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.

Figure 2 Roles of endoplasmic reticulum stress in the development of steatosis and progression to nonalcoholic steatohepatitis. ER stress interferes with hepatic lipid metabolism by activating lipogenesis and limiting VLDL formation and secretion. ER stress also acts indirectly on liver triglyceride accumulation by promoting insulin resistance in both the liver and adipose tissue. Furthermore, ER stress promotes the activation of Nrf2, JNK, NF-κB, CREBH, and CHOP, which actively participate in the inflammatory process and cell death. ER: Endoplasmic reticulum; VLDL: Very-low-density lipoprotein; Nrf2: Nuclear factor-erythroid-derived 2-related factor 2; JNK: c-Jun N-terminal kinase; NF-κB: Nuclear factor-κB; CREBH: Cyclic-AMP responsive element-binding protein H; CHOP: C/EBP-homologous protein; TRAF: Tumor-necrosis factor α-receptor-associated factor; TG: Triglyceride.