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Creg in Hepatocytes Ameliorates Liver Ischemia/Reperfusion Injury in a TAK1‐Dependent Manner in Mice
Author(s) -
Yang Ling,
Wang Weijun,
Wang Xiaozhan,
Zhao Jinfang,
Xiao Li,
Gui Wenfang,
Fan Huiqian,
Xia Jing,
Li Zhonglin,
Yan Jingjing,
Alasbahi Afnan,
Zhu Qingjing,
Hou Xiaohua
Publication year - 2019
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.30203
Subject(s) - liver injury , hepatocyte , mapk/erk pathway , kinase , in vivo , inflammation , reperfusion injury , liver function , protein kinase a , cancer research , biology , immunology , ischemia , microbiology and biotechnology , medicine , pharmacology , in vitro , biochemistry
Hepatic ischemia/reperfusion (I/R) is a major challenge for liver surgery and specific severe conditions of chronic liver disease. Current surgical and pharmacological strategies are limited to improve liver function after hepatic I/R injury. Thus, an in‐depth understanding of the liver I/R mechanism is pivotal to develop new therapeutic methods. The cellular repressor of E1A ‐stimulated genes (Creg), a key regulator of cellular proliferation, exerts protective roles in cardiovascular diseases and participates in lipid accumulation and inflammatory response in the liver. However, the role of Creg in hepatic I/R remains largely unknown. A genetic engineering technique was used to explore the function of Creg in hepatic I/R injury. Hepatocyte‐specific Creg knockout ( Creg ΔHep ) and transgenic mice were generated and subjected to hepatic I/R injury, as were the controls. Creg in hepatocytes prevented against liver I/R injury by suppressing cell death and inflammation. In vitro studies were performed using primary hepatocytes isolated from Creg ΔHep that were challenged by hypoxia/reoxygenation insult. These cells exhibited more cell death and inflammatory cytokines production similar to observations in vivo . Moreover, further molecular experiments showed that Creg suppressed mitogen‐activated protein kinase (MAPK) signaling by inhibiting TAK1 (TGF‐β‐activated kinase 1) phosphorylation. Inhibiting TAK1 by 5Z‐7‐ox or mutating the TAK1‐binding domain of Creg abolished the protective role of Creg indicating that Creg binding to TAK1 was required for prevention against hepatic I/R injury. Conclusion: These data demonstrate that Creg prevents hepatocytes from liver I/R injury. The Creg–TAK1 interaction inhibited the phosphorylation of TAK1 and the activation of MAPK signaling, which protected against cell death and inflammation during hepatic I/R injury.