DSpace DSpace 日本語

長崎県立大学学術リポジトリ >
学長裁量研究成果報告 >
H31 シーボルト校 >

Please use this identifier to cite or link to this item: http://hdl.handle.net/10561/1671

Title: イソプレノイド化合物によるパイロトーシス誘導メカニズムに関する研究
Other Titles: TLR4-mediated pyroptosis in human hepatoma-derived HuH-7 cells induced by a branched-chain polyunsaturated fatty acid, geranylgeranoic acid
Author: 四童子, 好廣
岡本, 恭子
Author's alias: SHIDOJI, Yoshihiro
Issue Date: Apr-2020
Publisher: 長崎県立大学
Shimei: 学長裁量研究成果報告書
Volume: 平成31年度
Issue: シーボルト校
Start page: 1
End page: 9
Abstract: A branched-chain polyunsaturated fatty acid, geranylgeranoic acid (GGA; C20:4), which is an endogenous metabolite derived from the mevalonate pathway in mammals, has been reported to induce cell death in human hepatoma cells. We previously showed that the lipid-induced unfolded protein response (UPR) is an upstream cellular process for an incomplete autophagic response that might be involved in GGA-induced cell death. Here, we found that Toll-like receptor 4 (TLR4)-mediated pyroptosis occurred by GGA treatment. The TLR4-specific inhibitor VIPER prevented both GGA-induced cell death and UPR. Knockdown of the TLR4 gene attenuated GGA-induced cell death significantly. Upon GGA-induced UPR, caspase-4 (CASP4) was activated immediately and gasdermin D (GSDMD) was translocated concomitantly to the plasma membrane after production of the Nterminal fragment of GSDMD. Then, cellular caspase-1 (CASP1) activation occurred following a second gradual upregulation of the intracellular Ca2+ concentration, suggesting that GGA activated the inflammasome. Indeed, the mRNA levels of NLRP3 and IL1B genes were upregulated dramatically with translocation of cytoplasmic NF-κB to nuclei after GGA treatment, indicating that GGA induced priming of the NLRP3 inflammasome through NF-κB activation. GGA-induced upregulation of CASP1 activity was blocked by either oleic acid, VIPER, MCC950 (a selective inhibitor of the NLRP3 inflammasome), or CASP4-specific inhibitor peptide cotreatment. Pyroptotic cell death was also confirmed morphologically by bleb formation in time-series live cell imaging of GGA-treated cells. Taken together, the present results strongly indicate that GGA causes pyroptotic cell death in human hepatoma via TLR4 signalling.
Keywords: TLR4
geranylgeranoic acid
Description: カラー図版あり
URI: http://hdl.handle.net/10561/1671
Appears in Collections:H31 シーボルト校

Files in This Item:

File Description SizeFormat
H31シ_shidoji.pdf1.36 MBAdobe PDFView/Open

Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.


Nagasaki Prefectural University attached library