UCP2 up-regulation in liver is also found in pathologic conditions such as steatosis and obesity, where increased or perturbed fatty acid oxidation is observed.27, 29 High UCP2 expression is also found in certain tumors where it is thought that the tumor cells utilize the GSH preserving qualities of UCP2 to promote growth and reduce ROS levels. UCP2 decreases

ROS in liver through a mechanism that is not completely understood,23, 24 yet the recent report of its crystal structure is an important step in understanding the function of UCP2.30 UCP2 may serve a protective role in mitochondria by reducing ROS levels directly, lowering mitochondrial membrane potential, transporting fatty acids and fatty EGFR inhibitor drugs acid peroxides, or a combination of the above. Most important, UCP2 is markedly induced by PPARα activation in liver, specifically hepatocytes7 coincident with the induction of mitochondrial and peroxisomal enzymes involved in fatty acid β-oxidation. Based on these data, UCP2 was viewed as a potential candidate

for a Wy-14,643-induced protein that could protect from APAP toxicity. Indeed, mice lacking expression of UCP2 were not protected against APAP toxicity by Wy-14,643, whereas forced overexpression of UCP2 in the liver of wildtype mice also protected against APAP-induced toxicity in the absence of Wy-14,643. It is noteworthy, however, that sustained expression of UCP2 may selleck products in fact be deleterious, suggesting that UCP2 expression must be tightly controlled in order to maintain its salubrious qualities. Furthermore, other UCP family members, namely UCP3, may also contribute to the protection given the reduced JNK phosphorylation in Ucp2-null mice treated with WY-14,643. Moreover, it is likely that the combined activities of PPARα

targets facilitate maximal protection, and their roles specifically at the level of maintaining mitochondrial function warrant further investigation. The question arises whether UCP2 plays a role in protecting the liver against ROS under normal physiological conditions, such as during mitochondrial fatty acid β-oxidation. In general, Ucp2-null mouse livers have elevated ROS compared with wildtype mice.31 Thus, UCP2 could serve MCE as a general protector of the liver and, in particular, of the mitochondria from oxidative stress produced by normal metabolism. Under conditions of fasting, PPARα is activated by endogenous ligands, resulting in induction of peroxisome and mitochondrial fatty acid oxidation.32 Indeed, PPARα activation by starvation results in elevated mitochondrial ROS.33 This results in elevated ROS that is neutralized by the coinduced UCP2. In the case of chemically induced hepatotoxicity that results in massively elevated and lethal levels of ROS, the protective effect of UCPs are even more essential.