3.2 Necroptosis in Liver fibrosis
As a basic biological process, cell demise controls the results and long term sequelae in nearly whole liver disease. Acute hepatic failure is featured by mass mortality of hepatic parenchymal cell, and is generally followed by restitution previous condition. However, cell demise in chronic liver disease (CLD) usually happens at lesser degree but it can induce to long-term transforms in tissue architecture and function, leading to chronic hepatic cell renewal, immunocyte enlistment and activation of hepatic stellate cells (HSCs), giving rise to the progress of hepatic fibrosis, liver cirrhosis and liver cancer. Animal experiment indicate that RIPK3 has lower expression in heathy mice liver compared with other organs (Luedde et al. 2014), but has higher expression in cells that are activated to go through necroptosis (Vucur et al. 2013). RIPK3-deficient mouse reveal descended hepatocyte death after acetaminophen poisoning and longtime ethyl alcohol feeding, indicating an participation of necroptosis in liver injury (Ramachandran et al. 2013). Nonalcoholic steatohepatitis (NASH) characterized by hepatocyte steatosis, inflammation, hepatocyte cell death and often fibrosis (Diehl and Day 2017). Evidences have shown that the effect of apoptosis as the unique cell demise form in NASH seems to be overrated, and necroptosis might be the fundamental factor in the process of NASH. It is reported that Nec-1s, another necroptosis inhibitor, can reverse the high expression of P-MLKL, MLKL, RIPK3 and P-RIPK3 protein levels in the livers of Sod1KO mice (Mice deficient in the antioxidant enzyme Cu/Zn-superoxide dismutase) which indicated that inflammation induced by necroptosis conduces to fibrosis in a mice model of increased oxidative stress and accelerated aging (Mohammed et al. 2021). Evidences show that inflammation and hepatic fibrosis by a RIPK3 mediates signal pathway restrained by Caspase-8 in human NASH and a steatohepatitis mice model. Further experiment study manifested that the activation of JNK mediated by RIPK3 contribute to the liberate of pro-inflammatory factors such as MCP-1, and appealing macrophages to the injured liver and further expansion RIPK3-mediate signal pathway, cell death, and hepatic fibrosis. According to the above results, there is enough reason to believe that RIPK3-dependent necroptosis play an important role in hepatic fibrosis which induced by NASH (Gautheron et al. 2014). In addition, instead of improvement effect, suppression of caspase 8 significantly increased liver injury and fibrosis in the ( methionine- and choline-deficient) MCD diet-induced mouse model(Gautheron et al. 2014), showing that coincide with its assumption role in development-a dominating character of caspase 8 in NASH is to prevent excessive -activation of necroptosis. By comparison, suppress RIPK3 in the MCD NASH model can improve liver injury and fibrosis (Gautheron et al. 2014), which indicating that necroptosis, rather than apoptosis, is the driving force of liver injury and fibrosis in this well-established mouse model of NASH. Besides with these discoveries in mice, a Western blot assay of frozen hepatic tissue from a group of patients with biopsy-proven NASH indicated that these patients had lower levels of intrahepatic caspase 3 cleavages but higher hepatic RIPK3 expression than healthy persons (Gautheron et al. 2014), showing a convert from apoptosis to necroptosis in the livers of these patients. Moreover, researchers found that RIPK3 knockout mice were also protected in a model of alcoholic hepatic injury (Roychowdhury et al. 2013), further demonstrated a remarkable function of necroptosis as a metabolic cell death pathway in the hepatic tissue. These studies illustrated that besides apoptosis, necroptosis is a critical siginal pathway in human metabolic liver disease. Targeting necroptosis may provide a specific treatment method for human metabolic liver disease. However, further clinical studies are needed to evaluate which parts of the pathway can be used as targets for the treatment of chronic liver disease.