Hsp72 overexpression protects from drug-induced- and lipotoxic liver injury

Introduction: Heat shock protein (Hsp) 72 is a molecular chaperone that is upregulated in a response to a variety of stress situations and possesses broad cytoprotective functions. The hepatic function of Hsp72 remains largely unknown.

Aims & methodology: 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 promoter (Hsp72-LAP mice). Acute liver injury was induced by a single intraperitoneal injection of acetaminophen (800 mg/kg). Long-term feeding (8 weeks) with methionine choline-deficient diet (MCD) was used to induce lipotoxic liver damage.

Results: Hsp72-LAP mice displayed doxycycline-regulated, robust Hsp72 overexpression in hepatocytes, but not in the other tissues or cell types. Eighteen hours after acetaminophen injection, a significantly lower liver injury was noted in Hsp72-LAP mice in comparison to single transgenes (ALT: 933 vs. 1977, p < 0.05). A trend towards a faster clearance of APAP from the serum was seen in Hsp72-LAP mice 4h after the injection (180 vs. 243, p = 0.05), Overexpression of Hsp72 protected also protected from formation of APAP protein adducts (p = 0.03) and JNK hyperphosphorylation. After MCD-feeding, Hsp72-LAP mice displayed lower ALT levels (105 vs. 225, p = 0.02) as well as decreased JNK phosphorylation and RIP-3 activation. While overexpression of Hsp72 did not affect the extent of MCD-diet induced steatosis, it resulted in higher phosphatidylcholine levels (p = 0.04) and a trend towards a lower C18/C16 ratio (p = 0.08).

Conclusions: Our results suggest that Hsp72 overexpression protects against specific types of liver injury.

Corresponding author: Levada, Kateryna

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