Progress of mitochondrial and endoplasmic reticulum-associated signaling and its regulation of chronic liver disease by Chinese medicine

Figure 2 Endoplasmic reticulum dysfunction modulates chronic liver disease. Upon occurrence of endoplasmic reticulum stress (ERS), BiP dissociates from the three ER transmembrane proteins and binds to unfolded proteins with high affinity, and the dissociated transmembrane proteins shift to an active state and activate downstream signaling. Upon dissociation from BiP upon ERS, PERK endoplasmic reticulum stress increases the expression of bispecific phosphatase 5 in hepatocytes through the PERK/eIF2α/CHOP pathway as a means of raising the intracellular activated caspase-3 levels, which ultimately induces hepatocyte death. ATF6 is cleaved upon dissociation from BiP during ERS onset, and cleaved ATF6α activates the transcription of XBP1u.IRE1α is activated and translocates to the cell membrane via the PI3K/AKT pathway, leading to extracellular Ca²⁺ inward flow, which disrupts the intracellular calcium homeostasis and triggers ERS, so that IRE1α, XBP1, PERK and CHOP upregulation, which ultimately leads to hepatic stellate cell activation and proliferation and promotes liver fibrosis. ER: Endoplasmic reticulum; VEGF: Vascular endothelial growth factor.