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

Abstract

BACKGROUND Endoplasmic reticulum (ER) stress contributes to the pathogenesis of chronic liver diseases, but how hepatocytes respond to ER stress has not been clarified. Alpha-fetoprotein (AFP) is secreted by hepatoma cells and elevated levels of serum AFP are associated with development of liver malignancies. AIM To investigate whether and how AFP could regulate ER stress and hepatocyte injury. METHODS The distribution of AFP and the degrees of ER stress in liver tissues and liver injury were characterized by histology, immunohistochemistry, and Western blot in biopsied human liver specimens, two mouse models of liver injury and a cellular model. The levels of AFP in sera and the supernatants of cultured cells were quantified by chemiluminescence. RESULTS High levels of intracellular AFP were detected in liver tissues, particularly in the necrotic areas, from patients with chronic liver diseases and mice after carbon tetrachloride (CCl 4 ) administration or induction of ER stress, but not from the controls. The induced intracellular AFP was accompanied by elevated activating transcription factor-6 (ATF6) expression and protein kinase R-like ER kinase (PERK) phosphorylation in mouse livers. ER stress induced AFP expression in LO2 cells and decreased their viability. ATF6, but not PERK, silencing mitigated the ER-stress-induced AFP expression in LO2 cells. Conversely, AFP silencing deteriorated the ER stress-mediated LO2 cell injury and CCl 4 administration-induced liver damages by increasing levels of cleaved caspase-3, the C/enhancer binding protein homologous protein expression, mixed lineage kinase domain-like pseudokinase and PERK phosphorylation, but decreasing ATF6 expression. CONCLUSION ER stress upregulated intra-hepatocyte AFP expression by activating ATF6 during the process of liver injury and intracellular AFP attenuated hepatocyte apoptosis and necroptosis by alleviating ER stress.

Protective Effects of Carnosol on Renal Interstitial Fibrosis in a Murine Model of Unilateral Ureteral Obstruction

“…In this study, CS treatment remarkably inhibited UUO-induced apoptosis and necroptosis, as evidenced by a decrease in the number of TUNEL-positive cells and the expression of key factors related to apoptosis (cleaved caspase-3, cleaved PARP-1, p53 and Bax) and necroptosis (RIPK1, RIPK3 and MLKL). Because both types of cell death can be induced by ER stress [ 84 , 85 ], the interplay between oxidative stress and ER stress can cause or exacerbate tubular cell apoptosis and necroptosis in UUO mice. Therefore, suppression of oxidative stress induced by CS may inhibit apoptosis and necroptosis through inhibiting UPR pathways.…”

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

“…It regulates ER stress response by regulating the expression of different downstream target signals, promoting the homeostasis of the cell microenvironment and affecting necroptosis. 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 ).…”

“…In contrast, IL-6/gp130 signaling may aggravate liver damage in autoimmune hepatitis (59). (70). However, it also upregulated RIP3 expression, which did not alleviate necroptosis of liver cells (69).…”

Uridine diphosphate glucuronosyltransferase 1A1 prevents the progression of liver injury

“…Furthermore, the research by Schiavon et al [ 59 ] has indicated that UCB activates the nuclear factor kappa-B (NF-κB) pathway in vitro , leading to the mediation of inflammatory responses. Our preliminary research found that ER stress activates the apoptosis and necroptosis of liver cells in the setting of acute liver injury[ 60 , 61 ]. In vitro studies have revealed that UCB intervention increases the apoptosis and necroptosis of oligodendrocyte precursor cells[ 58 ].…”