The Implications of CD36 Alteration on Rodent Skeletal Muscle Lipid Metabolism

Abstract

Fatty acid transport across the plasma membrane is an important site of regulation in skeletal muscle lipid metabolism, and is governed by a number of fatty acid transport proteins including, CD36, FABPpm, and FATP1 and 4. While each transporter is capable of independently stimulating fatty acid transport, less is known about their specific functions under various metabolic conditions, although CD36 appears to be key. The purpose of this thesis was to examine skeletal muscle fatty acid metabolism in several rodent models where CD36 has been altered, particularly via whole body deletion, by muscle specific overexpression, or in the face of permanent redistribution of CD36 to the plasma membrane. Using these models, this thesis sought to answer the following questions: 1) Is caffeine-stimulated fatty acid oxidation CD36-dependent? 2) Does CD36 function in tandem with FABPpm, and does this enhance fatty acid uptake at the plasma membrane and/or influence the metabolic fate of incoming fatty acids? 3) Is intramuscular lipid distribution altered in a rodent model of obesity, in which CD36-mediated fatty acid uptake is increased? Specific novel findings include the following: 1) Caffeine-stimulated calcium release can elicit the translocation of a number of fatty acid transporters in skeletal muscle, but CD36 is essential for caffeine-induced increases in fatty acid uptake and oxidation. 2) In spite of difficulties associated with protein co-overexpression, it appears that simultaneous overexpression of CD36 and FABPpm enhances fatty acid transport across the plasma membrane, and that these transporters may collaborate to increase insulin-induced fatty acid esterification and AICAR-induced oxidation. 3) Finally, in the obese Zucker rat model, augmented CD36-dependent fatty acid transport into muscle in combination with elevated lipid supply, results in lipid accretion within the IMF region of muscle, an effect that could not be explained by compartment-specific changes in selected glycerolipid synthesizing enzymes. Taken together, these studies emphasize the importance of CD36 in the regulation of plasmalemmal fatty acid transport, and further elucidate the metabolic implication of CD36 alteration on overall skeletal muscle metabolism.