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The Role of Mitochondrial Thioesterase-I, Uncoupling Protein-3, and CD36 in Cardiac Mitochondria

King, Kristen L.
http://rave.ohiolink.edu/etdc/view?acc_num=case1195177593

Abstract Details

2008, Doctor of Philosophy, Case Western Reserve University, Physiology and Biophysics.
Cardiac dysfunction and cardiomyopathy are associated with excessive accumulation of lipids in the heart. This condition can be mimicked by cardiac specific overexpression of peroxisome proliferator-activated receptor α (PPARα). Mitochondrial thioesterase I (MTE-I), a mitochondrial matrix protein whose expression is controlled by PPARα, de-esterifies long chain acyl-CoAs into coenzyme A and fatty acid anions (FA-), thus it may play a role in reducing mitochondrial accumulation of toxic long chain acyl-CoAs and preventing lipotoxic cardiomyopathy. It is unclear how the generated FA- leave the mitochondrial matrix, but two mitochondrial proteins capable of exporting FA- have recently been identified: uncoupling protein 3 (UCP3) and fatty acid translocase (FAT) CD36. While it has been shown that diabetes or pharmacological activation of PPARα up-regulate mRNA expression of MTE-I and UCP3, little is known about the effects on protein expression or FA- export from mitochondria. Thus the goal of this dissertation is to elucidate the roles of MTE-I, UCP3, and CD36 in cardiac mitochondria, specifically examining the effects of diabetes and PPARα stimulation. First we studied the effects of treatment with the PPARα agonist fenofibrate or streptozotocin-induced diabetes on MTE-I and UCP3 protein expression and activity in isolated cardiac mitochondria in rats. Both diabetes and fenofibrate increased cardiac 9 MTE-I mRNA, protein and activity approximately 4-fold compared to controls. UCP3 protein expression was not increased despite a 4-fold increase in mRNA. Palmitate export from mitochondria increased 6-fold in fenofibrate treated animals. Both diabetes and fenofibrate significantly decreased state III respiration of isolated mitochondria with pyruvate+malate as the substrate, but only diabetes reduced state III rates with palmitoylcarnitine. While the mechanism for this effect remains unclear, it appears that the decreased cardiac mechanical efficiency and increased myocardial oxygen consumption seen in diabetes is not related to changes in MTE-I activity or FA- transport. Secondly, we studied the role of another fatty acid transporter, FAT/CD36, in cardiac and skeletal muscle mitochondria. Pharmacological studies suggest that CD36 may play an essential role in mitochondrial fatty acid oxidation. We further postulated that CD36 transports FA- out of the mitochondrial matrix. We assessed mitochondrial respiration and palmitate export in isolated cardiac mitochondria from wild type and CD36 knock-out mice. Despite the clear presence of CD36 in cardiac mitochondria from WT mice, the absence of CD36 did not affect palmitoylcarnitine oxidation, or the export of FA- generated in the matrix. Thus CD36 does not play an essential role in mitochondrial uptake of fatty acids or export of FA-.
William Stanley (Advisor)
91 p.
Biology, Animal Physiology
Mitochondrial Thioesterase-I; Uncoupling Protein-3; CD36; Cardiac Mitochondria

Recommended Citations

Citations

  • King, K. L. (2008). The Role of Mitochondrial Thioesterase-I, Uncoupling Protein-3, and CD36 in Cardiac Mitochondria [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1195177593

    APA Style (7th edition)

  • King, Kristen. The Role of Mitochondrial Thioesterase-I, Uncoupling Protein-3, and CD36 in Cardiac Mitochondria. 2008. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1195177593.

    MLA Style (8th edition)

  • King, Kristen. "The Role of Mitochondrial Thioesterase-I, Uncoupling Protein-3, and CD36 in Cardiac Mitochondria." Doctoral dissertation, Case Western Reserve University, 2008. http://rave.ohiolink.edu/etdc/view?acc_num=case1195177593

    Chicago Manual of Style (17th edition)

case1195177593
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© 2007, all rights reserved.
This open access ETD is published by Case Western Reserve University School of Graduate Studies and OhioLINK.