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Gewählte Publikation:

SHR Neuro Krebs Kardio Lipid

Levada, K; Guldiken, N; Zhang, X; Vella, G; Mo, FR; James, LP; Haybaeck, J; Kessler, SM; Kiemer, AK; Ott, T; Hartmann, D; Hüser, N; Ziol, M; Trautwein, C; Strnad, P.
Hsp72 protects from liver injury via attenuation of hepatocellular death, oxidative stress and JNK-signaling.
J Hepatol. 2018;
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Autor/innen der Med Uni Graz:
Haybäck Johannes
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Abstract:
Heat shock protein (Hsp) 72 is a molecular chaperone that is upregulated in response to stress and possesses broad cytoprotective functions. To determine its hepatic function, we studied its expression in human liver disorders and its biological significance in newly generated transgenic animals. Double transgenic mice overexpressing Hsp72 (gene HSPA1A) under the control of a tissue-specific tetracycline-inducible system (Hsp72-LAP mice) were produced. Acute liver injury was induced by a single injection of acetaminophen (APAP). Feeding with methionine choline-deficient (MCD; 8 weeks) or 3,5-diethoxycarbonyl-1,4-dihydrocollidine-supplemented diet (DDC; 12 weeks) was used to induce lipotoxic injury and Mallory-Denk body (MDB) formation, respectively. Primary hepatocytes were subjected to treatment with palmitic acid. Patients with non-alcoholic steatohepatitis and chronic hepatitis C infection displayed elevated HSP72 levels. HSP72 levels increased with the extent of hepatic inflammation and HSP72 expression was induced after treatment with interleukin 1ß or interleukin 6. Hsp72-LAP mice exhibited robust, hepatocyte-specific Hsp72 overexpression. Primary hepatocytes from these animals were more resistant towards the isolation-induced stress and in in vivo models, Hsp72-LAP mice displayed lower hepatic injury. Hsp72 overexpressors had a lower amount of APAP protein adducts and were protected from oxidative stress and APAP-/MCD-induced cell death. Hsp72-LAP mice/hepatocytes displayed significantly attenuated JNK activation. Overexpression of Hsp72 did not affect the development of steatosis nor the extent of MDB formation. Our results demonstrate that Hsp72 induction occurs in human liver disease and because of its broad hepatoprotective function, Hsp72 represents an attractive therapeutic target. Hsp72 constitutes a stress-inducible, protective protein. Our data demonstrate that it is up-regulated in patients with chronic hepatitis C and non-alcoholic steatohepatitis. Moreover, Hsp72-overexpressing mice are protected from various liver stress situations. Copyright © 2018 European Association for the Study of the Liver. All rights reserved.

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