TY - JOUR
T1 - Increased expression and altered localization of cathepsin Z are associated with progression to jaundice stage in primary biliary cholangitis
AU - Aiba, Yoshihiro
AU - Harada, Kenichi
AU - Ito, Masahiro
AU - Suematsu, Takashi
AU - Aishima, Shinichi
AU - Hitomi, Yuki
AU - Nishida, Nao
AU - Kawashima, Minae
AU - Takatsuki, Mitsuhisa
AU - Eguchi, Susumu
AU - Shimoda, Shinji
AU - Nakamura, Hitomi
AU - Komori, Atsumasa
AU - Abiru, Seigo
AU - Nagaoka, Shinya
AU - Migita, Kiyoshi
AU - Yatsuhashi, Hiroshi
AU - Tokunaga, Katsushi
AU - Nakamura, Minoru
N1 - Funding Information:
We thank Tota Kugiyama, Hidetaka Shibata (Department of Gastroenterology and Hepatology, Nagasaki University), Clinical Laboratory Department staff member Kei Sato, Aya Iwanaga (Nagasaki Medical Center), and our NHO collaborator. This study was supported by Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science to Yoshihiro Aiba (#15K19357, 17K09449), and to Minoru Nakamura (#26293181, 17H04169); and by a Grant-in-Aid for Clinical Research from the National Hospital Organization to Minoru Nakamura. This study was also conducted and supported by Health Labour Science Research Grants from Research on Measures for Intractable Diseases, Intractable Hepato-Biliary Diseases Study Group, in Japan.
Publisher Copyright:
© 2018, The Author(s).
PY - 2018/12/1
Y1 - 2018/12/1
N2 - Our recent genome-wide association study found that the NELFCD/CTSZ locus was significantly associated with progression of primary biliary cholangitis (PBC) to jaundice stage in the Japanese population. In this study, we investigated the role of cathepsin Z in the etiology and pathology of PBC. Serum cathepsin Z levels were measured using enzyme-linked immunosorbent assay. The expression and localization of cathepsin Z in liver specimens were analyzed by western blotting and immunohistochemistry. In PBC patients, serum cathepsin Z levels were significantly increased with disease progression. In addition, its levels were positively correlated with alanine transaminase, aspartate transaminase and total bilirubin, and were negatively correlated with platelet count and albumin. Cathepsin Z expression was markedly increased in hepatocytes at later stages of PBC, and its localization was altered from the peri-bile canaliculus to the cytoplasm, where a fraction was no longer colocalized with endosomal/lysosomal vesicles. Similar altered expression of cathepsin Z was observed in end-stage of other cholestatic liver diseases including sepsis, obstructive jaundice, and Alagille syndrome. Our results indicate that altered expression and localization of cathepsin Z in hepatocytes are characteristic features of PBC and other cholestatic liver diseases, and are implicated in the progression of PBC.
AB - Our recent genome-wide association study found that the NELFCD/CTSZ locus was significantly associated with progression of primary biliary cholangitis (PBC) to jaundice stage in the Japanese population. In this study, we investigated the role of cathepsin Z in the etiology and pathology of PBC. Serum cathepsin Z levels were measured using enzyme-linked immunosorbent assay. The expression and localization of cathepsin Z in liver specimens were analyzed by western blotting and immunohistochemistry. In PBC patients, serum cathepsin Z levels were significantly increased with disease progression. In addition, its levels were positively correlated with alanine transaminase, aspartate transaminase and total bilirubin, and were negatively correlated with platelet count and albumin. Cathepsin Z expression was markedly increased in hepatocytes at later stages of PBC, and its localization was altered from the peri-bile canaliculus to the cytoplasm, where a fraction was no longer colocalized with endosomal/lysosomal vesicles. Similar altered expression of cathepsin Z was observed in end-stage of other cholestatic liver diseases including sepsis, obstructive jaundice, and Alagille syndrome. Our results indicate that altered expression and localization of cathepsin Z in hepatocytes are characteristic features of PBC and other cholestatic liver diseases, and are implicated in the progression of PBC.
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U2 - 10.1038/s41598-018-30146-w
DO - 10.1038/s41598-018-30146-w
M3 - Article
C2 - 30087368
AN - SCOPUS:85051198187
VL - 8
JO - Scientific Reports
JF - Scientific Reports
SN - 2045-2322
IS - 1
M1 - 11808
ER -