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Monosodium urate attenuates bile acid induced hepatocyte apoptosis by modulating ER stress and JNK activation : Monosodium urate가 bile에 의한 간세포 자멸사에 미치는 영향
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- Authors
- Advisor
- 윤정환
- Major
- 의과대학 의학과
- Issue Date
- 2014-02
- Publisher
- 서울대학교 대학원
- Keywords
- Monosodium urate ; Bile acid ; Apoptosis ; Endoplasmic reticulum ; c-Jun N-terminal kinase ; Inflammasome
- Description
- 학위논문 (석사)-- 서울대학교 대학원 : 의학과, 2014. 2. 윤정환.
- Abstract
- Background: In cholestasis, accumulated bile acids within the liver tissue trigger hepatocyte apoptosis, primarily by activating proapoptotic signaling cascades. Monosodium urate (MSU) crystal is produced after release of uric acid during cellular death, and activates a cytosolic complex of proteins termed inflammasome via the sensory molecule NLRP3 leading to inflammation. This study aimed to investigate the effects of MSU in bile acid-induced hepatocyte apoptosis, and to identify the signaling pathway modulated by MSU.
Methods and Results: We performed in vitro studies using Huh-BAT cells, which are Huh-7 cells stably transfected with the sodium-dependent bile acid transporting polypeptide. Deoxycholate (DC) was used to induce hepatocyte apoptosis. Cell growth was assessed using MTS assay and apoptosis was quantified using 4′,6-diamidino-2-phenylindole dihydrochloride staining. The apoptotic and kinase signaling pathways were explored by immunoblot analysis and immunoprecipitation. MSU attenuated bile acid-induced hepatocyte apoptosis by reducing mitochondrial apoptotic signaling, such as caspase 9 and 7. Augmentation of eIF2α phosphorylation and subsequent JNK activation induced by DC treatment were attenuated by MSU pretreatment. However, TRAIL-R2 oligomerization and caspase 8 recruitment to death-inducing signaling complex following DC treatment and TRAIL-induced activation of caspase 9 and 7 were not altered by MSU pre-treatemnt.
Conclusion: MSU attenuates bile acid-induced ER stress and subsequent JNK activation, leading to hepatocyte protection against bile acid-induced apoptosis. The antiapoptotic effect of MSU is independent of death receptor signaling pathway.
- Language
- English
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