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.
Highlights
Cholestasis is a chronic, progressive cholangiopathies with a broad etiology, characterized by hepatocellular injury, bile duct proliferation, and fibrosis, resulting in liver failure [1]
Given that oxidative stress caused by extremely high concentrations of bile acids (BAs) and the infiltration of a large number of inflammatory cells have been detected during cholestasis, many studies have focused on the role of oxidative stress in cholestatic hepatocellular injury and fibrosis, considering it an important contributor to the pathological process of this disease [4,5]
We reported that Peroxiredoxin 4 (PRDX4) can protect against diabetes mellitus, atherosclerosis, insulin resistance, and nonalcoholic fatty liver disease by suppressing oxidative damage, inflammatory cytokines, and apoptotic activities, at least in part [23,24,25,26,27]
Summary
Cholestasis is a chronic, progressive cholangiopathies with a broad etiology, characterized by hepatocellular injury, bile duct proliferation, and fibrosis, resulting in liver failure [1]. Given that oxidative stress caused by extremely high concentrations of bile acids (BAs) and the infiltration of a large number of inflammatory cells have been detected during cholestasis, many studies have focused on the role of oxidative stress in cholestatic hepatocellular injury and fibrosis, considering it an important contributor to the pathological process of this disease [4,5]. N-acetylcysteine (NAC) decreased fibrosis in these rats and prevented the increase in γ-glutamyl transpeptidase (GGT), alkaline phosphatase (ALP), and total bilirubin levels [18] Similar to these results, after treatment with polyphenols, which are chemicals extracted from plants, a reduction in liver injury and fibrosis was observed during cholestasis [19]. 5 fields in WT mice versus 100.0 ± 8.38 per 5 fields in Tg mice; p < 0.001) (necrotic: 170.5 ± 5.7 per f5iefiledlsdisninWWTTmmiciecevevresrusus s10160.66.6±±4.54.p5epre5r f5iefiledlsdisninTgTgmmiciec;ep; p<
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