DHA Protects Hepatocytes from Oxidative Injury through GPR120/ERK-Mediated Mitophagy.

Jinglong Chen,Danping Wang,Yibo Zong,Xiaojing Yang

doi:10.3390/ijms22115675

Jinglong Chen, Danping Wang + Show 2 more

Open Access

https://doi.org/10.3390/ijms22115675

Copy DOI

Abstract

Oxidative stress occurs in a variety of clinical liver diseases and causes cellular damage and mitochondrial dysfunction. The clearance of damaged mitochondria by mitophagy may facilitate mitochondrial biogenesis and enhance cell survival. Although the supplementation of docosahexaenoic acid (DHA) has been recognized to relieve the symptoms of various liver diseases, the antioxidant effect of DHA in liver disease is still unclear. The purpose of our research was to investigate the antioxidant effect of DHA in the liver and the possible role of mitophagy in this. In vitro, H2O2-induced injury was caused in AML12 cells. The results showed that DHA repressed the level of reactive oxygen species (ROS) induced by H2O2 and stimulated the cellular antioxidation response. Most notably, DHA restored oxidative stress-impaired autophagic flux and promoted protective autophagy. In addition, PINK/Parkin-mediated mitophagy was activated by DHA in AML12 cells and alleviated mitochondrial dysfunction. The ERK1/2 signaling pathway was inhibited during oxidative stress but reactivated by DHA treatment. It was proven that the expression of ERK1/2 was involved in the regulation of mitophagy by the ERK1/2 inhibitor. We further proved these results in vivo. DHA effectively alleviated the liver oxidative damage caused by CCl4 and enhanced antioxidation capacity; intriguingly, autophagy was also activated. In summary, our data demonstrated that DHA protected hepatocytes from oxidative damage through GPR120/ERK-mediated mitophagy.

Highlights

A large number of studies have demonstrated that most clinical liver disease is associated with an increasing oxidative stress injury, including NAFLD and NASH [1,2]
Oxidative stress was induced in AML12 cells using H2O2 (400 uL/2 h), and pretreating the cells with docosahexaenoic acid (DHA) or a GPR120 agonist for 12 h
Antioxidant-related protein expression of SOD1 and HO-1, as the major enzymes for reactive oxygen species (ROS) clearance in vivo, were significantly increased (Figure 1E). These results suggest that DHA and TUG891 enhance the scavenging ability of ROS in hepatocytes with oxidative damage and increase the ability to counteract stress

Summary

Introduction

A large number of studies have demonstrated that most clinical liver disease is associated with an increasing oxidative stress injury, including NAFLD (non-alcoholic fatty liver disease) and NASH (non-alcoholic steatohepatitis) [1,2]. Subsequent excessive production of reactive oxygen species (ROS) would damage cellular components and induce hepatocyte apoptosis [3]. ROS are highly reactive radicals that are normally generated in the mitochondria; they impair mitochondrial function during redox imbalance conditions. Previous studies found that mitochondrial dysfunction and the activation of hepatic stellate cells caused by ROS accelerate the progression of NAFLD to fibrosis or HCC (hepatocellular carcinoma) [4,5]. Maintaining the balance of redox status and eliminating damaged mitochondria are effective methods for alleviating oxidative damage to hepatocytes and reducing the progression of liver disease

Objectives

Methods

Results

Discussion

Conclusion