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 employed to explore the function of CREG in hepatic I/R injury. Hepatocyte-specific Creg knockout (Creg ) and transgenic (HTG) 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 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 MAPK signaling by inhibiting TAK1 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 demonstrated 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. This article is protected by copyright. All rights reserved.

This study aimed to analyze the diagnostic accuracy of liver stiffness for predicting esophageal variceal grading and the risk of esophageal variceal bleeding (EVB) in cases of cirrhosis. Hematological and biochemical parameters were measured and transient elastography was performed in 88 patients with hepatitis B-related cirrhosis undergoing endoscopy for esophageal varices. Esophageal varices grade was highly correlated with liver stiffness measurement (LSM) and the liver stiffness spleen diameter-to-platelet score in cirrhosis. Compared with those from endoscopy, the LSM and the liver stiffness spleen diameter-to-platelet score for the absence of esophageal varices were as follows: area under the receiver operating characteristic curve (AUROC), 0.894/0.926; sensitivity, 0.836/0.818; and specificity, 0.875/1.000, respectively. The AUROC and the sensitivity and specificity of LSM and the liver stiffness spleen diameter-to-platelet score for predicting grade III esophageal varices were 0.954 and 0.901, respectively. The AUROCs of LSM and the liver stiffness spleen diameter-to-platelet score for discriminating grades II and III from grade I or the absence of esophageal varices were 0.958 and 0.941, respectively. We also found that EVB was closely associated with LSM and spleen diameter. The AUROC, sensitivity, and specificity were 0.855/0.819, 0.857/0.875, and 0.747/0.780, respectively. Meanwhile, LSM and spleen diameter were 2 independent factors for predicting EVB. These data suggest that LSM and the liver stiffness spleen diameter-to-platelet score could accurately rule out cirrhosis without esophageal varices and differentiate high- and low-risk patients. Furthermore, LSM and spleen diameter had excellent abilities to predict EVB.

Chronic insult and persistent injury can cause liver inflammation, fibrosis, and carcinogenesis; it can also be associated with metabolic disorders. Identification of critical molecules that link the process of inflammation and carcinogenesis will provide prospective therapeutic targets for liver diseases. Rapid advancements in gene engineering technology have allowed the elucidation of the underlying mechanism of transformation, from inflammation and metabolic disorders to carcinogenesis. Transforming growth factor-β-activated kinase 1 (TAK1) is an upstream intracellular protein kinase of nuclear factor kappa-B (NF-κB) and c-Jun N-terminal kinases, which are activated by numerous cytokines, growth factors, and microbial products. In this study, we highlighted the functional roles of TAK1 and its interaction with transforming growth factor-β, WNT, AMP-activated protein kinase, and NF-κB signaling pathways in liver inflammation, steatosis, fibrosis, and carcinogenesis based on previously published articles.