Recombinant Human HPS Protects Mice and Nonhuman Primates from Acute Liver Injury.

Yang Yang,Hui Chen,Lihou Dong,Yue Wan,Miao Yu,Chutse Wu,Huali Zhai,Taoyun Liu,Xiaofang Wang,Guifang Dou

doi:10.3390/ijms222312886

Abstract

Acute liver injury shares a common feature of hepatocytes death, immune system disorders, and cellular stress. Hepassocin (HPS) is a hepatokine that has ability to promote hepatocytes proliferation and to protect rats from D-galactose (D-Gal)- or carbon tetrachloride (CCl4)-induced liver injury by stimulating hepatocytes proliferation and preventing the high mortality rate, hepatocyte death, and hepatic inflammation. In this paper, we generated a pharmaceutical-grade recombinant human HPS using mammalian cells expression system and evaluated the effects of HPS administration on the pathogenesis of acute liver injury in monkey and mice. In the model mice of D-galactosamine (D-GalN) plus lipopolysaccharide (LPS)-induced liver injury, HPS treatment significantly reduced hepatocyte death and inflammation response, and consequently attenuated the development of acute liver failure. In the model monkey of D-GalN-induced liver injury, HPS administration promoted hepatocytes proliferation, prevented hepatocyte apoptosis and oxidation stress, and resulted in amelioration of liver injury. Furthermore, the primary pharmacokinetic study showed natural HPS possesses favorable pharmacokinetics; the acute toxicity study indicated no significant changes in behavioral, clinical, or histopathological parameters of HPS-treated mice, implying the clinical potential of HPS. Our results suggest that exogenous HPS has protective effects on acute liver injury in both mice and monkeys. HPS or HPS analogues and mimetics may provide novel drugs for the treatment of acute liver injury.

Highlights

Liver injury is a common disease that seriously threatens the life and health of patients
Acute liver failure (ALF) is characterized by a fast-evolving hepatic dysfunction associated with massive hepatocyte apoptosis, hemorrhagic necrosis, inflammation, coagulopathy, sepsis, and multi-organ failure, which causes over 60% mortality if liver transplantation is not provided [1]
Plasma HPS concentrations were elevated in patients with nonalcoholic fatty liver disease (NAFLD) [11], diabetes [12], and hyperglycemic crisis [13], while decreased significantly in subjects with hyperglycemic crisis after standard treatment accompanied by improved hepatic functions [13]

Summary

Introduction

Liver injury is a common disease that seriously threatens the life and health of patients. Despite different causes of ALF, hepatocytes death, immune system disorders, and mitochondrial dysfunction are certain pathological features [2,3]. Strategies targeting these pathogenic processes are efficacious therapeutic approaches for the treatment of human liver diseases. Bone marrow-derived mesenchymal stem cells (BMSCs) have been demonstrated to exert extensive therapeutic effects on acute liver injury, such as inhibition of hepatocyte apoptosis and acceleration of liver regeneration [15]. Mice lacking HPS accelerated the development of HCC following tumor induction [18] These data indicated that HPS might possess growth suppression activity in HCC. Further studies to elucidate the pharmacological roles of HPS in detail would provide important insights for the use of HPS as a therapeutic drug to treat liver diseases

Methods

Results

Conclusion