Increased Expression and Altered Localization of Cathepsin Z Are Associated with Progression to Jaundice Stage in Primary Biliary Cholangitis

Overview

Journal Sci Rep

Specialty Science

Date 2018 Aug 9

PMID 30087368

Citations 2

Authors

Yoshihiro Aiba

Kenichi Harada

Masahiro Ito

Takashi Suematsu

Shinichi Aishima

Yuki Hitomi

Nao Nishida

Minae Kawashima

Mitsuhisa Takatsuki

Susumu Eguchi

Shinji Shimoda

Hitomi Nakamura

Atsumasa Komori

Seigo Abiru

Shinya Nagaoka

Kiyoshi Migita

Hiroshi Yatsuhashi

Katsushi Tokunaga

Minoru Nakamura

Affiliations

Soon will be listed here.

Abstract

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.

Citing Articles

Generalized precursor prediction boosts identification rates and accuracy in mass spectrometry based proteomics.

Scott A, Karlsson C, Mohanty T, Hartman E, Vaara S, Linder A Commun Biol. 2023; 6(1):628.

PMID: 37301900 PMC: 10257694. DOI: 10.1038/s42003-023-04977-x.

Proteomic Analysis of Niemann-Pick Type C Hepatocytes Reveals Potential Therapeutic Targets for Liver Damage.

Balboa E, Marin T, Oyarzun J, Contreras P, Hardt R, van den Bosch T Cells. 2021; 10(8).

PMID: 34440927 PMC: 8392304. DOI: 10.3390/cells10082159.

References

Beuers U, Bilzer M, Chittattu A, Kullak-Ublick G, Keppler D, Paumgartner G . Tauroursodeoxycholic acid inserts the apical conjugate export pump, Mrp2, into canalicular membranes and stimulates organic anion secretion by protein kinase C-dependent mechanisms in cholestatic rat liver. Hepatology. 2001; 33(5):1206-16. DOI: 10.1053/jhep.2001.24034. View

Wendt W, Zhu X, Lubbert H, Stichel C . Differential expression of cathepsin X in aging and pathological central nervous system of mice. Exp Neurol. 2007; 204(2):525-40. DOI: 10.1016/j.expneurol.2007.01.007. View

Ratovitski T, Chighladze E, Waldron E, Hirschhorn R, Ross C . Cysteine proteases bleomycin hydrolase and cathepsin Z mediate N-terminal proteolysis and toxicity of mutant huntingtin. J Biol Chem. 2011; 286(14):12578-89. PMC: 3069459. DOI: 10.1074/jbc.M110.185348. View

Kos J, Vizin T, Fonovic U, Pislar A . Intracellular signaling by cathepsin X: molecular mechanisms and diagnostic and therapeutic opportunities in cancer. Semin Cancer Biol. 2014; 31:76-83. DOI: 10.1016/j.semcancer.2014.05.001. View

Hafner A, Glavan G, Obermajer N, Zivin M, Schliebs R, Kos J . Neuroprotective role of γ-enolase in microglia in a mouse model of Alzheimer's disease is regulated by cathepsin X. Aging Cell. 2013; 12(4):604-14. DOI: 10.1111/acel.12093. View

Nakanuma Y, Zen Y, Harada K, Sasaki M, Nonomura A, Uehara T . Application of a new histological staging and grading system for primary biliary cirrhosis to liver biopsy specimens: Interobserver agreement. Pathol Int. 2010; 60(3):167-74. DOI: 10.1111/j.1440-1827.2009.02500.x. View

Nakamura M, Kondo H, Mori T, Komori A, Matsuyama M, Ito M . Anti-gp210 and anti-centromere antibodies are different risk factors for the progression of primary biliary cirrhosis. Hepatology. 2006; 45(1):118-27. DOI: 10.1002/hep.21472. View

Nagler D, Menard R . Human cathepsin X: a novel cysteine protease of the papain family with a very short proregion and unique insertions. FEBS Lett. 1998; 434(1-2):135-9. DOI: 10.1016/s0014-5793(98)00964-8. View

. EASL Clinical Practice Guidelines: The diagnosis and management of patients with primary biliary cholangitis. J Hepatol. 2017; 67(1):145-172. DOI: 10.1016/j.jhep.2017.03.022. View

10.

Pislar A, Zidar N, Kikelj D, Kos J . Cathepsin X promotes 6-hydroxydopamine-induced apoptosis of PC12 and SH-SY5Y cells. Neuropharmacology. 2013; 82:121-31. DOI: 10.1016/j.neuropharm.2013.07.040. View

11.

Urbanelli L, Emiliani C, Massini C, Persichetti E, Orlacchio A, Pelicci G . Cathepsin D expression is decreased in Alzheimer's disease fibroblasts. Neurobiol Aging. 2006; 29(1):12-22. DOI: 10.1016/j.neurobiolaging.2006.09.005. View

12.

Nagler D, Kruger S, Kellner A, Ziomek E, Menard R, Buhtz P . Up-regulation of cathepsin X in prostate cancer and prostatic intraepithelial neoplasia. Prostate. 2004; 60(2):109-19. DOI: 10.1002/pros.20046. View

13.

Carbone M, Sharp S, Flack S, Paximadas D, Spiess K, Adgey C . The UK-PBC risk scores: Derivation and validation of a scoring system for long-term prediction of end-stage liver disease in primary biliary cholangitis. Hepatology. 2015; 63(3):930-50. PMC: 6984963. DOI: 10.1002/hep.28017. View

14.

Aiba Y, Harada K, Komori A, Ito M, Shimoda S, Nakamura H . Systemic and local expression levels of TNF-like ligand 1A and its decoy receptor 3 are increased in primary biliary cirrhosis. Liver Int. 2013; 34(5):679-88. DOI: 10.1111/liv.12296. View

15.

Lammers W, Hirschfield G, Corpechot C, Nevens F, Lindor K, Janssen H . Development and Validation of a Scoring System to Predict Outcomes of Patients With Primary Biliary Cirrhosis Receiving Ursodeoxycholic Acid Therapy. Gastroenterology. 2015; 149(7):1804-1812.e4. DOI: 10.1053/j.gastro.2015.07.061. View

16.

Vizin T, Christensen I, Wilhelmsen M, Nielsen H, Kos J . Prognostic and predictive value of cathepsin X in serum from colorectal cancer patients. BMC Cancer. 2014; 14:259. PMC: 4021260. DOI: 10.1186/1471-2407-14-259. View

17.

Tanaka A, Hirohara J, Nakanuma Y, Tsubouchi H, Takikawa H . Biochemical responses to bezafibrate improve long-term outcome in asymptomatic patients with primary biliary cirrhosis refractory to UDCA. J Gastroenterol. 2014; 50(6):675-82. DOI: 10.1007/s00535-014-0998-z. View

18.

Gissen P, Arias I . Structural and functional hepatocyte polarity and liver disease. J Hepatol. 2015; 63(4):1023-37. PMC: 4582071. DOI: 10.1016/j.jhep.2015.06.015. View

19.

Krueger S, Kalinski T, Hundertmark T, Wex T, Kuster D, Peitz U . Up-regulation of cathepsin X in Helicobacter pylori gastritis and gastric cancer. J Pathol. 2005; 207(1):32-42. DOI: 10.1002/path.1820. View

20.

Nishida N, Aiba Y, Hitomi Y, Kawashima M, Kojima K, Kawai Y . NELFCD and CTSZ loci are associated with jaundice-stage progression in primary biliary cholangitis in the Japanese population. Sci Rep. 2018; 8(1):8071. PMC: 5966418. DOI: 10.1038/s41598-018-26369-6. View