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.
Highlights
Nonalcoholic fatty liver disease (NAFLD), a kind of lifestyle disease ranging from simple steatosis to steatohepatitis, is the most prevalent liver disease in the world
To characterize the pathological features of this model, we first investigated the status of Nonalcoholic steatohepatitis (NASH) symptoms, i.e. fat accumulation, hepatocyte cell death, infiltration of immune cells, and fibrosis after the CDE diet feeding
The Oil Red O staining revealed that the increased fat deposition in hepatocytes was evident 1 day after CDE diet feeding and that drastic accumulation of lipid droplets was observed by 2 days after feeding (Fig. 1a)
Summary
Nonalcoholic fatty liver disease (NAFLD), a kind of lifestyle disease ranging from simple steatosis to steatohepatitis, is the most prevalent liver disease in the world. The type of cell death involved in the onset of NASH has not been investigated, as it is quite difficult to specify the timing of cell death occurring after simple steatosis in long-term disease models. We have established a method for distinguishing apoptosis and necrosis in the liver and have evaluated the type of hepatocyte cell death by using cell death-related inhibitory agents and knockout mice in this model. From these experiments, we discovered the role of ferroptosis as the initial cell death that triggers steatohepatitis
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