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

Joselyn Allen, Jingtao Zhang, Michael D. Quickel, Mary J. Kennett, Andrew David Patterson, Pamela Hankey Giblin

Research output: Contribution to journalArticle

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. 1H 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.

Original languageEnglish (US)
Pages (from-to)3268-3280
Number of pages13
JournalJournal of Proteome Research
Volume17
Issue number9
DOIs
StatePublished - Sep 7 2018

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Nutrition
Liver
Fibrosis
Collagen
Diet
Chemical activation
Ligands
Military electronic countermeasures
Lipids
Fatty Liver
Gene encoding
Macrophages
Apolipoproteins E
Metabolites
Pyruvic Acid
Gene expression
Glycine
Anti-Inflammatory Agents
Fats
Cholesterol

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Chemistry(all)

Cite this

@article{9d11b77b6e1b4c46b68e8ff94106e249,
title = "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. 1H 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.",
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Ron Receptor Signaling Ameliorates Hepatic Fibrosis in a Diet-Induced Nonalcoholic Steatohepatitis Mouse Model. / Allen, Joselyn; Zhang, Jingtao; Quickel, Michael D.; Kennett, Mary J.; Patterson, Andrew David; Giblin, Pamela Hankey.

In: Journal of Proteome Research, Vol. 17, No. 9, 07.09.2018, p. 3268-3280.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Ron Receptor Signaling Ameliorates Hepatic Fibrosis in a Diet-Induced Nonalcoholic Steatohepatitis Mouse Model

AU - Allen, Joselyn

AU - Zhang, Jingtao

AU - Quickel, Michael D.

AU - Kennett, Mary J.

AU - Patterson, Andrew David

AU - Giblin, Pamela Hankey

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