TY  - JOUR
A1  - Henkel, Janin
A1  - Coleman Mac Gregor of Inneregny, Charles Dominic
A1  - Schraplau, Anne
A1  - Jöhrens, Korinna
A1  - Weiss, Thomas Siegfried
A1  - Jonas, Wenke
A1  - Schürmann, Annette
A1  - Püschel, Gerhard Paul
T1  - Augmented liver inflammation in a microsomal prostaglandin E synthase 1 (mPGES-1)-deficient diet-induced mouse NASH model
JF  - Scientific Reports
N2  - 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 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.
KW  - suppress VLDL secretion
KW  - mice lacking
KW  - nonalcoholic steatohepatthis
KW  - insulin-resistance
KW  - rat hepatocytes
KW  - kupffer cells
KW  - E-2
KW  - disease
KW  - expression
KW  - accumulation
Y1  - 2018
U6  - https://doi.org/10.1038/s41598-018-34633-y
SN  - 2045-2322
IS  - 8
SP  - 1
EP  - 11
PB  - Nature Research
CY  - London
ER  -