Augmented liver inflammation in a microsomal prostaglandin E synthase 1 (mPGES-1)-deficient diet-induced mouse NASH model

Janin Henkel,Charles Dominic Coleman,Wenke Jonas,Annette Schürmann,Gerhard Paul Püschel,Anne Schraplau,Korinna Jöhrens,Thomas Siegfried Weiss

doi:10.1038/s41598-018-34633-y

Abstract

In a subset of patients, non-alcoholic fatty liver disease (NAFLD) is complicated by cell death and inflammation resulting in non-alcoholic steatohepatitis (NASH), which may progress to fibrosis and subsequent organ failure. Apart from cytokines, prostaglandins, in particular prostaglandin E2 (PGE2), play a pivotal role during inflammatory processes. Expression of the key enzymes of PGE2 synthesis, cyclooxygenase 2 and microsomal PGE synthase 1 (mPGES-1), was increased in human NASH livers in comparison to controls and correlated with the NASH activity score. Both enzymes were also induced in NASH-diet-fed wild-type mice, resulting in an increase in hepatic PGE2 concentration that was completely abrogated in mPGES-1-deficient mice. PGE2 is known to inhibit TNF-α synthesis in macrophages. A strong infiltration of monocyte-derived macrophages was observed in NASH-diet-fed mice, which was accompanied with an increase in hepatic TNF-α expression. Due to the impaired PGE2 production, TNF-α expression increased much more in livers of mPGES-1-deficient mice or in the peritoneal macrophages of these mice. The increased levels of TNF-α resulted in an enhanced IL-1β production, primarily in hepatocytes, and augmented hepatocyte apoptosis. In conclusion, attenuation of PGE2 production by mPGES-1 ablation enhanced the TNF-α-triggered inflammatory response and hepatocyte apoptosis in diet-induced NASH.

Highlights

Besides its function as a glucostat[1,2], the liver fulfills central functions in lipid metabolism[3,4]
To test whether prostaglandin E2 (PGE2) might be a relevant factor for the development of non-alcoholic steatohepatitis (NASH), mRNA expression of these two key synthesis enzymes was determined in a set of histologically confirmed human NASH liver samples in comparison with healthy controls[24,25]
The current study showed that the hepatic expression of enzymes for PGE2 synthesis increased with the severity of NASH in patients (Fig. 1) as well as in a diet-induced mouse NASH model (Fig. 3)

Summary

Introduction

Besides its function as a glucostat[1,2], the liver fulfills central functions in lipid metabolism[3,4]. In order to elucidate the potential role of PGE2 in hepatic NASH development, control mice and mice lacking mPGES-1 were fed a cholesterol-containing high-fat diet with a high content of ω6-polyunsaturated fatty acids (PUFA), which has previously been shown to induce NASH in mice[23]. While both control and mPGES-1-deficient mice developed comparable obesity and hepatic steatosis, the inflammatory response including TNF-α production and the ensuing hepatocyte apoptosis was significantly stronger in livers of mPGES-1-deficient mice, indicating that PGE2 might attenuate the inflammatory response during NASH development

Methods

Results

Conclusion