK1 (TGF-Beta Activated Kinase-1) and MEKs (MAPK/ERK kinases). These kinases inhibit the activities of PPAR-Alpha and PPAR-Gamma. In contrast, GPCR (G-Protein Coupled Receptors) mediated phosphorylation of PKA (Protein Kinase-A) by cAMP (cyclic Adenosine-3, 5' Monophosphate) or p38 MAPK activates PPAR-Alpha. This differential regulation of PPAR activity by signal transduction events provides a mechanism for rapid, cell-specific control of PPAR target gene expression by extracellular stimuli (Ref.7).
The PPAR regulatory pathway plays a critical role in the regulation of diverse biologic processes within the cardiovascular system. PPAR-Alpha acts as part of a transcription factor complex that regulates the expression of a number of genes implicated in atherogenesis and plaque stability. Recently, the PPAR-Alpha gene regulatory pathway has been implicated in the hepatic metabolic response to Diabetes Mellitus and PPAR-Alpha ligands such as Wy-14, 643; ciprofibrate and clofibrate have been implicated in peroxisome proliferation and liver tumors. PPAR-Gamma is expressed on all major cells of the vasculature, including endothelial cells, VSMCs (Vascular Smooth Muscle Cells) and monocytes/macrophages, human coronary artery smooth muscle cells, umbilical artery smooth muscle cells, umbilical endothelial cells, and aortic smooth muscle cells. Mutations that alter the function of PPAR-Gamma cause a syndrome of insulin resistance, hypertension, and dyslipidemia characteristic of the cardiovascular dysmetabolic syndrome (Ref.2). Activation of PPAR-Gamma inhibits monocyte and macrophage inflammatory responses by preventing the activation of nuclear transcription factors, such as NF-KappaB (Nuclear Factor-KappaB), Activating Protein-1 and STAT1 (Signal Transducer and Activator of Transcription-1). Since inflammation plays an important role in atherogenesis, this anti-inflammatory effect of PPAR-Gamma helps to reduce the risk of atherogenesis (Ref.4). Recent evidence suggests that PPAR-Gamma ligands have an anti-tumor effect in humans as these compounds decrease cell growth and induce apoptosis in several malignant human cell types, including HCC (Hepatocellular Carcinoma), breast adenocarcinoma and colon adenocarcinoma (Ref.3). Mutations of PPAR-Gamma results in the development of severe insulin resistant, Type-2 diabetes, hypertension in the absence of obesity, elevated triglycerides and low HDL levels and, a number of components of the metabolic syndrome. PPAR-Delta is a potential downstream target of APC (Adenomatous Polyposis Coli)/Beta-Catenin/ TCF4 (T-Cell Factor-4) tumor suppressor pathway, which is involved in the regulation of growth promoting genes such as c-Myc and Cyclin-D1. PPAR-Beta plays an antiapoptotic role in keratinocytes via transcriptional control of the Akt/PKB (Protein Kinase-B) signaling pathway. Both PI3K (Phosphatidylinositol-3 Kinase) and integrin-linked kinase are target genes of PPAR-Beta (Ref.3). Many naturally occurring or synthetic compounds are agonists for the PPARs. 15d-Ptg is the most potent endogenous PPAR-Gamma agonist known. Other PPAR-Gamma agonists include the insulin-sensitizing thiazolidinedione family of antidiabetic drugs (the glitazones) that enhance insulin-mediated glucose transport into adipose and skeletal muscle and are clinically used pharmacological ligands to treat rheumatoid arthritis. Many synthetic compounds such as the NSAIDs (Non-Steroid Anti-Inflammatory Drugs) are PPAR-Alpha and PPAR-Gamma agonists (Ref.4). PPAR-Alpha agonists also include fibric acids, gemfibrozil and fenofibrate that limit cytokine-induced activation of inflammatory functions of VCAM1 in response to TNF-Alpha (Tumor Necrosis Factor-Alpha) and tissue factor gene expression (Ref.2).
Lipogenesis: the pathway of fatty acid synthesis
AB - Triglyceride (TAG) synthesis during nitrogen starvation and recovery was addressed using Coccomyxa subellipsoidea by analyzing acyl-chain composition and redistribution using a bioreactor-controlled time course. Galactolipids, phospholipids and TAGs were profiled using liquid chromatography tandem mass spectroscopy (LC-MS/MS). TAG levels increased linearly through 10. days of N starvation to a final concentration of 12.6% dry weight (DW), while chloroplast membrane lipids decreased from 5% to 1.5% DW. The relative quantities of TAG molecular species, differing in acyl chain length and glycerol backbone position, remained unchanged from 3 to 10. days of N starvation. Six TAG species comprised approximately half the TAG pool. An average of 16.5% of the acyl chains had two or more double bonds consistent with their specific transfer from membrane lipids to TAGs during N starvation. The addition of nitrate following 10. days of N starvation resulted in a dramatic shift from chloroplast-derived to endoplasmic reticulum-derived galactolipids (from 40%). A model for TAG synthesis in C. subellipsoidea was developed based on the acquired data and known plant pathways and data presented.