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

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.

The Forebrain-Specific Overexpression of Acid Sphingomyelinase Induces Depressive-Like Symptoms in Mice

“…Quantitative real-time PCR was performed using cDNA from cortical and hippocampal tissue using a LightCycler 480 real-time PCR system (Roche, Mannheim, Germany) in SYBR Green format. We analyzed the expression of the following genes, for which the primer sequences can be found in our earlier publication [28]: Asah1, Asah2, Cerk, CerS1, CerS2, CerS3, CerS4, CerS5, CerS6, Galc, Gba, Gba2, Sgms1, Sgms2, Sgpl1, Smpd1, Smpd3, Sphk1, and Sphk2; Gapdh was used as a reference gene. qPCR reactions contained 5 µL FastStart Essential DNA Green Master Mix (Roche, Mannheim, Germany), 0.5 µM of each primer (20 µM) and 2.5 µL diluted cDNA (corresponding to 12.5 ng RNA) in a total volume of 10 µL.…”

Role of Sphingolipid Signaling in Glomerular Diseases: Focus on DKD and FSGS

“…The same study demonstrated that Smpdl3b knockdown results in enhanced responsiveness to Toll-like receptor stimulation (TLR4) and increased inflammatory response. SMPDL3b expression has also been found in pancreatic zymogen granules [ 91 ], in plasma protein-depleted cerebrospinal fluid [ 92 ], in saliva exosomes [ 93 ], in human milk [ 94 ], liver [ 95 ], and hepatocellular carcinoma [ 96 ], suggesting a diverse function of SMPDL3b in different tissues and organs.…”

Acid sphingomyelinase – a regulator of canonical transient receptor potential channel 6 (TRPC6) activity

“…Bioactive sphingolipids have regulatory functions since they define specific membrane environments such as caveolae or lipid rafts that provide platforms for specific cellular processes such as membrane trafficking or intracellular signaling (Beech ). It is postulated that ASM is of major importance in peripheral and also central inflammation, like multiple sclerosis (Becker et al ; Samapati et al ; Becker et al ), bacterial infection (Becker et al ; Simonis and Schubert‐Unkmeir ), chronic stress (Reichel et al ), and MDD (Kornhuber et al ; Gulbins et al ). Interestingly, several commonly used antidepressants (named functional inhibitors of ASM activity , FIASMAs) strongly inhibit ASM activity.…”