Abstract
Background: Heat shock protein (Hsp) 72 is a molecular chaperone which is upregulated in response to a variety of stress situations and possesses broad cytoprotective functions. However its hepatic function remains largely unknown. Aims and Methods: To study the importance of Hsp72 in the liver, we generated transgenic mice overexpressing Hsp72 under the control of a tissue-specific tetracycline-inducible system and crossed them with animals carrying the tetracycline-responsive transactivator under the control of the liver activator protein promotor (Hsp72-LAP mice). Acute liver injury was induced by a single intraperitoneal injection of acetaminophen (800mg/kg) or the anti-CD95 antibody Jo2 (0.30mg/g). The severity of experimental liver injury was determined via serological and histological analyses. Results: Hsp72-LAP mice displayed doxycycline-regulated, robust Hsp72 overexpression in hepatocytes, but not in the other tissues tested. 18 hours after acetaminophen injection, a significantly lower liver injury was noted in Hsp72-LAP mice compared to single transgenes (ALT: 933 vs. 1977, p < 0.05). No differences in acetaminophen metabolism were seen. On the other hand, injection of anti-CD95 antibody resulted in a more profound injury in Hsp72-LAP vs. single transgenic animals (ALT level: 6435 vs. 2574, p = 0.004). Conclusions: Hsp72-LAP mice represent a unique tool to study the role of Hsp72 in the liver in a timeand cell-type-specific manner. Our results suggest that Hsp72, dependent on context, both ameliorates and promotes liver injury.
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