Combination of psychosocial stress and a NASH-inducing diet in mice

A sedentary life stile combined with high calorie intake is the major cause of non-alcoholic fatty liver disease (NAFLD). This life style often coincides with chronic psychosocial stress.

The aim of this study was to characterize the effect of a model of chronic psychosocial stress on liver physiology and to combine it with a dietary model of non-alcoholic steatohepatitis (NASH) in mice.

Methods and Results: Chronic psychosocial stress was induced in male C57BL/6 mice by chronic subordinate colony (CSC) housing, a preclinically validated paradigm relevant for human psychiatric and somatic disorders. Thereby, four experimental (CSC; 19–22g)) mice are continuously subordinated to a larger (30–35g) dominant male for 19 consecutive days. Single housed (SHC) male mice served as controls. Liver Histology and serum transaminase levels did not differ significantly between CSC and control mice. However, qPCR analysis revealed slightly but significantly higher MCP-1 and HMOX mRNA expression, indicative for oxidative stress and beginning hepatic inflammation. Next, we combined the CSC model with a NASH-inducing Western-type diet (high fat, cholesterol and fructose) starting one week before and continuing during CSC exposure. SHC mice fed with the NASH-diet served as control. Interestingly, and in contrast to previous findings employing standard mouse diet, body weight gain was significantly increased in CSC-compared to SHC mice. Most likely this was caused by an increased calorie intake in chronically-stressed individuals, which had been already described before. The NASH-diet caused a marked increase of hepatic triglyceride levels, as well as expression of HMOX and MCP-1 and the profibrogenic cytokine TGF-beta to control fed mice, which was to our surprise equally pronounced in both groups, despite SHC mice probably consumed less of the NASH diet.

Conclusion: Increased calorie intake in mice in response to chronic psychosocial stressor exposure interferes with dietary NASH-models. Still, similar induction of pro-inflammatory and pro-fibrogenic gene expression in CSC- and SHC mice indirectly indicates that chronic stress exposure affects NAFLD-progression.