Mitochondrial fatty acid oxidation (FAQ) serves as a chief energy transduction pathway in tissues with high oxidative energy demands such as heart and liver. The capacity for cellular FAQ is altered in a variety of inherited and acquired human diseases including cardiomyopathy, diabetes mellitus, and obesity. Recent studies have identified a role for the lipid-activated nuclear receptor, the peroxisome proliferator-activated receptor a (PPARa) and its coactivator, PPARy coactivator-1 (PGC-1), in the transcriptional control of genes encoding mitochondrial FAQ enzymes. This renewal proposal is designed to test the hypothesis that the PPARa/PGC-1 transcriptional regulatory complex serves a critical role in the control of FAQ enzyme gene expression under physiologic conditions known to alter energy demands and substrate availability. Experiments proposed in Specific Aim 1 are designed to further characterize the role of the PPARa/PGC-1 complex in the control of FAQ and other mitochondrial energy metabolic pathways. The goal of Specific Aim 2 is to extend our studies aimed at the characterization of the role of the PPARcL regulatory complex in the transcriptional control of FAQ enzyme gene expression in response to physiologic conditions known to precipitate clinical manifestations in humans with inborn errors in FAO enzymes. First, the proximal regulatory pathways involved in the activation of PPARa and PGC-1 in response to short-term fasting will be characterized. Second, exercise studies will be performed with wild-type and PPARcL-null mice to evaluate the potential role of PPARcL in mediating the known augmentation of skeletal muscle mitochondrial FAQ enzyme expression in response to training.
Specific Aims 3 and 4 are designed to develop mice with altered PGC-1 function in heart using transgenic and cre-lox-mediated gene disruption approaches. The PGC-1-nulLmice will be evaluated in the physiologic contexts described in Specific Aim 2 in order to rigorously define the role played by this coactivator as a transducer of physiologic stimuli to the control of mitochondrial FAQ. The long-term objective of this project is to develop novel experimental and, ultimately, therapeutic strategies to modulate mitochondrial FAQ capacity in vivo in the context of human diseases such as obesity, heart failure, and diabetes mellitus.
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