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A possible involvement of endoplasmic reticulum stress in biliary epithelial autophagy and senescence in primary biliary cirrhosis

  • Original Article—Liver, Pancreas, and Biliary Tract
  • Published:
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Abstract

Background

Deregulated autophagy followed by cellular senescence in biliary epithelial cells (BECs) may be closely related to the abnormal expression of mitochondrial antigens and following autoimmune pathogenesis in primary biliary cirrhosis (PBC). We examined an involvement of endoplasmic reticulum (ER) stress in the deregulated autophagy and cellular senescence in PBC.

Methods

We examined the degree of ER stress using markers; glucose-regulated protein 78 (GRP78) and protein disulfide isomerases (PDI), autophagy and cellular senescence in cultured BECs treated with an ER stress inducer, tunicamycin (TM), glycochenodeoxycholic acid (GCDC), and palmitic acid (PA), and the effect of pretreatment with tauroursodeoxycholic acid (TUDCA). We examined the expression of PDI and GRP78 in livers taken from the patients with PBC (n = 43) and 75 control livers.

Results

The expression of ER stress markers was significantly increased in cultured BECs treated with TM, GCDC or PA in BECs (p < 0.05), and pretreatment with TUDCA significantly suppressed the induced ER stress (p < 0.05). Autophagy, deregulated autophagy, and cellular senescence were induced in BECs treated with TM, GCDC, or PA. Pretreatment with TUDCA further increased autophagy in BECs treated with PA and suppressed cellular senescence caused by treatments with TM, GCDC, or PA (p < 0.05). A granular expression of PDI and GRP78 was significantly more extensive in small bile ducts in PBC, compared with control livers (p < 0.05). The expression of GRP78 was seen in senescent BECs in PBC.

Conclusions

ER stress may play a role in the pathogenesis of deregulated autophagy and cellular senescence in biliary epithelial lesions in PBC.

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Acknowledgments

This study was supported in part by a Grant-in-Aid for Scientific Research (C) from the Ministry of Education, Culture, Sports, and Science and Technology of Japan (21590366 and 24590409).

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Human Pathology, Kanazawa University Graduate School of Medicine, Kanazawa, 920-8640, Japan

    Motoko Sasaki, Masami Yoshimura-Miyakoshi, Yasunori Sato & Yasuni Nakanuma

  2. Department of Pathology, Shizuoka Cancer Center, Shizuoka, 411-8777, Japan

    Yasuni Nakanuma

Authors
  1. Motoko Sasaki
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  2. Masami Yoshimura-Miyakoshi
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  3. Yasunori Sato
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  4. Yasuni Nakanuma
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Correspondence to Motoko Sasaki.

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Sasaki, M., Yoshimura-Miyakoshi, M., Sato, Y. et al. A possible involvement of endoplasmic reticulum stress in biliary epithelial autophagy and senescence in primary biliary cirrhosis. J Gastroenterol 50, 984–995 (2015). https://doi.org/10.1007/s00535-014-1033-0

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  • DOI: https://doi.org/10.1007/s00535-014-1033-0

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