The mammalian heart has evolved to serve as a constant pump for the life span of an organism. Furthermore, to maintain efficient circulatory support, the cardiomyocyte has developed specialized homeostatic mechanism to maintain high-level energy production in the context of diverse physiologic conditions. The regulation of mitochondrial energy production is at the core of this adaptation, and fatty acid beta-oxidation (FAO) pathway is the chief source of the mitochondrial ATP production in the heart. Many of the key components of the FAO pathway are regulated by members of the nuclear receptor super family at the transcriptional level. Peroxisome proliferators-activated receptor alpha (PPARalpha) is a nuclear receptor that has been well established for its role in FAO, and there is emerging evidence that the orphan nuclear receptor, estrogen-related receptor alpha (ERRalpha), is also a component of this metabolic regulatory pathway. Currently, very little is known about the mechanistic underpinning of the cellular metabolic stress response in the heart or how this may be related to nuclear receptor activity. Recently, we have identified the oncogene Bcl3, using a yeast two-hybrid screen, as a potent activator of PPARalpha and ERRalpha. Furthermore, Bcl3 acts synergistically with peroxisome proliferators-activated receptor gamma coactivator 1alpha (PGC1alpha), a known inducible coactivator of PPARalpha and ERRalpha, to enhance the activation of these nuclear receptors. This proposal is designed to test the hypothesis that nuclear receptor/Bcl3/PGC1alpha complex modulates nuclear receptor activity to increase FAO in the heart during times of stress. This will be approached by 1) characterizing the structural and functional analyses of the nuclear receptor/Bcl3/PGC1alpha interactions, 2) delineating the upstream stimuli relevant to the modulation of Bcl3 in cardiomyocytes, and 3) identifying the metabolic and functional response downstream of this transcriptional complex in cardiomyocytes. The long-term goal of this project is to determine whether this physiologic metabolic stress response translates into an adaptive or maladaptive response in the pathologic state such as heart failure or myocardial ischemia, and, if so, determine whether it represents a rational therapeutic target.
|Yang, John; Williams, R Sanders; Kelly, Daniel P (2009) Bcl3 interacts cooperatively with peroxisome proliferator-activated receptor gamma (PPARgamma) coactivator 1alpha to coactivate nuclear receptors estrogen-related receptor alpha and PPARalpha. Mol Cell Biol 29:4091-102|
|Yang, John; Sambandam, Nandakumar; Han, Xianlin et al. (2007) CD36 deficiency rescues lipotoxic cardiomyopathy. Circ Res 100:1208-17|