Downregulation of RIP3 Improves the Protective Effect of ATF6 in an Acute Liver Injury Model

Abstract

Background. Activating transcription factor 6 (ATF6) and receptor-interacting protein 3 (RIP3) are important signaling proteins in endoplasmic reticulum (ER) stress and necroptosis, respectively. However, their regulatory relationship and clinical significance are unknown. We investigate the impact of ATF6 on RIP3 expression, and its role in hepatocyte necroptosis in an acute liver injury model. Methods. In vivo and in vitro experiments were carried out. LO2 cells were treated with thapsigargin (TG). In vivo, male BALB/c mice were treated with carbon tetrachloride (CCl4, 1 mL/kg) or tunicamycin (TM, 2 mg/kg). Then, the impact of ATF6 or RIP3 silencing on liver injury, hepatocyte necroptosis, and ER stress-related protein expression was examined. Results. TG induced ER stress and necroptosis and ATF6 and RIP3 expression in LO2 cells. The knockdown of ATF6 significantly decreased RIP3 expression ( p < 0.05 ) and increased ER stress and necroptosis. The downregulation of RIP3 significantly reduced necroptosis and ER stress ( p < 0.05 ). Similar results were observed in CCl4 or the TM-induced mouse model. The knockdown of ATF6 significantly decreased CCl4-induced RIP3 expression and increased liver injury, necroptosis, and ER stress in mice livers ( p < 0.05 ). In contrast, the downregulation of RIP3 significantly reduced liver injury, hepatocyte necroptosis, and ER stress. Conclusions. Hepatocyte ATF6 has multiple roles in acute liver injury. It reduces hepatocyte necroptosis via negative feedback regulation of ER stress. In addition, ATF6 can upregulate the expression of RIP3, which is not helpful to the recovery process. However, downregulating RIP3 reduces hepatocyte necroptosis by promoting the alleviation of ER stress. The findings suggest that RIP3 could be a plausible target for the treatment of liver injury.

Curcumin affects apoptosis of colorectal cancer cells through ATF6‐mediated endoplasmic reticulum stress

“…In the study, we discovered the reduction of CHOP and Grp78 protein levels and Ca 2+ concentration and the rise of SW620 cell proliferation, which demonstrated that knockdown of ATF6 partially negated the proapoptotic effect of curcumin on CRC cells. In a mouse experiment, necroptosis, liver damage, and ER stress are greatly stifled in mice with ATF6 knockdown (Huang et al., 2021). More convincingly, the raised expression of ATF6 in cervical cancer cells is associated with increased proliferation and decreased apoptosis (Liu et al., 2020).…”

The gp130/STAT3-endoplasmic reticulum stress axis regulates hepatocyte necroptosis in acute liver injury

“…ER stress can also activate NF-κB to enhance TNF-α expression and necroptosis ( 66 - 68 ). Our previous studies have shown that ER stress enhances hepatocyte necroptosis during acute liver injury ( 32 ) and activates ATF6 to partially alleviate hepatocyte necroptosis ( 69 ). ATF6 is an ER stress sensor and transcription factor.…”

“…In our study, ATF6 alleviated necroptosis through upregulating AFP in liver injury ( 70 ). However, it also upregulated RIP3 expression, which did not alleviate necroptosis of liver cells ( 69 ). Therefore, although ATF6 alleviates hepatocyte necroptosis during liver injury, its specific regulatory effect is extremely complex and remains to be investigated.…”

Intracellular alpha-fetoprotein mitigates hepatocyte apoptosis and necroptosis by inhibiting endoplasmic reticulum stress

“…We have reported that ATF6 is important for hepatocyte apoptosis and programmed necrosis[ 40 ]. It is possible that intracellular AFP may interact with intracellular proteins, transcription factors, kinases, co-activators and cell cycle regulators, such as PTEN to activate the PI3K/AKT/mTOR signaling to support the hepatocyte survival[ 41 ].…”