Abstract

Background and Aims: Hepatocyte growth factor (HGF) is a multifunctional pleiotropic protein involved in tissue regeneration, protection, angiogenesis, anti-inflammatory and anti-fibrotic responses, and tumorigenesis, through binding to its receptor MET. Recombinant HGF protein has been shown to mitigate various liver disease models, such as alcohol-induced liver injury, hepatic ischemia-reperfusion injury, and fibrosis. This study aimed to investigate the anti-inflammatory, anti-fibrotic, and anti-lipogenic effects of exogenous administration of feline HGF on a non-alcoholic steatohepatitis (NASH) mouse model.Methods: Wild-type C57BL/6 mice were fed a choline-deficient amino acid defined (CDAA) diet for 3 weeks to create the mouse model of NASH, which displays hepatic steatosis, inflammation, injury, and very mild fibrosis. One mg/kg of recombinant feline HGF was administered intravenously daily in the last 7 days of the total 3 weeks of CDAA diet feeding. Then, hepatic steatosis, inflammation, injury, and fibrogenic gene expression was examined.Results: After 3 weeks of a CDAA diet-feeding, the vehicle-treated mice exhibited evident deposition of lipid droplets in hepatocytes, inflammatory cell infiltration, and hepatocyte ballooning along with increased serum ALT levels whereas recombinant HGF-treated mice showed reduced hepatic steatosis, inflammation, and ballooned hepatocytes with a reduction of serum ALT levels. Recombinant HGF administration promoted hepatocyte proliferation. Increased hepatic lipid accumulation was accompanied by elevated expression of lipogenesis genes Fasn and Dgat1 in vehicle-treated mice. In HGF-treated mice, these genes were reduced with a decrease of lipid accumulation in the liver. Consistent with the anti-inflammatory property of HGF, augmented macrophage infiltration and upregulation of chemokines, Cxcl1, Ccl2, and Ccl5 in the CDAA diet fed mice, were suppressed by the addition of the HGF treatment. Finally, we examined the fibrotic response. The vehicle-treated mice had mild fibrosis with upregulation of Col1a1, Acta2, Timp1, Tgfb1, and Serpine1 expression. Recombinant HGF treatment significantly suppressed fibrogenic gene expression and collagen deposition in the liver.Conclusion: Recombinant feline HGF treatment suppressed the progression of NASH in a CDAA diet feeding mouse model.This suggests that recombinant HGF protein has therapeutic potential for NASH.

Highlights

  • Non-alcoholic fatty liver disease (NAFLD) is a hepatic manifestation of metabolic syndrome, which is characterized by excessive accumulation of fat content in hepatocytes

  • Three weeks of choline-deficient amino acid-defined (CDAA) diet feeding showed an evident accumulation of lipid droplets in hepatocytes, inflammatory cell infiltration, ballooned hepatocytes, and mild fibrosis in the vehicle-treated mice compared to choline-supplemented L-amino aciddefined diet (CSAA) diet feeding

  • The recombinant Hepatocyte growth factor (HGF) treatment significantly suppressed the development of inflammation, hepatocyte ballooning, and fibrosis induced by CDAA diet feeding (Figures 1A,B)

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Summary

Introduction

Non-alcoholic fatty liver disease (NAFLD) is a hepatic manifestation of metabolic syndrome, which is characterized by excessive accumulation of fat content in hepatocytes. NAFLD encompasses two clinicopathological entities, simple steatosis and non-alcoholic steatohepatitis (NASH). NASH is histologically characterized by hepatic steatosis along with inflammatory cell infiltration, ballooned hepatocytes, and pericellular, “chicken wire,” fibrosis [1,2,3,4]. NASH-mediated cirrhosis is the second leading cause of liver transplantation, and it is predicted that this disease will be the leading cause of liver transplantation within the 10 years [5]. Recombinant HGF protein has been shown to mitigate various liver disease models, such as alcohol-induced liver injury, hepatic ischemia-reperfusion injury, and fibrosis. This study aimed to investigate the anti-inflammatory, anti-fibrotic, and anti-lipogenic effects of exogenous administration of feline HGF on a non-alcoholic steatohepatitis (NASH) mouse model

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