LIVER

Bilirubin inhibits bile acid induced apoptosis in rat hepatocytes

A Granato¹, G Gores², M T Vilei¹, R Tolando³, C Ferraresso¹ and M Muraca¹

¹ Clinica Medica 1, University of Padova, Italy
² Division of Gastroenterology and Hepatology, Mayo Medical School, Clinic and Foundation, Rochester, Minnesota, USA
³ GlaxoSmithKline Research Centre, Verona, Italy

Correspondence to:
Correspondence to:
Dr M Muraca
Department of Medical and Surgical Sciences, University of Padova, Via Giustiniani, 2, I-35128 Padova, Italy; muraca{at}unipd.it

Background and aims: Hydrophobic bile acids contribute to hepatocellular injury in cholestasis and rapidly induce apoptosis in vitro; however, unlike Fas agonists, cholestasis does not cause extensive hepatocyte apoptosis. As antioxidants provide protection against bile acid induced liver injury, our premise was that bilirubin, a free radical scavenger with increased plasma levels in the presence of liver disease, could protect hepatocytes against bile acid induced apoptosis.

Methods: Freshly isolated rat hepatocytes were incubated for four hours with 100 µmol/l glycochenodeoxycholate (GCDC) alone or with increasing concentrations of unconjugated (UCB) or conjugated (CB) bilirubin.

Results: Both UCB and CB inhibited GCDC induced apoptosis in a dose dependent fashion and suppressed the generation of reactive oxygen species by hepatocytes.

Conclusions: The antiapoptotic effect of bilirubin associated with its antioxidant properties indicates that hyperbilirubinaemia may have a protective role in liver disease.

Keywords: apoptosis; bile acids; bilirubin; cholestasis; rat hepatocytes

Abbreviations: GCDC, glycochenodeoxycholate; UCB, unconjugated bilirubin; CB, conjugated bilirubin; ROS, reactive oxygen species; DAPI, diamidino-2-phenylindole dihydrochloride; BSA, bovine serum albumin; DCF, dichlorofluorescein; LDH, lactate dehydrogenase; GLDH, glutamate dehydrogenase; AST, aspartate aminotransferase

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