The Anti-hepatic Injury Activity Of Recombinant Human Hepassocin

Liver is an important organ which plays multiple biological functions in human body, including metabolism, detoxification, immunization and coagulation.Meanwhile, liver is also sensitive to various stimulations, which will induce liver dysfunction, acute liver failure, and even death. Hepatopathy is always a public health problem in our country and acute liver injury?ALI? or acute liver failure?ALF?induced by virus or drug is characterized with rapid development, poor prognosis and high mortality. There is still lacking effective treatments for acute liver injury and acute liver failure in clinical. Therefore, it is challenged and urgent to investigate effective drugs to prevent liver cells necrosis and promote liver regeneration.Hepassocin?HPS? is identified as a mitogenic factor and specifically expressed in the liver. Besides, HPS has been reported to regulate normal liver cells proliferation through autocrine loop, and HPS can decrease alanine aminotransferase?ALT? and aspartate aminotransferase?AST? levels to protect liver function in CCl₄- or D-gal Ninduced liver injury rats model.In this study, we aimed to evaluate the preclinical pharmacodynamics and activity of HPS in vivo and vitro based on the characteristic. Firstly, the doze of HPS was determined by using CCl₄-induced liver injury mice model and then the protect effects of HPS on liver injury were evaluated. The mice/rats were intraperitoneaneally injected with HPS at 12 h before injury as well as 24 h,48h and 72 h after injury induced by various factors. As a result, HPS enhanced the survival rate of mice with liver injury and decreased the levels of ALT and AST. Meanwhile, HPS could improve liver tissue necrosis and reduce hepatocytes apoptosis according to the results of HE stain and terminal deoxynucleotidyl transferase-mediated d UTP nick-end lablling?TUNEL? assays, respectively. In addition, HPS enhanced liver cells proliferation with a high rate of PCNA-positive cells in chemically induced liver injured mice.Then the activity of HPS was also estimated in D-galactosamine and lipopolysaccharide?LPS? induced liver injured mice. Consistently, HPS could increase the survival rate of liver injured mice, decrease the levels of ALT and AST as well as improve the necrosis statue of liver tissue. Real time PCR was utilized to detect the m RNA levels of apoptosis- and inflammatory- related factors. CBA was also performed to examine the concentrations of inflammatory factors in serum. The results proved that HPS could reduce the m RNA and protein expression levels of apoptosis- and inflammatory- related factors. Furthermore, the protective effects of HPS on hepatic injury were evaluated in CCl₄- and D-gal N- induced liver injured rats and concanavalin A?Con A?-induced liver injured mice model. HPS activated MAPK/ERK signaling pathway in Hep G2 cell and mouse primary hepatocytes and promoted the proliferation of mouse primary hepatocytes in vitro. Our study also indicated that administration of HPS could weaken L02 cell injury induced by CCl₄.In the present study, the relationship between serum HPS level and the degree of liver injury induced by CCl₄ or PHx were investigated. As a result, the mortality rate of mice and the degree of liver injure were increased significantly with CCl₄ dose increasing. The expression level of HPS in serum and liver tissue was also significantly up-regulated and closely related with the degree of liver injury, which was similar in mice after PHx.In conclusion, HPS is closely related to the degree of liver injury and has the protective activity for liver injury. Therefore, HPS may be used as a new molecular marker for liver injury, and developed as a specific and effective drug for the treatment of ALF.