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.