Sestrin2 protects against cholestatic liver injury by inhibiting endoplasmic reticulum stress and NLRP3 inflammasome-mediated pyroptosis

Chronic exposure to bile acid in the liver due to impaired bile flow induces cholestatic liver disease, resulting in hepatotoxicity and liver fibrosis. Sestrin2, a highly conserved, stress-inducible protein, has been implicated in cellular responses to multiple stress conditions and the maintenance of cellular homeostasis. However, its role in cholestatic liver injury is not fully understood. In this study, we investigated the role of hepatic Sestrin2 in cholestatic liver injury and its underlying mechanisms using in vivo and in vitro approaches. Hepatic Sestrin2 expression was upregulated by activating transcription factor 4 (ATF4) and CCAAT/enhancer-binding protein-beta (C/EBP-beta) after treatment with bile acids and correlated with endoplasmic reticulum (ER) stress responses. Bile-duct ligation (BDL)-induced hepatocellular apoptosis and liver fibrosis were exacerbated in Sestrin2-knockout (Sesn2(-/-)) mice. Moreover, Sestrin2 deficiency enhanced cholestasis-induced hepatic ER stress, whereas Sestrin2 overexpression ameliorated bile acid-induced ER stress. Notably, the mammalian target of rapamycin (mTOR) inhibitor rapamycin and the AMP-activated protein kinase (AMPK) activator AICAR reversed bile acid-induced ER stress in Sestrin2-deficient cells. Furthermore, Sestrin2 deficiency promoted cholestasis-induced hepatic pyroptosis by activating NLRP3 inflammasomes. Thus, our study provides evidence for the biological significance of Sestrin2 and its relationship with cholestatic liver injury, suggesting the potential role of Sestrin2 in regulating ER stress and inflammasome activation during cholestatic liver injury. Liver disease: Minimizing the stress from bile blockage A protein that manages the response to cellular stress can help prevent disruptions in bile flow from progressing to liver fibrosis or failure. Disrupted flow leads to the accumulation of bile acids, which triggers a state known as endoplasmic reticulum (ER) stress, fueling inflammation and eventual cell death. Researchers led by Hwan-Woo Park and Jongdae Shin at Konyang University, Daejon, South Korea, have demonstrated that the Sestrin2 protein plays a prominent role in managing this ER stress response to cytotoxic bile acids in cultured liver cells. They subsequently used a Sestrin2-deficient mouse model to demonstrate that the absence of this protein contributes to heightened ER stress and greatly increased liver damage following impaired bile flow. These results suggest that Sestrin2 modulators could offer effective treatments for liver disorders associated with bile flow obstruction.