TRAF2 can recruit IκB kinase (IKK) and promote NF-κB–mediated inflammation.16, 17 Proapoptotic Bcl2 proteins, which regulate apoptotic cell death via altering calcium homeostasis, have been linked to the ER stress response and in particular to the IRE1α branch.12, 18 When activated, these Bcl2 proteins can lead to calcium release, calpain activation which can cause mitochondrial depolarization, and increased reactive oxygen species (ROS),19 as well as the activation of caspase-4 which along with JNK modulates apoptosis. On the other hand, BAX and BAK have been shown to form a complex with the

cytosolic domain of IRE1α and selleck chemicals regulate IRE signaling in cells undergoing ER stress. Double knockouts of BAX and BAK apoptotic factors demonstrate a phenotype similar to that of IRE1α-deficient mice.18 ER-associated caspase-12 plays an important role in ER stress

response–induced apoptosis in rodents but not in humans20; Calcium release is selleckchem a critical factor in affecting mitochondrial function, particularly in areas in which the ER is in close association with the mitochondria, so-called mitochondria-associated membrane21, 22; PERK-induced ATF4 as well as ATF6 can increase the expression of CHOP, which promotes ER stress response through numerous mechanisms. CHOP promotes oxidative stress and inflammation, and results in down-regulation of antiapoptotic Bcl2 proteins and increased transcription of proapoptotic Bcl2 member Bim.23 CHOP induces GADD34 (Growth arrest and DNA damage-inducible protein 34), which associates with protein phosphatase-1 and promotes dephosphorylation

of P-eIF2α (phosphorylated eIF2α) a mechanism aiming to recover ER homeostasis by resuming protein synthesis but which could be harmful if protein overload were to continue. In addition, CHOP and ATF4 together induce TRB3 (tribbles homolog 3), which inhibits the cytoprotective, insulin-sensitizing Akt kinase.13, 24 Hepatocytes, like other secretory cells, are rich in ER. Because of their high protein synthesizing capacity, it is easy to postulate that UPR/ER stress medchemexpress response plays an important role either in preventing or mediating pathological changes in various liver diseases. Despite the identification of up-regulation or dysregulation of ER stress signaling mediators in various forms of liver injury and the rapid growth in the field of ER stress research in liver diseases, the exact contribution of ER stress response to many forms of hepatic injury remains to be fully established.25 Here, we review and update some well-established associations between ER stress response and liver disease (Fig. 2).