Abstract
Endoplasmic reticulum (ER) stress functions as a protein folding and quality control mechanism to maintain cell homeostasis. Emerging evidence indicates that ER stress is also involved in metabolic and inflammatory diseases. However, the link between ER stress and inflammation remains not well characterized. In this study, we have demonstrated that ER stress-induced inflammasome activation plays a critical role in the pathogenesis of hepatic steatosis. By utilizing genetic and pharmacological agent-induced hepatic steatosis animal models, we found that hepatic steatosis was associated with inflammasome activation and ER stress. Our results show that caspase-1 ablation alleviated liver inflammation and injury. Liver tissues from caspase-1 KO mice had significantly reduced production of IL-1β under ER stress conditions. We also found that ER stress promoted inflammasome activation and IL-1β processing in both hepatocytes and Kupffer cells/macrophages. Moreover, lack of caspase-1 ameliorated cell death or pyropoptosis of hepatocytes induced by ER stress. Taken together, our findings suggest that ER stress-induced inflammasome activation and IL-1β production generate a positive feedback loop to amplify inflammatory response, eventually leading to liver steatosis and injury.
Highlights
The endoplasmic reticulum (ER) is an intracellular organelle that serves many functions involving in the biosynthesis of membrane and secretory proteins, synthesis of lipids and sterols, and maintenance of intracellular calcium homeostasis [1,2]
Hepatic steatosis is associated with inflammasome activation and ER stress To investigate the interaction of inflammasome and ER stress pathways in vivo, we utilized ob/ob mice and pharmacological agents-induced steatosis models. ob/ob mice exhibit obesity and diabetes-like syndromes because of spontaneous leptin mutation
Our results show that inflammasomes and IL-1β contributed to ER stress-induced liver inflammation and injury
Summary
The endoplasmic reticulum (ER) is an intracellular organelle that serves many functions involving in the biosynthesis of membrane and secretory proteins, synthesis of lipids and sterols, and maintenance of intracellular calcium homeostasis [1,2]. ER stress occurs when unfolded and misfolded proteins accumulate in the ER lumen. To maintain ER homeostasis, cells initiate a series of signal transduction pathways collectively termed as Unfolded Protein Response (UPR), which mainly includes inositol-requiring enzyme 1α (IRE1α), doublestranded RNA-dependent protein kinase (PKR)-like ER kinase (PERK), and activating transcription factor-6 (ATF6) pathways [3,4,5]. While UPR is an adaptive response for stressed cells to adjust translational and transcriptional programs to retain ER homeostasis, prolonged or dysregulated UPR can cause cell death and tissue damage. Numerous studies have demonstrated that ER stress is involved in many diseases including neurodegenerative diseases, metabolic diseases, and inflammatory diseases. It remains not fully understood how elevated ER stress contributes to these diseases
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