Format

Send to

Choose Destination

See 1 citation found by title matching your search:

Cell Death Dis. 2019 Jun 18;10(6):449. doi: 10.1038/s41419-019-1678-y.

Hepatic ferroptosis plays an important role as the trigger for initiating inflammation in nonalcoholic steatohepatitis.

Author information

1
Department of Regenerative Medicine, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan.
2
Laboratory of Stem Cell Regulation, Institute for Quantitative Biosciences, The University of Tokyo, Tokyo, Japan.
3
Department of Biochemistry, Toho University School of Medicine, Tokyo, Japan.
4
School of Pharmaceutical Sciences, Kitasato University, Tokyo, Japan.
5
Centre for Heart Research, The Westmead Institute for Medical Research, Westmead, NSW, Australia.
6
Laboratory of Stem Cell Therapy, Institute for Quantitative Biosciences, The University of Tokyo, Tokyo, Japan.
7
Department of Regenerative Medicine, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan. m-tanaka@ri.ncgm.go.jp.
8
Laboratory of Stem Cell Regulation, Institute for Quantitative Biosciences, The University of Tokyo, Tokyo, Japan. m-tanaka@ri.ncgm.go.jp.

Abstract

Nonalcoholic steatohepatitis (NASH) is a metabolic liver disease that progresses from simple steatosis to the disease state of inflammation and fibrosis. Previous studies suggest that apoptosis and necroptosis may contribute to the pathogenesis of NASH, based on several murine models. However, the mechanisms underlying the transition of simple steatosis to steatohepatitis remain unclear, because it is difficult to identify when and where such cell deaths begin to occur in the pathophysiological process of NASH. In the present study, our aim is to investigate which type of cell death plays a role as the trigger for initiating inflammation in fatty liver. By establishing a simple method of discriminating between apoptosis and necrosis in the liver, we found that necrosis occurred prior to apoptosis at the onset of steatohepatitis in the choline-deficient, ethionine-supplemented (CDE) diet model. To further investigate what type of necrosis is involved in the initial necrotic cell death, we examined the effect of necroptosis and ferroptosis inhibition by administering inhibitors to wild-type mice in the CDE diet model. In addition, necroptosis was evaluated using mixed lineage kinase domain-like protein (MLKL) knockout mice, which is lacking in a terminal executor of necroptosis. Consequently, necroptosis inhibition failed to block the onset of necrotic cell death, while ferroptosis inhibition protected hepatocytes from necrotic death almost completely, and suppressed the subsequent infiltration of immune cells and inflammatory reaction. Furthermore, the amount of oxidized phosphatidylethanolamine, which is involved in ferroptosis pathway, was increased in the liver sample of the CDE diet-fed mice. These findings suggest that hepatic ferroptosis plays an important role as the trigger for initiating inflammation in steatohepatitis and may be a therapeutic target for preventing the onset of steatohepatitis.

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center