fatigue and protecting them from future stress. Initiating apoptosis In conditions of prolonged stress, the goal of the UPR changes from being one that promotes cellular survival to one that commits the cell to a pathway of apoptosis. Proteins downstream of all 3 UPR receptor pathways have been identified as having pro-apoptotic roles. However, the point at which the 'apoptotic switch' is activated has not yet been determined, but it is a logical consideration that this should be beyond a certain time period in which resolution of the stress has not been achieved. The two principal UPR receptors involved are Ire1 and PERK. By binding with the protein TRAF2, Ire1 activates a JNK signaling pathway, at which point human procaspase 4 is believed to cause apoptosis by activating downstream caspases. Although PERK is recognised to produce a translational block, certain genes can bypass this block. An important example is that the proapoptotic protein CHOP (CCAAT/-enhancer-binding protein homologous protein), is upregulated downstream of the bZIP transcription factor ATF4 (activating transcription factor 4) and uniquely responsive to ER stress. CHOP causes downregulation of the anti-apoptotic mitochondrial protein Bcl-2, favouring a pro-apoptotic drive at the mitochondria by proteins that cause mitochondrial damage, cytochrome c release and caspase 3 activation. Diseases Diseases amenable to UPR inhibition include Creutzfeldt–Jakob disease, Alzheimer's disease, Parkinson's disease, and Huntington's disease. Endoplasmic reticulum stress was reported to play a major role in non‐alcoholic fatty liver disease (NAFLD) induction and progression. High fat diet fed rats showed increased ER stress markers CHOP, XBP1, and GRP78. ER stress is known to activate hepatic de novo lipogenesis, inhibit VLDL secretion, promote insulin resistance and inflammatory process, and promote cell apoptosis. Thus it increase the level of fat accumulation and worsens the NAFLD to a more serious hepatic state. Zingiber officinale (ginger) extract and omega‐3 fatty acids were reported to ameliorate endoplasmic reticulum stress in a nonalcoholic fatty liver rat model. As stated above, the UPR can also be activated as a compensatory mechanism in disease states. For instance, the UPR is up-regulated in an inherited form of dilated cardiomyopathy due to a mutation in gene encoding the Phospholamban protein. Further activation proved therapeutic in a human induced pluripotent stem cell model of PLN mutant dilated cardiomyopathy. Chemical inducers Brefeldin A is a very common inducer of the unfolded protein response or endoplasmic reticulum stress response (ER stress). thapsigargin leads to ER Ca2+