Protective Effects of Peroxiredoxin 4 (PRDX4) on Cholestatic Liver Injury

Abstract

Accumulating evidence indicates that oxidative stress plays a critical role in initiating the progression of inflammatory and fibrotic liver diseases, including cholestatic hepatitis. Peroxiredoxin 4 (PRDX4) is a secretory antioxidase that protects against oxidative damage by scavenging reactive oxygen species (ROS) in both the intracellular compartments and extracellular space. In this study, we examined the in vivo net effects of PRDX4 overexpression in a murine model of cholestasis. To induce cholestatic liver injury, we subjected C57BL/6J wild-type (WT) or human PRDX4 (hPRDX4) transgenic (Tg) mice to sham or bile duct ligation (BDL) surgery for seven days. Our results showed that the liver necrosis area was significantly suppressed in Tg BDL mice with a reduction in the severity of liver injuries. Furthermore, PRDX4 overexpression markedly reduced local and systemic oxidative stress generated by BDL. In addition, suppression of inflammatory cell infiltration, reduced proliferation of hepatocytes and intrahepatic bile ducts, and less fibrosis were also found in the liver of Tg BDL mice, along with a reduced mortality rate after BDL surgery. Interestingly, the composition of the hepatic bile acids (BAs) was more beneficial for Tg BDL mice than for WT BDL mice, suggesting that PRDX4 overexpression may affect BA metabolism during cholestasis. These features indicate that PRDX4 plays an important role in protecting against liver injury following BDL and might be a promising therapeutic modality for cholestatic diseases.

Oxidation of peroxiredoxin-4 induces oligomerization and promotes interaction with proteins governing protein folding and endoplasmic reticulum stress

“…PRDX4 is emerging as an important therapeutic target in numerous diseases, such as metabolic syndromes ( 33 ), idiopathic pulmonary fibrosis (IPF) ( 34 ), liver injury ( 35 ), amyloid-beta aggregate-induced neuronal apoptosis ( 36 ). PRDX4 is a complex protein as it can form multiple oligomeric structures based on its oxidation status, can shift from having peroxidase function to acting as a chaperone, and is localized either in the ER or extracellularly.…”

Acupuncture on ST36, CV4 and KI1 Suppresses the Progression of Methionine- and Choline-Deficient Diet-Induced Nonalcoholic Fatty Liver Disease in Mice

“…To evaluate the severity of NAFLD, we determined the intensity of inflammation (inflammatory score) using an anti-mouse Mac-2 monoclonal antibody (1:1000; Cedarlane Laboratories Ltd., Burlington, Ontario, Canada). As described previously [44], we counted the number of positive macrophages in 10 randomly selected fields per liver section (original magnification: ×200). The NAFLD liver tissues were then classified into four (inflammation score) grades, as follows: no inflammation (score = 0); <10 inflammatory foci, each consisting of >5 inflammatory cells (score = 1); ≥10 inflammatory foci (score = 2) or uncountable diffuse or fused inflammatory foci (score = 3).…”

“…We used the HistoMouse™-Plus Kit (Invitrogen Corporation, Camarillo, CA, USA) to block endogenous IgG and then stained tissue with a monoclonal mouse anti-human α-SMA antibody (1:1000; Dako Cytomation, Carpenteria, CA, USA.). The number of activated stellate cells was then counted in 10 randomly selected fields per section (original magnification: ×200), as described previously [44]. To determine the ROS/oxidative stress or expression in hepatocytes after acupuncture, we used an 8-OHdG monoclonal antibody (1:200; Japan Institute for the Control of Aging, Fukuroi, Japan) and quantified the number of hepatocytes positive for either antibodies in 10 randomly selected fields per section (original magnification: ×200), as previously described.…”

Regulation of Antioxidant Defenses, DNA Damage Repair, the Immune Response, and Neuroprotection During Hibernation in the Thirteen-Lined Ground Squirrel

“…PRDX4 is another crucial antioxidant enzyme that has been reported to be significantly cytoprotective against the initiation and development of various metabolic syndromes. It has been reported to protect against diabetes mellitus, atherosclerosis, insulin resistance, nonalcoholic fatty liver disease, inflammatory cytokines and certain apoptotic activities [116]. PRDX4 has been shown to regulate apoptosis whereby PRDX suppression or knockdown increases apoptosis.…”

“…Therefore, it is possible that PRDX4 may play an important role in this regulation and offers some level of cytoprotection during hibernation. PRDX4 has also been shown to reduce the number of 8-OH-dG-positive cells in cholestatic liver injury (8-OH-dG being a marker of DNA damage) [116]. It is proposed that PRDX4 reduces extracellular oxidant stress and mitochondrial dysfunction by suppressing the release of inflammatory cytokines and neutrophil infiltration.…”