Hsp72 overexpression protects from acetaminophen and DDC-associated liver injury but enhances protein aggregation

Abstract

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. 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 (800 mg/kg). Long-term feeding (12 weeks) with 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) was used to induce Mallory-Denk-body (MDB) formation. Hsp72-LAP mice displayed doxycycline-regulated, robust Hsp72 overexpression in hepatocytes, but not in the other tissues or cell types tested. 18 hours after acetaminophen injection, significantly lower liver transaminase levels were noted in Hsp72-LAP mice compared to single transgenes (ALT: 933 vs. 1977, p < 0.05). No differences in acetaminophen metabolism were seen, but Hsp72 overexpression protected from formation of APAP protein adducts (p = 0.027). After DDC-feeding, Hsp72-LAP mice experienced a lower weight loss (p = 0.03) and lower ALT levels (650 vs. 875, p = 0.03). On the other hand, DDC-feeding resulted in a more abundant MDB formation in Hsp72-LAP mice vs. single transgenes. Conclusions: Our results suggest that Hsp72 overexpression protects from liver injury in two independent models but precipitates aggregate formation.