Creg in Hepatocytes Ameliorates Liver Ischemia/Reperfusion Injury in a TAK1‐Dependent Manner in Mice

作者：Ling Yang, Weijun Wang, Xiaozhan Wang, Jinfang Zhao, Li Xiao, Wenfang Gui, Huiqian Fan, Jing Xia, Zhonglin Li, Jingjing Yan, Afnan Ahmed Mohamed Al-Asbahi, Qingjing Zhu, Xiaohua Hou · 发表于：Hepatology · 年份：2018 · DOI：10.1002/hep.30203 · 被引用次数：75 · 研究领域：Liver physiology and pathology、Organ Transplantation Techniques and Outcomes、Liver Disease Diagnosis and Treatment

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 ( CregΔHep ) 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 CregΔHep 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 protectiv...