Heart failure is a major medical problem of the modern society and 1 in 9 deaths in the United States (2007) is caused by heart failure. The heart is a high energy-demanding organ that uses fatty acids as the major fuel source. However, under stressed conditions such as cardiomyopathy, the stressed myocardium often switches energy usage preference from lipid to glucose. Intriguingly, elevated expression of COUP-TFII was observed in stressed hearts of non-ischemic cardiomyopathy patients and also in a pressure overload mouse model. To investigate the role of COUP-TFII in cardiac dysfunction, we generated a mouse model over-expressing COUP- TFII specifically in the cardiomyocytes. Our preliminary results showed that over-expression of COUP-TFII results in the suppression of the expression of key enzymes essential for fatty acid trafficking and oxidation, suggesting a switch of fuel usage. The expression of many enzymes involved in fatty acid metabolism is regulated by the PGC/ERR axis. Interestingly, we also showed reduced expression of PGC1/ and ERR/, thus strongly implicating COUP-TFII as a regulator for controlling the PGC/ERR axis to alter fuel usage and mitochondrial function, leading to dysregulation of energy metabolism. Interestingly, we also showed that mice over-expressing SRC-2 also reduces lipid usage in the cardiac muscle, phenotypes analogous to COUP-TFII over-expression. Taken together, we hypothesize that COUP-TFII and SRC-2 act jointly to control cardiac function through modulating the expression of key genes involved in energy metabolism. To dissect the role of COUP-TFII and SRC-2 in the dysregulation of cardiac energy metabolism, three specific aims are proposed: 1. Dissect the role of COUP-TFII in the regulation of cardiac energy metabolism;2. Identify pathways regulated by COUP-TFII in the heart and 3. Investigate the functional interaction between COUP-TFII and SRC- 2 in regulating cardiac fuel usage. These studies will increase our understanding of how COUP-TFII and SRC-2 jointly regulate transcriptional networks in cell types that are pivotal in the regulation of metabolic pathways that govern energy homeostasis in vivo.

Public Health Relevance

Heart disease is a major health hazard in the US in which a healthy heart uses fatty acids, while a stressed heart uses glucose as its fuel source. Elevated expression of either COUP-TFII or SRC-2 in the heart results in a switch of fuel usage from fatty acids to glucose, resembling conditions of a stressed heart. Understanding how COUP-TFII and SRC-2 act in concert to regulate energy metabolism in the heart will likely lead to the timely discovery of new treatments for these debilitating diseases.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Molecular and Cellular Endocrinology Study Section (MCE)
Program Officer
Wong, Renee P
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Baylor College of Medicine
Anatomy/Cell Biology
Schools of Medicine
United States
Zip Code
Zhao, Fei; Franco, Heather L; Rodriguez, Karina F et al. (2017) Elimination of the male reproductive tract in the female embryo is promoted by COUP-TFII in mice. Science 357:717-720
Xie, Xin; Wu, San-Pin; Tsai, Ming-Jer et al. (2017) The Role of COUP-TFII in Striated Muscle Development and Disease. Curr Top Dev Biol 125:375-403
Lee, Hui-Ju; Kao, Chung-Yang; Lin, Shih-Chieh et al. (2017) Dysregulation of nuclear receptor COUP-TFII impairs skeletal muscle development. Sci Rep 7:3136
Wang, Leiming; Xu, Mafei; Qin, Jun et al. (2016) MPC1, a key gene in cancer metabolism, is regulated by COUPTFII in human prostate cancer. Oncotarget 7:14673-83
Xie, Xin; Tsai, Sophia Y; Tsai, Ming-Jer (2016) COUP-TFII regulates satellite cell function and muscular dystrophy. J Clin Invest 126:3929-3941
Wu, San-Pin; Yu, Cheng-Tai; Tsai, Sophia Y et al. (2016) Choose your destiny: Make a cell fate decision with COUP-TFII. J Steroid Biochem Mol Biol 157:7-12
Lin, Shih-Chieh; Kao, Chung-Yang; Lee, Hui-Ju et al. (2016) Dysregulation of miRNAs-COUP-TFII-FOXM1-CENPF axis contributes to the metastasis of prostate cancer. Nat Commun 7:11418
Han, Sang Jun; Jung, Sung Yun; Wu, San-Pin et al. (2015) Estrogen Receptor ? Modulates Apoptosis Complexes and the Inflammasome to Drive the Pathogenesis of Endometriosis. Cell 163:960-74
Wu, San-Pin; Kao, Chung-Yang; Wang, Leiming et al. (2015) Increased COUP-TFII expression in adult hearts induces mitochondrial dysfunction resulting in heart failure. Nat Commun 6:8245
Tang, Ke; Tsai, Sophia Y; Tsai, Ming-Jer (2015) COUP-TFs and eye development. Biochim Biophys Acta 1849:201-9

Showing the most recent 10 out of 21 publications