Role of endoplasmic reticulum stress in the pathogenesis of nonalcoholic fatty liver disease

Figure 1 The unfolded protein response pathway. When the unfolded protein response is activated, the first event is the dissociation of the chaperone Bip from the three integral proteins PERK, IRE1, and ATF6, leading to their activation. When activated, PERK phosphorylates and inhibits eiF2α, leading to a global decrease in protein translation. Moreover, p-eiF2α activates ATF4, which induces the expression of several genes, including amino acid transporters, chaperones, and CHOP. Activation of IRE1 promotes the splicing of XBP1 mRNA and the subsequent transcription of molecular chaperones and genes involved in ERAD. Finally, activated ATF6 undergoes proteolytic cleavage in the Golgi, transactivating genes such as endoplasmic reticulum (ER) chaperones and foldases. Bip: Binding immunoglobulin protein; ATF6: Activating transcription factor-6; IRE1: Inositol requiring enzyme-1; PERK: Protein kinase RNA-like ER kinase; XBP1: X-box-binding protein-1; eiF2α: Eukaryotic translation initiation factor 2α; ATF4: Transcription factor 4; ERAD: Endoplasmic reticulum associated protein degradation; CHOP: C/EBP-homologous protein.