Uncoupling proteins (UCPs) are conserved mitochondrial inner membrane proteins which can dissipate mitochondrial proton gradient to generate heat instead of ATP. UCP2, one member of UCPs family, is ubiquitously expressed and could increase the GDP sensitive proton conductance across the mitochondrial inner membrane. UCP2 activity may require certain activators such as reactive oxygen species (ROS) and free fatty acids (FFA) for its function of proton conductance. Activated UCP2 may result in mild uncoupling and reduce the protonic membrane potential of mitochondria. On one hand, decreased membrane potential may reduce ATP production; on another hand, mild uncoupling may inhibit mitochondrial ROS production. UCP2 appears to play a critical role in regulating mitochondrial function and energy metabolism. Thus, UCP2 may represent an important drug target for metabolic disorders and oxidative stress diseases.However, although there are a number of studies on UCP2, the physiological functions of UCP2 still have arguments and more and more studies has showed UCP2 may have different function in different tissue.

Liver is an important metabolic organ of organism. Interestingly, UCP2 normally is not expressed in healthy adult hepatocytes but is restricted in Kupffer cells. However, UCP2 expression becomes significantly abundant in hepatocytes of fatty liver or liver injury. As a result, it seems significantly important to know how UCP2 plays roles in liver injury which may contribute to better understand the molecular pathogenesis of liver diseases.

Recently, researchers in Dr. Quan Chen’s lab in Institute of Zoology took an approach to target expression of UCP2 in mouse liver and addressed the functional roles of UCP2 in acute liver injury. They found targeted expression of UCP2 in mouse hepatocytes still functions to mediate proton leak and mild uncoupling in a GDP repressible manner. Mitochondria from the genetically manipulated mouse liver have lower mitochondrial membrane potential and reduced ATP production, thus the altered mitochondrial physiology. Importantly, they showed UCP2 liver-specific transgenic mouse is susceptibility to LPS/GalN induced acute liver injury and UCP2 expression in liver promote hepatocyte apoptosis. Further studies showed that targeted expression of UCP2 induced significant ATP level decrease and changed [ATP]/[AMP] ratio in liver, which activate 5’-AMP activated protein kinase (AMPK). In LPS/GalN induced acute liver injury, activated AMPK subsequently lead to c-Jun N-terminal kinase (JNK) activation which may further regulate Bcl-2 family proteins (such as Bax) expression and activation to promote hepatocyte apoptosis.

These results provide us valuable information for further understanding the role of UCP2 in acute liver injury and suggest inhibition of UCP2 induced ATP decrease in liver damage may be an effective method to alleviate liver injury. UCP2 may be an potential pharmic target for liver injury therapy. This study, mainly finished by Dr. Yingli Shang, has been published recently on HEPATOLGOY, an authoritative international journal on liver research (Hepatology. 2009 Oct;50(4):1204-16. IF=11.355). This work was supported by National 973 Program.