Ron Receptor Signaling Ameliorates Hepatic Fibrosis in a Diet-Induced Nonalcoholic Steatohepatitis Mouse Model

Abstract

Liver fibrosis is commonly observed in the terminal stages of nonalcoholic steatohepatitis (NASH) and with no specific and effective antifibrotic therapies available, this disease is a major global health burden. The MSP/Ron receptor axis has been shown to have anti-inflammatory properties in a number of mouse models, due at least in part, to its ability to limit pro-inflammatory responses in tissue-resident macrophages and hepatocytes. In this study, we established the role of the Ron receptor in steatohepatitis-induced hepatic fibrosis using Ron ligand domain knockout mice on an apolipoprotein E knockout background (DKO). After 18 weeks of high-fat high-cholesterol feeding, loss of Ron activation resulted in exacerbated NASH-associated steatosis which is precedent to hepatocellular injury, inflammation and fibrosis. H nuclear magnetic resonance (NMR)-based metabolomics identified significant changes in serum metabolites that can modulate the intrahepatic lipid pool in hepatic steatosis. Serum from DKO mice had higher concentrations of lipids, VLDL/LDL and pyruvate, whereas glycine levels were reduced. Parallel to the aggravated steatohepatitis, increased accumulation of collagen, inflammatory immune cells and collagen producing-myofibroblasts were seen in the livers of DKO mice. Gene expression profiling revealed that DKO mice exhibited elevated expression of genes encoding Ron receptor ligand MSP, collagens, ECM remodeling proteins and pro-fibrogenic cytokines in the liver. Our results demonstrate the protective effects of Ron receptor activation on NASH-induced hepatic fibrosis.

MSP-RON Pathway: Potential Regulator of Inflammation and Innate Immunity

“…MSP-RON with clinical diseases.SepsisThe survival time of RON knockout mice reduced with increased liver damage in a sepsis mouse model (44) RON antagonizes inflammatory response induced by oxidized low-density lipoproteins and LPS via activating the AMPK signaling pathway (46). Activation of RON improves diet-induced fibrosis in non-alcoholic fatty liver mice, and RON knockout mice exhibit higher levels of inflammatory cell infiltration, collagen, ECM remodeling proteins, and profibrotic cytokine expression(47) Obesity MSP-RON reduces inflammation, increases tissue repair capacity, and induces macrophages to switch to M2 phenotype in mouse obesity model(48); RON knockout resulted in increased serum levels of inflammatory factors in mice with high-fat diet(49) …”

Metabolic Profiling Reveals Aggravated Non-Alcoholic Steatohepatitis in High-Fat High-Cholesterol Diet-Fed Apolipoprotein E-Deficient Mice Lacking Ron Receptor Signaling

“…In DKO mice, livers exhibited higher expression Cyp2e1 , Cyp4a10 , and the antioxidant enzyme catalase ( Figure 3 G). In our previous study, we investigated the effects of diet-induced chronic liver injury on the expression of Ron receptor ligand and mitogenic liver-derived growth factor, MSP [ 36 ]. Extensive liver injury in DKO mice was paralleled by upregulated hepatic MSP mRNA expression [ 36 ].…”

“…In our previous study, we investigated the effects of diet-induced chronic liver injury on the expression of Ron receptor ligand and mitogenic liver-derived growth factor, MSP [ 36 ]. Extensive liver injury in DKO mice was paralleled by upregulated hepatic MSP mRNA expression [ 36 ]. Similarly, this upregulation of MSP (or MST1) expression was also observed in human patients with NASH ( Figure 3 H).…”

“…Previously we have shown that the loss of Ron activity in mice results in elevated serum FFA levels, another marker for AT expansion and dysregulation [ 36 ]. In contrast, pro-lipolytic lipase genes in DKO eWAT were downregulated, which may be due to the inhibitory effects of hyperinsulinemia on adipocyte-specific Atgl and Hsl gene expression [ 48 , 49 , 50 ].…”

“…The HNF4A1/CYP7A1 pathway is also suppressed by cytokines that are produced by Kupffer cells. We have previously shown that the livers of DKO mice exhibit a higher expression of macrophage-specific inflammatory mediators including Il-12b , Tnfα , and Inos [ 9 , 36 ]. The decreased synthesis of bile acids in DKO-derived liver may be in response to the exacerbated inflammatory response induced primarily by classically activated (M1) liver macrophages.…”