Hsp72 overexpression protects from liver injury and hepatocellular death via attenuation of oxidative stress and JNK-signaling

Background & aims: Heat shock protein (Hsp) 72 is a molecular chaperone that is upregulated in response to a variety of stress situations and possesses broad cytoprotective functions. To determine its hepatic function, we studied its expression in various human liver disorders and its biological significance in newly generated transgenic animals.

Aim & methods: Transgenic mice overexpressing Hsp72 under the control of a tissue-specific tetracycline-inducible system were crossed 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). 8 week feeding with methionine choline-deficient (MCD) and 12 week exposure to 0.1% 3,5-diethoxycarbonyl-1,4-dihydrocollidine-supplemented diet (DDC) was used to induce lipotoxic liver damage and Mallory-Denk body (MDB) formation, respectively. Primary hepatocytes were subjected to treatment with palmitic acid (0,5mM, 24h).

Results: Patients with non-alcoholic steatohepatitis and chronic hepatitis C infection displayed elevated Hsp72 levels. Hsp72 levels progressively increased with the extent of hepatic inflammation. Hsp72-LAP mice exhibited doxycycline-regulated, robust Hsp72 overexpression in hepatocytes, but not in the other tissues or cell types. Primary hepatocytes isolated from these animals were more resistant towards the isolation-induced stress. In all liver injury models (DDC, MCD, APAP), Hsp72-LAP mice displayed lower ALT levels. Hsp72 overexpressors also had a lower amount of APAP protein adducts (p = 0.03) and showed protection towards oxidative stress and APAP-/MCD-induced cell death. In all tested models (isolated hepatocytes, APAP/MCD-treated mice), Hsp72-LAP mice/hepatocytes displayed significantly attenuated JNK activation. On the other hand, overexpression of Hsp72 did affect the extent of steatosis neither after MCD treatment nor after palmitic acid exposure.

Conclusions: Our results demonstrate that Hsp72 overexpression exhibits a broad hepatoprotective function via attenuation of oxidative stress, hepatocellular death and JNK signaling.