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

  • 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 E-2 (PGE(2)), play a pivotal role during inflammatory processes. Expression of the key enzymes of PGE(2) 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 PGE(2) concentration that was completely abrogated in mPGES-1-deficient mice. PGE(2) is known to inhibit TNF-alpha 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-alpha expression. Due to the impaired PGE(2) production, TNF-alpha expression increased muchIn 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 E-2 (PGE(2)), play a pivotal role during inflammatory processes. Expression of the key enzymes of PGE(2) 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 PGE(2) concentration that was completely abrogated in mPGES-1-deficient mice. PGE(2) is known to inhibit TNF-alpha 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-alpha expression. Due to the impaired PGE(2) production, TNF-alpha expression increased much more in livers of mPGES-1-deficient mice or in the peritoneal macrophages of these mice. The increased levels of TNF-alpha resulted in an enhanced IL-1 beta production, primarily in hepatocytes, and augmented hepatocyte apoptosis. In conclusion, attenuation of PGE(2) production by mPGES-1 ablation enhanced the TNF-alpha-triggered inflammatory response and hepatocyte apoptosis in diet-induced NASH.show moreshow less

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Author details:Janin HenkelORCiD, Charles Dominic Coleman, Anne SchraplauGND, Korinna Joehrens, Thomas Siegfried Weiss, Wenke Jonas, Annette SchürmannORCiDGND, Gerhard Paul PüschelORCiDGND
DOI:https://doi.org/10.1038/s41598-018-34633-y
ISSN:2045-2322
Pubmed ID:http://www.ncbi.nlm.nih.gov/pubmed?term=30382148
Title of parent work (English):Scientific reports
Publisher:Nature Publ. Group
Place of publishing:London
Publication type:Article
Language:English
Date of first publication:2018/10/31
Completion year:2018
Release date:2021/07/20
Volume:8
Number of pages:11
Funding institution:Deutsche Forschungsgemeinschaft (German Research Foundation)German Research Foundation (DFG); DFGGerman Research Foundation (DFG) [HE-7032/1-1]; Open Access Publication Fund of the University of Potsdam
Organizational units:Humanwissenschaftliche Fakultät / Strukturbereich Kognitionswissenschaften / Department Sport- und Gesundheitswissenschaften
DDC classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
License (German):License LogoCC BY - Namensnennung, 4.0 International