Chronic Psychosocial Stress in Mice Is Associated With Increased Acid Sphingomyelinase Activity in Liver and Serum and With Hepatic C16:0-Ceramide Accumulation.

Martin Reichel,Andrea M Füchsl,Lukasz Japtok,Lena M Hofmann,Cosima Rhein,Dominik Langgartner,Burkhard Kleuser,Claus Hellerbrand,Erich Gulbins,Juliana Monti,Stefan O Reber,Johannes Kornhuber

doi:10.3389/fpsyt.2018.00496

Abstract

Chronic psychosocial stress adversely affects human morbidity and is a risk factor for inflammatory disorders, liver diseases, obesity, metabolic syndrome, and major depressive disorder (MDD). In recent studies, we found an association of MDD with an increase of acid sphingomyelinase (ASM) activity. Thus, we asked whether chronic psychosocial stress as a detrimental factor contributing to the emergence of MDD would also affect ASM activity and sphingolipid (SL) metabolism. To induce chronic psychosocial stress in male mice we employed the chronic subordinate colony housing (CSC) paradigm and compared them to non-stressed single housed control (SHC) mice. We determined Asm activity in liver and serum, hepatic SL concentrations as well as hepatic mRNA expression of genes involved in SL metabolism. We found that hepatic Asm activity was increased by 28% (P = 0.006) and secretory Asm activity by 47% (P = 0.002) in stressed mice. C16:0-Cer was increased by 40% (P = 0.008). Gene expression analysis further revealed an increased expression of tumor necrosis factor (TNF)-α (P = 0.009) and of several genes involved in SL metabolism (Cers5, P = 0.028; Cers6, P = 0.045; Gba, P = 0.049; Gba2, P = 0.030; Ormdl2, P = 0.034; Smpdl3B; P = 0.013). Our data thus provides first evidence that chronic psychosocial stress, at least in mice, induces alterations in SL metabolism, which in turn might be involved in mediating the adverse health effects of chronic psychosocial stress and peripheral changes occurring in mood disorders.

Highlights

Stress, defined as the physiological response of the body to any demand [1], serves the principal goal to mobilize energy for appropriate, fight or flight’ response
Hepatic Asm activity in chronic subordinate colony housing (CSC) mice was increased by 28% in comparison to single housed control (SHC) mice (Figure 1A; relative Asm activity in SHC: 1.00 ± 0.18, n = 8; CSC: 1.28 ± 0.17, n = 8; P = 0.006)
S-Asm activity of CSC mice was increased by 57% (Figure 1B; relative S-Asm activity in SHC: 1.00 ± 0.34, n = 16; CSC: 1.57 ± 0.37, n = 14; P = 0.0001)

Summary

Introduction

Stress, defined as the physiological response of the body to any demand [1], serves the principal goal to mobilize energy for appropriate, fight or flight’ response. The primary response includes the activation of the sympathetic nervous system and the hypothalamus-pituitary-adrenal axis, resulting in the secretion of catecholamines and glucocorticoids from the adrenal gland. Albeit this adaptation promotes survival of physical threats to homeostasis, chronic psychosocial threats are well-known to adversely affect human health [2,3,4]. In conjunction with viral hepatitis, cirrhosis, and hepatocellular carcinoma is thought to contribute to the development and progression of liver disease [5]. Chronic stress is a well-known risk factor for the development of obesity and metabolic syndrome [6, 7]. Animal studies further support the hypothesis that chronic stress induces [8] and aggravates [9, 10] liver injury, causes hepatic oxidative stress [11, 12] and insulin resistance [13], alters hepatic metabolism and gene transcription [14], and disrupts the regulation of lipid synthesis [15]

Methods

Results

Conclusion