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Brandon Abstract 2010

Brandon Abstract 2010

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Published by: Brandon Allen Tanner on Jun 06, 2011
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Background: Peroxisome proliferator-activated receptor (PPAR) ± is a nuclear receptor protein that can bind to various ligands, such

as PGC-1 (4) or a pharmacological ligand (2), and increase the expression of various proteins such as Cluster of Differentiation 36 (CD-36) and Pyruvate Dehydrogenase Kinase Isozyme 4 (PDK4). CD-36 is a fatty acid transporter that transports fatty acids into the cytosol. Via phosphorylation, PDK4 inhibits Pyruvate Dehydrogenase, the ratelimiting step of glucose oxidation. An increase in the two proteins would increase fatty acid oxidation while decreasing glucose oxidation. Therefore, we hypothesised that a PPAR± agonist ligand (WG7647) will increase the expression of both CD-36 and PDK4 by increasing the activity of PPAR- . Method: 7-day old rabbits were IP-injected GW7647 twice daily (1.5 mg/kg/injection). At 21 days of age, the hearts were isolated and perfuse for 15 min left working heart, 20 min biventricular working heart, 25 min isothermic no flow global ischemia, and reperfused for 30 min. The perfusion buffer was modified Krebs-Henseleit buffer (1.2 mM palmitate, 5.5 mM glucose, and 100QU/ml insulin). The heart was separated into right and left ventricle and flash frozen in liquid N2 for Western Blot analyses. Results: Hearts treated with GW7647 had significantly depressed aerobic cardiac work (69.7%, of that of control). Recovery after ischemia had also significantly decreased in untreated and treated hearts, to 77.7% and 23.0%, from pre-ischemia output, respectively. PGC-1 expression was significantly decreased by 33.7% in the right ventricle and remained unchanged in the left ventricle, compared to control. Conversely, PDK4 expression increased significantly in both right and left ventricle by 18.3% and 28.7% respectively, to that of control (P<0.01). GW7647 did not affect CD-36 protein expression in these neonatal hearts. Conclusion: The detrimental affects of GW7647 on neonatal hearts could be due to the selectiveness of PPAR- /GW7647 to promote PDK4 expression but not CD-36.

Also recent studies have shown that the effects of PPAR± are aided by another nuclear receptor protein called Peroxisome proliferator-activated receptor gamma coactivator-1 (PGC-1).

1. Transcriptional Regulation of Metabolic Switching PDK4 Gene under Various Physiological Conditions. Araki M, Nozaki Y, Motojima K 2. Peroxisome proliferator activated receptor _ (PPAR_) and PPAR gamma coactivator (PGC-1_) induce carnitine palmitoyltransferase IA (CPT-1A) via independent gene elements. Shulan Songa, Ramy R. Attia a, Sara Connaughtona, Melissa I. Niesend, Gene C. Nessd, Marshall B. Elama,c, Roderick T. Horib, George A. Cooka, Edwards A. Parka, 3. Dual promoter structure of mouse and human fatty acid translocase/CD36 genes and unique transcriptional activation by peroxisome proliferator-activated receptor alpha and gamma ligands. Sato O, Kuriki C, Fukui Y, Motojima K.

KELLY1.4. HUSS.1 AND DANIEL P.2 . RICK B. VEGA. The Coactivator PGC-1 Cooperates with Peroxisome Proliferator-Activated Receptor a in Transcriptional Control of Nuclear Genes Encoding Mitochondrial Fatty Acid Oxidation Enzymes.1 JANICE M.

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