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Int J Clin Exp Pathol 2013;6(8):1585-1593

Original Article
Effect of chronic psychosocial stress on nonalcoholic steatohepatitis in mice

Barbara Czech, Inga D Neumann, Martina Müller, Stefan O Reber, Claus Hellerbrand

Department of Internal Medicine I, University Hospital Regensburg, Germany; Department of Behavioral and Molecular Neurobiology, Institute of
Zoology, University of Regensburg, Germany; Laboratory for Molecular Psychosomatics, Clinic for Psychosomatic Medicine and Psychotherapy,
University of Ulm, Germany. These authors contributed equally.

Received May 22, 2013; Accepted June 20, 2013; Epub July 15, 2013; Published August 1, 2013

Abstract: Nonalcoholic fatty liver disease (NAFLD) is characterized by hepatic lipid accumulation which may progress towards inflammation
(nonalcoholic steatohepatitis (NASH)). NAFLD is regarded as a consequence of a sedentary, food-abundant lifestyle which, in the modern
world, often coincides with chronically high levels of perceived psychosocial stress. Here, we aimed to characterize the effect of chronic
psychosocial stress on the development of NAFLD/NASH in male mice either fed with standard chow or NASH-inducing high fat diet. Chronic
psychosocial stress was induced by chronic subordinate colony housing (CSC), a pre-clinically validated paradigm relevant for human affective
and somatic disorders. Single housed (SHC) mice served as controls. Under standard chow conditions CSC mice revealed lower hepatic
triglyceride levels but higher hepatic TNFα, MCP-1 and HMOX mRNA expression, while serum transaminase levels did not significantly differ
from SHC mice. Under the NASH-inducing high-fat diet CSC and SHC mice showed similar body weight-gain and serum levels of glucose and
adiponectin. Moreover, liver histology as well as TNFα, MCP-1 and HMOX expression were similar in CSC and SHC mice fed with HFD.
Surprisingly, CSC showed even significantly lower transaminase levels than SHC mice fed with the same NASH-inducing diet. Together, these
data indicate that under normal dietary conditions the CSC model induces noticeable hepatic oxidative stress and inflammation without
causing manifest hepatocellular injury. In contrast, CSC exhibited a protective effect on hepatocellular injury in a dietary NASH-model.
Identification of the underlying mechanisms of this phenomenon may lead to novel therapeutic strategies to prevent progression of NAFLD.
(IJCEP1305027).

Keywords: Chronic psychosocial stress, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH)

Address correspondence to: Dr. Claus Hellerbrand, Department of Internal Medicine I, University of Regensburg, D-93042 Regensburg,
Germany. Phone: +49-941-944-7155; Fax:  +49-941-944-7154; E-mail: claus.hellerbrand@ukr.de