Abstract
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-β (C/EBP-β) 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.
Highlights
Bile acids are amphipathic molecules synthesized in hepatocytes as the major products of cholesterol catabolism and act as biological detergents that promote the absorption, transport, and distribution of lipids and fat-soluble vitamins[1]
Our results suggest that hepatic Sestrin[2] expression is mediated by activating transcription factor 4 (ATF4) and CCAAT/enhancer-binding protein-β (C/EBP-β) upon cholestasis or bile acid treatment and correlates with Endoplasmic reticulum (ER) stress responses
Sestrin[2] expression is upregulated in cholestatic livers We evaluated the protein expression of Sestrin[2] in HepG2 cells that were stimulated with the major components of bile acids: Chenodeoxycholic acid (CDCA) and cholic acid (CA)
Summary
Bile acids are amphipathic molecules synthesized in hepatocytes as the major products of cholesterol catabolism and act as biological detergents that promote the absorption, transport, and distribution of lipids and fat-soluble vitamins[1]. Bile acids are required to modulate metabolic pathways, including glucose metabolism, lipid metabolism, and energy expenditure[2]. Due to blockage of the biliary tract or genetic defects, causes the accumulation of bile acids in the liver and systemic circulation and results in cholestatic liver diseases such as cholestasis, which leads to progressive liver fibrosis and liver failure[3–5]. Despite progress in understanding the physiological events, the cellular mechanisms by which bile acids induce liver injury remain elusive. Unresolved ER stress can contribute to the development of liver fibrosis[7]. The inflammasome results in the activation of caspase-1, leading to the cleavage of inactive pro-IL-1β into its biologically active form and the cleavage of gasdermin D (GSDMD) to mediate pyroptosis[12–14]. Increasing evidence shows that the NLRP3 inflammasome is activated in cholestatic liver injury in mice[15,16]
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