Fig. 8. A working model for CGI-58 to regulate cardiac function.

Under normal condition, CGI-58 binds and activates ATGL to promote lipolysis, which then provides energy to the heart. Conversely, CGI-58 knockout inhibits lipolysis and increases lipid accumulation in ER, which results in activation of ER stress and excessive ROS production thereby leading to mitochondrial dysfunction and heart failure. Blocking ER stress reverses mitochondrial dysfunction, ROS production, and cardiac dysfunction.