Cystatin A expression reduces bile salt-induced apoptosis in a rat hepatoma cell line

Blake Jones, Patricia J. Roberts, William A. Faubion, Eiki Kominami, Gregory J. Gores

Research output: Contribution to journalArticlepeer-review

89 Scopus citations


We have previously demonstrated abrogation of bile salt-induced apoptosis by cathepsin B inhibitors. However, caspases have been strongly implicated in apoptosis, and the mechanistic interface between caspase and cathepsin B activation is unclear. Thus our aims were to determine the mechanistic relationship between caspases and cathepsin B in bile salt- induced apoptosis in a rat hepatoma cell line. Expression of cystatin A was used to inhibit cathepsin B, whereas Z-Val-Ala-Asp-fluoromethyl ketone (Z- VAD-FMK) was used to inhibit caspases. Cystatin A expression prevented cathepsin B activation and apoptosis during treatment with glycochenodeoxycholate (GCDC), a toxic bile salt. Caspase N-acetyl-Asp-Glu- Val-Asp-7-amino-4-methylcoumarin (DEVD-AMC) hydrolytic activity increased in both wild-type and cystatin A-transfected cells treated with GCDC, demonstrating caspase activation despite inhibition of cathepsin B. In contrast, Z-VAD-FMK blocked both DEVD-AMC hydrolytic activity and cathepsin B activity during GCDC treatment. Our data demonstrate that 1) bile salt- induced apoptosis can be inhibited by the cystatin A transgene and 2) caspase and cathepsin B activation are linked mechanistically with cathepsin B downstream of caspases.

Original languageEnglish (US)
Pages (from-to)G723-G730
JournalAmerican Journal of Physiology - Gastrointestinal and Liver Physiology
Issue number4 38-4
StatePublished - 1998


  • 4',6'-diamidino-2-phenylindole dihydrochloride
  • Caspase 3
  • Cathepsin B
  • Cholestasis

ASJC Scopus subject areas

  • Physiology
  • Hepatology
  • Gastroenterology
  • Physiology (medical)


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