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.
Highlights
IntroductionOur 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
Serum cathepsin Z levels were significantly higher in jaundice-stage primary biliary cholangitis (PBC) (5.37 ± 3.46 ng/ml) as compared to early-stage PBC (P = 5.3 × 10−7) and late-stage PBC (P = 0.04). In contrast to these results, there was no significant difference in serum cathepsin Z levels between early-stage chronic hepatitis C (CHC) and late-stage CHC, and levels were significantly lower in CHC (0.80 ± 1.07 ng/ml) than in late-stage and jaundice-stage PBC (P = 0.04 and P = 2.37 × 10−6, respectively). (Fig. 1)
We report several novel findings about the role of cathepsin Z in the pathogenesis of cholestatic liver diseases, primary biliary cholangitis
Summary
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 PBC patients, serum cathepsin Z levels were significantly increased with disease progression. 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. We previously reported that the pattern of PBC progression can be classified into three different types: (1) slowly progressive, which does not influence life expectancy; (2) progressive, which proceeds to liver cirrhosis and/or portal hypertension, but rarely to jaundice and end-stage hepatic failure; and (3) progressive, which proceeds to jaundice and end-stage hepatic failure[4] Using this method of classification, we recently found that genetic polymorphisms (rs13720 and rs163800) at the NELFCD/CTSZ locus were associated with progression to jaundice stage in PBC in a Japanese population[7]. We investigated pathoetiological roles of cathepsin Z in disease progression in PBC
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