Augmented liver inflammation in a microsomal prostaglandin E synthase 1 (mPGES-1)-deficient diet-induced mouse NASH model.
Augmented liver inflammation in a microsomal prostaglandin E synthase 1 (mPGES-1)-deficient diet-induced mouse NASH model.
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DOI：
10.1038/s41598-018-34633-y
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发表时间：
2018-10-31
影响因子：
4.6
通讯作者：
Püschel GP
中科院分区：
文献类型：
--
作者：
Henkel J;Coleman CD;Schraplau A;Jöhrens K;Weiss TS;Jonas W;Schürmann A;Püschel GP
在一部分患者中，非酒精性脂肪性肝病（NAFLD）因细胞死亡和炎症而复杂化，导致非酒精性脂肪性肝炎（NASH），可能进展为纤维化和随后的器官衰竭。除了细胞因子，前列腺素，特别是前列腺素E2（PGE 2），在炎症过程中发挥关键作用。与对照组相比，人NASH肝脏中PGE 2合成的关键酶，环氧合酶2和微粒体PGE合酶1（mPGES-1）的表达增加，并与NASH活性评分相关。这两种酶也诱导NASH饮食喂养的野生型小鼠，导致肝脏PGE 2浓度的增加，在mPGES-1缺陷型小鼠中完全消除。已知PGE 2抑制巨噬细胞中TNF-α的合成。在NASH饮食喂养的小鼠中观察到单核细胞源性巨噬细胞的强烈浸润，伴随肝脏TNF-α表达的增加。由于PGE 2产生受损，mPGES-1缺陷小鼠的肝脏或这些小鼠的腹腔巨噬细胞中的TNF-α表达增加得更多。TNF-α水平升高导致IL-1β产生增加（主要在肝细胞中），并增加肝细胞凋亡。总之，通过mPGES-1消融减弱PGE 2的产生增强了饮食诱导的NASH中TNF-α触发的炎症反应和肝细胞凋亡。
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.
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DOI：
10.1016/j.bbalip.2006.02.003
发表时间：
2006-02-01
影响因子：
4.8
作者：
Pérez, S;Aspichueta, P;Chico, Y
通讯作者：
Chico, Y
影响因子：
3.7
作者：
Ii H;Yokoyama N;Yoshida S;Tsutsumi K;Hatakeyama S;Sato T;Ishihara K;Akiba S
通讯作者：
Akiba S
DOI：
10.1124/jpet.107.128264
发表时间：
2007-12-01
影响因子：
3.5
作者：
Horrillo, Raquel;Planaguma, Anna;Claria, Joan
通讯作者：
Claria, Joan
影响因子：
7.3
作者：
Neuschaefer-Rube, F.;Pathe-Neuschaefer-Rube, A.;Pueschel, G. P.
通讯作者：
Pueschel, G. P.
影响因子：
4.8
作者：
Kamei, D;Yamakawa, K;Kudo, I
通讯作者：
Kudo, I