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

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.

• Authors: Motoko Sasaki, Masami Yoshimura-Miyakoshi, Yasunori Sato, Yasuni Nakanuma
• Journal: Journal of gastroenterology (J Gastroenterol) Vol. 50 Issue 9 Pg. 984-95 (Sep 2015) ISSN: 1435-5922 [Electronic] Japan
• PMID: 25552342 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Biomarkers
• Endoplasmic Reticulum Chaperone BiP
• HSPA5 protein, human
• Heat-Shock Proteins
• Hspa5 protein, mouse
• Protein Disulfide-Isomerases

Topics

• Animals
• Autophagy (physiology)
• Bile Ducts (pathology)
• Biomarkers (metabolism)
• Cell Culture Techniques
• Cellular Senescence (physiology)
• Endoplasmic Reticulum Chaperone BiP
• Endoplasmic Reticulum Stress (physiology)
• Epithelial Cells (metabolism)
• Fluorescent Antibody Technique
• Heat-Shock Proteins (metabolism)
• Humans
• Immunoblotting
• Immunohistochemistry
• Liver (metabolism, pathology)
• Liver Cirrhosis, Biliary (metabolism, physiopathology)
• Mice
• Protein Disulfide-Isomerases (metabolism)
• Real-Time Polymerase Chain Reaction