Acid Sphingomyelinase Inhibition Stabilizes Hepatic Ceramide Content and Improves Hepatic Biotransformation Capacity in a Murine Model of Polymicrobial Sepsis

Abstract

Liver dysfunction during sepsis is an independent risk factor leading to increased mortality rates. Specifically, dysregulation of hepatic biotransformation capacity, especially of the cytochrome P450 (CYP) system, represents an important distress factor during host response. The activity of the conserved stress enzyme sphingomyelin phosphodiesterase 1 (SMPD1) has been shown to be elevated in sepsis patients, allowing for risk stratification. Therefore, the aim of the present study was to investigate whether SMPD1 activity has an impact on expression and activity of different hepatic CYP enzymes using an animal model of polymicrobial sepsis. Polymicrobial sepsis was induced in SMPD1 wild-type and heterozygous mice and hepatic ceramide content as well as CYP mRNA, protein expression and enzyme activities were assessed at two different time points, at 24 h, representing the acute phase, and at 28 days, representing the post-acute phase of host response. In the acute phase of sepsis, SMPD1+/+ mice showed an increased hepatic C16- as well as C18-ceramide content. In addition, a downregulation of CYP expression and activities was detected. In SMPD1+/− mice, however, no noticeable changes of ceramide content and CYP expression and activities during sepsis could be observed. After 28 days, CYP expression and activities were normalized again in all study groups, whereas mRNA expression remained downregulated in SMPD+/+ animals. In conclusion, partial genetic inhibition of SMPD1 stabilizes hepatic ceramide content and improves hepatic monooxygenase function in the acute phase of polymicrobial sepsis. Since we were also able to show that the functional inhibitor of SMPD1, desipramine, ameliorates downregulation of CYP mRNA expression and activities in the acute phase of sepsis in wild-type mice, SMPD1 might be an interesting pharmacological target, which should be further investigated.

Keep Your Friends Close, but Your Enemies Closer: Role of Acid Sphingomyelinase During Infection and Host Response

“…Thus, these enzymes are estimated to be responsible for metabolizing >75% of drugs which are in daily clinical use. Pharmacological inhibition of ASM has an important impact on expression and activity of different hepatic CYP enzymes using an animal model of polymicrobial sepsis in the acute as well as in the postsepsis phase ( 167 ).…”

“…On the other hand, there is a clear association of ASM activity with the severity of sepsis and unfavorable outcome ( 34 , 113 , 128 ). It has to be mentioned that in heterogeneous mice by FIASMA treatment, a temporary status similar to complete loss of function was shown, underlining the effectiveness of functional ASM inhibition ( 167 ). A residual activity of 15% is insufficient to prevent clinical features of Niemann-Pick diseases over time ( 17 ).…”

Acid sphingomyelinase deficiency exacerbates LPS‐induced experimental periodontitis

“…Mice with ASMase deficiency are animal models for human type A or B Niemann–Pick disease, which is a lysosomal lipid storage disease characterized with hepatosplenomegaly and neurological symptoms (Schuchman & Wasserstein, ). In addition to the studies on the pathogenesis of human type A or B Niemann–Pick disease, mice with ASMase deficiency have been also used as animal model by a large number of studies to define the role of ASMase in human inflammatory diseases (Becker et al, ; Beckmann et al, ; von Bismarck et al, ; Boini, Xia, Koka, Gehr, & Li, ; Chung et al, ; Dannhausen et al, ; Dhami, He, & Schuchman, ; Hoehn et al, ; Ikegami, Dhami, & Schuchman, ; Nakatsuji, Tang, Zhang, Gallo, & Huang, ; Novgorodov et al, ; Opreanu et al, ; Osawa et al, ). Interestingly, while most of these studies demonstrated that ASMase deficiency attenuated inflammation (Becker et al, ; Beckmann et al, ; von Bismarck et al, ; Boini et al, ; Chung et al, ; Dhami et al, ; Hoehn et al, ; Nakatsuji et al, ; Novgorodov et al, ; Opreanu et al, ), a few studies showed that ASMase deficiency enhanced inflammation (Dannhausen et al, ; Ikegami et al, ; Osawa et al, ).…”

Glycosphingolipids and Infection. Potential New Therapeutic Avenues

“…Mice treated with the ASMase inhibitor amitriptyline show reduced lung edema upon S. aureus exposure. The effect on sepsis of various ASMase inhibitors (imipramine, desipramine, and amitriptyline), is presently studied in animal models (Chung et al, 2018; Xia et al, 2019).…”