Abstract
Fibrogenesis is induced by repeated injury to the liver and reactive regeneration and leads eventually to liver cirrhosis. Pigment epithelium derived factor (PEDF) has been shown to prevent liver fibrosis induced by carbon tetrachloride (CCl4). A 44 amino acid domain of PEDF (44-mer) was found to have a protective effect against various insults to several cell types. In this study, we investigated the capability of synthetic 44-mer to protect against liver injury in mice and in primary cultured hepatocytes. Acute liver injury, induced by CCl4, was evident from histological changes, such as cell necrosis, inflammation and apoptosis, and a concomitant reduction of glutathione (GSH) and GSH redox enzyme activities in the liver. Intraperitoneal injection of the 44-mer into CCl4-treated mice abolished the induction of AST and ALT and markedly reduced histological signs of liver injury. The 44-mer treatment can reduce hepatic oxidative stress as evident from lower levels of lipid hydroperoxide, and higher levels of GSH. CCl4 caused a reduction of Bcl-xL, PEDF and PPARγ, which was markedly restored by the 44-mer treatment. Consequently, the 44-mer suppressed liver fibrosis induced by repeated CCl4 injury. Furthermore, our observations in primary culture of rat hepatocytes showed that PEDF and the 44-mer protected primary rat hepatocytes against apoptosis induced by serum deprivation and TGF-β1. PEDF/44-mer induced cell protective STAT3 phosphorylation. Pharmacological STAT3 inhibition prevented the antiapoptotic action of PEDF/44-mer. Among several PEDF receptor candidates that may be responsible for hepatocyte protection, we demonstrated that PNPLA2 was essential for PEDF/44-mer-mediated STAT3 phosphorylation and antiapoptotic activity by using siRNA to selectively knockdown PNPLA2. In conclusion, the PEDF 44-mer protects hepatocytes from single and repeated CCl4 injury. This protective effect may stem from strengthening the counter oxidative stress capacity and induction of hepatoprotective factors.
Highlights
With its major function of detoxification, the liver is constantly exposed to toxic chemicals from the environment, food and medicines
The mechanism through which Pigment epithelium derived factor (PEDF) protects against liver fibrosis is being elucidated gradually
A 34-mer peptide derived from PEDF was found to alleviate CCl4-induced liver fibrosis by suppressing the fibrogenic responses of rat hepatic stellate cells (HSCs) and through inhibiting platelet-derived growth factor (PDGF)-mediated mitotic signaling [9]
Summary
With its major function of detoxification, the liver is constantly exposed to toxic chemicals from the environment, food and medicines. Liver cells may be damaged by ischemia-reperfusion injury during surgery. Under these circumstances, oxidative stress may lead to liver cell death [1,2,3]. CCl4 is an industrial solvent and known hepatotoxin which is metabolically activated by the hepatic microsomal cytochrome p450. This renders it capable of inducing lipid peroxidation of unsaturated fatty acid membranes and organelle membranes, eventually leading to liver cell necrosis. CCl4-induced liver injury is used widely in experimental approaches to identify agents that can enhance the capacity of liver cells to handle oxidative stress and to protect these cells [5]
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