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

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.

• Authors: Janin Henkel, Charles Dominic Coleman, Anne Schraplau, Korinna Jöhrens, Thomas Siegfried Weiss, Wenke Jonas, Annette Schürmann, Gerhard Paul Püschel
• Journal: Scientific reports (Sci Rep) Vol. 8 Issue 1 Pg. 16127 (10 31 2018) ISSN: 2045-2322 [Electronic] England
• PMID: 30382148 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Interleukin-1beta
• Tumor Necrosis Factor-alpha
• Prostaglandin-E Synthases
• Ptges protein, mouse
• Dinoprostone

Topics

• Animals
• Apoptosis
• Dinoprostone (biosynthesis)
• Disease Models, Animal
• Feedback, Physiological
• Hepatocytes (metabolism)
• Humans
• Inflammation (pathology)
• Interleukin-1beta (metabolism)
• Liver (pathology)
• Macrophages, Peritoneal (metabolism)
• Mice, Inbred C57BL
• Microsomes (enzymology)
• Models, Biological
• Non-alcoholic Fatty Liver Disease (enzymology, pathology)
• Prostaglandin-E Synthases (metabolism)
• Tumor Necrosis Factor-alpha (metabolism)
• Up-Regulation