We also observed a marked reduction in cleaved caspase 3 following treatment with exendin-4 in cells containing fat when compared to non-fat loaded hepatocytes. We speculated that cell survival was the consequence of enhanced capacity to handle the unfolded protein response and thereby prevent hepatocyte cell death via apoptosis. GRP78 is the cardinal chaperone protein that binds to unfolded proteins and reduces ER stress, preventing ATF-6 activation that in turn Axitinib cost promotes CHOP expression and initiates downstream apoptosis effectors . We observed that exendin-4 induced the expression of GRP78 in hepatocytes and liraglutide did the same in mouse livers fed a high fat high fructose diet. These data suggest that while free fatty acids result in an increase in unfolded protein accumulation, there is an insufficient or effective level of GRP78 to abate the unfolded protein response. Exendin-4 on the other hand increased the amount of GRP78. Furthermore, if ER stress persists; C/EBP homologous protein activation can promote an imbalance between survival and apoptosis in favor of the latter. CHOP is ubiquitously expressed at very low levels. However, it is robustly expressed by perturbations that induce stress . As we observed in vitro, FFA induced stress leads to an accumulation of CHOP. This observation is in contrast to that of Puri et al. , where CHOP expression was suppressed in NAFL and NASH in human liver samples. We demonstrated here that CHOP levels were increased in hepatocytes that showed high steatosis with either of the fatty acid types. This expression is reversed following exendin- 4 treatment. These data were also seen following liraglutide therapy in the ALIOS-fed mice. Taken together, increased availability of the chaperone GRP78 and reduction in CHOP expression provides stress-relief to hepatocytes, suppressing apoptosis and promoting hepatocyte survival.