Arachidonic acid suppresses hepatic cell growth through ROS-mediated activation of transglutaminase.

Xian‐Yang Qin,Jun Lu,Muyi Cai,Soichi Kojima

doi:10.1002/2211-5463.12511

Abstract

We previously reported a profound augmentation in the hepatic levels of a pro‐inflammatory precursor, arachidonic acid (AA), during liver tumorigenesis. Here, we report a critical role of the induced reactive oxygen species (ROS)‐mediated cellular activation of a protein cross‐linking enzyme, transglutaminase 2 (TG2), in liver injury by AA. In cultures of hepatic cells, AA dose‐dependently suppressed cell growth, which accompanied the induced nuclear accumulation of TG2, as demonstrated in EGFP‐tagged, TG2‐overexpressing hepatic cells. A chemical inhibitor/shRNA that acts against TG2 prevented AA‐mediated cell growth suppression. In addition, AA provoked significant production of ROS, and antioxidants blocked AA‐induced activation of nuclear TG2 and hepatic cell growth suppression. We propose that AA‐mediated oxidative stress and TG2 transamidase activity might contribute to chronic liver injury and inflammation and thereby serve as potential therapeutic targets for the chemoprevention of hepatocellular carcinoma.

Highlights

Lipogenesis in the liver is induced abundantly in individuals with nonalcoholic steatohepatitis (NASH) and chronic hepatitis virus infection and is associated with a high risk and poor prognosis of NASH-related hepatocellular carcinoma (HCC) [1]
We propose that arachidonic acid (AA)-mediated oxidative stress and transglutaminase 2 (TG2) transamidase activity might contribute to chronic liver injury and inflammation and thereby serve as potential therapeutic targets for the chemoprevention of hepatocellular carcinoma
It is reported that fatty acids (FAs) released from fat-accumulated hepatocytes induce an increase in the production of mitochondrial-derived reactive oxygen species (ROS) and cause cell death in intrahepatic CD4+ T lymphocytes, which leads to the loss of immune surveillance and accelerated NASH-driven hepatic tumorigenesis [2]

Summary

Introduction

Lipogenesis in the liver is induced abundantly in individuals with nonalcoholic steatohepatitis (NASH) and chronic hepatitis virus infection and is associated with a high risk and poor prognosis of NASH-related hepatocellular carcinoma (HCC) [1]. AA provoked significant production of ROS, and antioxidants blocked AA-induced activation of nuclear TG2 and hepatic cell growth suppression. We explored this hypothesis and obtained in vitro evidence that the suppression of hepatic cell growth by AA accompanies ROS production and the activation of nuclear TG2.

Results

Conclusion