**2.2 Endoplasmic reticulum stress**

Endoplasmic reticulum (ER) stress is another pathway associated with the pathophysiology of NAFLD and NASH [10]. Unfolded proteins can accumulate within the ER, due to the increased protein synthesis input, the dysfunctional ER or a lack of ATP, which can activate the so-called "unfolded protein response (UPR)," an adaptive response designed to alleviate ER stress [11]. To identify the protein-folding defect that would otherwise result in the onset of apoptosis, UPR activation involves adaptive mechanisms such as reduction of protein synthesis, increased capacity for protein transit through the ER (**Figure 2**), increased protein folding and transport, and activation of pathways for protein degradation. The ER stress has been explained by various biological stresses, including hyperlipidaemia, hyperinsulinemia, high blood sugar, hypercholesterolaemia, oxidative stress, mitochondrial damage that depletes ATP, and low phosphatidylcholine levels. These can facilitate various pathways that could lead to mitochondrial dysfunction, IR, inflammation and apoptosis, which have been considered as the major factors that cause UPR in NAFLD [6, 8]. UPR has been identified to stimulate c-junk terminal kinase (JNK), a potent enhancer of inflammation and apoptosis. Although the activity of JNK was suggested to differentiate between patients with NASH from those with simple steatosis, its silencing in animal models suppresses both steatosis and steatohepatitis. JNK activity is also linked with decreased insulin signaling, which could initiate the episode of DM. Future research on the consequence of ER stress in NAFLD and NASH is important because it was investigated to have a significant implication on alcohol-induced steatohepatitis [6].
