Kateryna Levada1, Nurdan Guldiken2, Xiaoji Zhang2, Giovanna Vella3, Fa-Rong Mo3, Laura P James4, Johannes Haybaeck5, Sonja M Kessler6, Alexandra K Kiemer6, Thomas Ott7, Daniel Hartmann8, Norbert Hüser8, Marianne Ziol9, Christian Trautwein3, Pavel Strnad10. 1. Department of Internal Medicine III, RWTH University Hospital Aachen, Germany; Interdisciplinary Center for Clinical Research (IZKF), RWTH University Hospital Aachen, Germany; Center for Functionalized Magnetic Materials (FunMagMa), Immanuel Kant Baltic Federal University, Kaliningrad, Russian Federation. 2. Department of Internal Medicine III, RWTH University Hospital Aachen, Germany; Interdisciplinary Center for Clinical Research (IZKF), RWTH University Hospital Aachen, Germany. 3. Department of Internal Medicine III, RWTH University Hospital Aachen, Germany. 4. Arkansas Children's Hospital Research Institute and Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AK, USA. 5. Department of Pathology, Medical Faculty, Otto-von-Guericke University Magdeburg, Germany; Institute of Pathology, Medical University of Graz, Graz, Austria. 6. Department of Pharmacy, Pharmaceutical Biology, Saarland University, Saarbrücken, Germany. 7. Core Facility Transgenic Animals, University of Tübingen, Tübingen, Germany. 8. Department of Surgery, Klinikum rechts der Isar, Technische Universität München, Munich, Germany. 9. Pathology Department, GH Paris-Seine-Saint-Denis, APHP, Bondy, France; University Paris 13, Bobigny, France; Centre de Ressources Biologiques - Hôpital Jean Verdier, GH Paris-Seine-Saint-Denis, APHP, Bondy, France. 10. Department of Internal Medicine III, RWTH University Hospital Aachen, Germany; Interdisciplinary Center for Clinical Research (IZKF), RWTH University Hospital Aachen, Germany. Electronic address: pstrnad@ukaachen.de.
Abstract
BACKGROUND & AIMS: Heat shock protein (Hsp) 72 is a molecular chaperone that has broad cytoprotective functions and is upregulated in response to stress. To determine its hepatic functions, we studied its expression in human liver disorders and its biological significance in newly generated transgenic animals. METHODS: 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 either a methionine choline-deficient (MCD; 8 weeks) or a 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 treated with palmitic acid. RESULTS: Patients with non-alcoholic steatohepatitis and chronic hepatitis C infection displayed elevated HSP72 levels. These levels increased with the extent of hepatic inflammation and HSP72 expression was induced after treatment with either interleukin (IL)-1β or IL-6. Hsp72-LAP mice exhibited robust, hepatocyte-specific Hsp72 overexpression. Primary hepatocytes from these animals were more resistant to isolation-induced stress and Hsp72-LAP mice displayed lower levels of hepatic injury in vivo. Mice overexpressing Hsp72 had fewer APAP protein adducts and were protected from oxidative stress and APAP-/MCD-induced cell death. Hsp72-LAP mice and/or hepatocytes displayed significantly attenuated Jnk activation. Overexpression of Hsp72 did not affect steatosis or the extent of MDB formation. CONCLUSIONS: Our results demonstrate that HSP72 induction occurs in human liver disease, thus, HSP72 represents an attractive therapeutic target owing to its broad hepatoprotective functions. LAY SUMMARY: HSP72 constitutes a stress-inducible, protective protein. Our data demonstrate that it is upregulated in patients with chronic hepatitis C and non-alcoholic steatohepatitis. Moreover, Hsp72-overexpressing mice are protected from various forms of liver stress.
BACKGROUND & AIMS: Heat shock protein (Hsp) 72 is a molecular chaperone that has broad cytoprotective functions and is upregulated in response to stress. To determine its hepatic functions, we studied its expression in human liver disorders and its biological significance in newly generated transgenic animals. METHODS: 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 either a methionine choline-deficient (MCD; 8 weeks) or a 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 treated with palmitic acid. RESULTS: Patients with non-alcoholic steatohepatitis and chronic hepatitis C infection displayed elevated HSP72 levels. These levels increased with the extent of hepatic inflammation and HSP72 expression was induced after treatment with either interleukin (IL)-1β or IL-6. Hsp72-LAP mice exhibited robust, hepatocyte-specific Hsp72 overexpression. Primary hepatocytes from these animals were more resistant to isolation-induced stress and Hsp72-LAP mice displayed lower levels of hepatic injury in vivo. Mice overexpressing Hsp72 had fewer APAP protein adducts and were protected from oxidative stress and APAP-/MCD-induced cell death. Hsp72-LAP mice and/or hepatocytes displayed significantly attenuated Jnk activation. Overexpression of Hsp72 did not affect steatosis or the extent of MDB formation. CONCLUSIONS: Our results demonstrate that HSP72 induction occurs in human liver disease, thus, HSP72 represents an attractive therapeutic target owing to its broad hepatoprotective functions. LAY SUMMARY: HSP72 constitutes a stress-inducible, protective protein. Our data demonstrate that it is upregulated in patients with chronic hepatitis C and non-alcoholic steatohepatitis. Moreover, Hsp72-overexpressing mice are protected from various forms of liver stress.
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