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

Ha-Yeun Chung,Jorge Hurtado-Oliveros,Amelie Lupp,Markus Gräler,Ralf Claus,C Witt,Jonathan Wickel

doi:10.3390/ijms19103163

Ha-Yeun Chung, Jorge Hurtado-Oliveros + Show 5 more

Open Access

https://doi.org/10.3390/ijms19103163

Copy DOI

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.

Highlights

Sepsis is characterized by an increasing incidence over the past 40 years currently ranging between 0.4/1000 and 1/1000 of the population
Their essential role in sepsis is demonstrated by an exacerbated pro-inflammatory response and an increased mortality rate following pharmacological inhibition of monooxygenases in an animal model of systemic inflammation using zymosan injection [36]
Injection of endotoxin resulted in a significant suppression of Cytochrome P450 (CYP) activity, which correlated to the degree of circulating IL-6 in plasma in these individuals [14]

Summary

Introduction

Sepsis is characterized by an increasing incidence over the past 40 years currently ranging between 0.4/1000 and 1/1000 of the population. The liver is a central metabolic and immunologic organ, the function of which is impaired due to yet unclear molecular mechanisms during the course of the disease. It is composed of 60% parenchymal (hepatocytes) and 40% non-parenchymal cells (endothelial cells, hepatic stellate cells, Kupffer-cells), and these cells underlie complex interactions and adaptive mechanisms influencing metabolic and immunological capacity during host response [3]. Administration of endotoxin to healthy individuals resulted in an inhibition of CYP related drug metabolism [14], and biotransformation of atorvastatin was shown to be impaired in critically ill patients resulting in supra-therapeutic plasma concentrations [15]

Objectives

Methods

Results

Conclusion