Interventional Potential of Recombinant Feline Hepatocyte Growth Factor in a Mouse Model of Non-alcoholic Steatohepatitis

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.

The endothelial dysfunction blocker CU06-1004 ameliorates choline-deficient L-amino acid diet-induced non-alcoholic steatohepatitis in mice

“…The choline-deficient, L-amino acid-defined (CDAA) diet-induced mouse model of NASH is commonly used to study aggressive NASH. Mice on the CDAA diet reliably develop hepatic steatosis, inflammation, liver fibrosis, and insulin resistance [ 18 ]. Indeed, mice fed a CDAA diet for 3 weeks typically have increased liver weight, hepatic triglyceride, inflammation, and mild fibrosis [ 19 ].…”

“…Indeed, mice fed a CDAA diet for 3 weeks typically have increased liver weight, hepatic triglyceride, inflammation, and mild fibrosis [ 19 ]. In addition, CDAA diet induced mice for 6 weeks were developed increased fatty liver with fibrosis score than CDAA diet induced mice for 3 weeks [ 18 , 20 ]. In this study, we investigated the effects of oral treatment with CU06-1004 on hepatic steatosis, inflammation, fibrosis, and LSEC capillarization using a CDAA-induced mouse model of NASH for 3- or 6-weeks.…”

Exploring the Gamut of Receptor Tyrosine Kinases for Their Promise in the Management of Non-Alcoholic Fatty Liver Disease

“…HGF regulates farnesoid-X receptor (FXR) pathways and controls peroxisome proliferator activated receptor-α (PPAR-α), which facilitates fatty acid oxidation. [ 56 , 57 , 58 ]. The effect of HGF on β-oxidation was corroborated by Kroy D. et al (2014) using cMET knockout mice fed on a Methionine/Choline Deficient (MCD) diet.…”

“…Among these, the PI3K/AKT pathway is found to be regulated by various RTK, such as EGFR, AXL, and VEGFR [ 58 , 60 , 69 , 70 , 90 , 92 , 93 ]. The activation of the PI3K/AKT pathway has already been reported in NAFLD patients.…”

Liver Regeneration: Different Sub-Populations of Parenchymal Cells at Play Choreographed by an Injury-Specific Microenvironment

“…Importantly, when in the DR niche, they secrete Wnt3a which activates the Wnt/β-catenin pathway, the activation of which is related to the DR hepatocyte specification [101]. Another interesting approach could be the administration of growth factors, such as HGF, an important mitogen for angiogenesis and hepatocytic proliferation [114,115]. As it secretes growth factors as well as forming new vasculature necessary to promote and orient hepatocyte proliferation, the endothelium represents an attractive candidate for manipulation, via angiogenic agents for example [116].…”