Over-expressing the soluble gp130-Fc does not ameliorate methionine and choline deficient diet-induced non alcoholic steatohepatitis in mice

Helene L. Kammoun, Tamara Louise Allen, Darren Colin Henstridge, Michael James Kraakman, Lone Peijs, Stefan Rose-John, Mark Anthony Febbraio

Research output: Contribution to journalArticleResearchpeer-review

3 Citations (Scopus)

Abstract

Non-alcoholic steatohepatitis (NASH) is a liver disease with the potential to lead to cirrhosis and hepatocellular carcinoma. Interleukin-6 (IL-6) has been implicated in the pathogenesis of NASH, with the so-called IL-6 ‘trans-signaling’ cascade being responsible for the proinflammatory actions of this cytokine. We aimed to block IL-6 ‘trans-signaling’, using a transgenic mouse that overexpresses human soluble glycoprotein130 (sgp130Fc Tg mice) fed a commonly used dietary model of inducing NASH (methionine and choline deficient-diet; MCD diet) and hypothesized that markers of NASH would be ameliorated in such mice. Sgp130Fc Tg and littermate control mice were fed a MCD or control diet for 4 weeks. The MCD diet induced many hallmarks of NASH including hepatomegaly, steatosis, and liver inflammation. However, in contrast with other mouse models and, indeed, human NASH, the MCD diet model did not increase the mRNA or protein expression of IL-6. Not surprisingly, therefore, markers of MCD diet-induced NASH were unaffected by sgp130Fc transgenic expression. While the MCD diet model induces many pathophysiological markers of NASH, it does not induce increased IL-6 expression in the liver, a key hallmark of human NASH. We, therefore, caution the use of the MCD diet as a viable mouse model of NASH.

Original languageEnglish
Article numbere0179099
Number of pages13
JournalPLoS ONE
Volume12
Issue number6
DOIs
Publication statusPublished - 20 Jun 2017

Keywords

  • diet
  • mouse models
  • inflammation
  • cholines
  • macrophages
  • methionine
  • fats
  • nutritional deficiencies

Cite this

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title = "Over-expressing the soluble gp130-Fc does not ameliorate methionine and choline deficient diet-induced non alcoholic steatohepatitis in mice",
abstract = "Non-alcoholic steatohepatitis (NASH) is a liver disease with the potential to lead to cirrhosis and hepatocellular carcinoma. Interleukin-6 (IL-6) has been implicated in the pathogenesis of NASH, with the so-called IL-6 ‘trans-signaling’ cascade being responsible for the proinflammatory actions of this cytokine. We aimed to block IL-6 ‘trans-signaling’, using a transgenic mouse that overexpresses human soluble glycoprotein130 (sgp130Fc Tg mice) fed a commonly used dietary model of inducing NASH (methionine and choline deficient-diet; MCD diet) and hypothesized that markers of NASH would be ameliorated in such mice. Sgp130Fc Tg and littermate control mice were fed a MCD or control diet for 4 weeks. The MCD diet induced many hallmarks of NASH including hepatomegaly, steatosis, and liver inflammation. However, in contrast with other mouse models and, indeed, human NASH, the MCD diet model did not increase the mRNA or protein expression of IL-6. Not surprisingly, therefore, markers of MCD diet-induced NASH were unaffected by sgp130Fc transgenic expression. While the MCD diet model induces many pathophysiological markers of NASH, it does not induce increased IL-6 expression in the liver, a key hallmark of human NASH. We, therefore, caution the use of the MCD diet as a viable mouse model of NASH.",
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author = "Kammoun, {Helene L.} and Allen, {Tamara Louise} and Henstridge, {Darren Colin} and Kraakman, {Michael James} and Lone Peijs and Stefan Rose-John and Febbraio, {Mark Anthony}",
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Over-expressing the soluble gp130-Fc does not ameliorate methionine and choline deficient diet-induced non alcoholic steatohepatitis in mice. / Kammoun, Helene L.; Allen, Tamara Louise; Henstridge, Darren Colin; Kraakman, Michael James; Peijs, Lone; Rose-John, Stefan; Febbraio, Mark Anthony.

In: PLoS ONE, Vol. 12, No. 6, e0179099, 20.06.2017.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Over-expressing the soluble gp130-Fc does not ameliorate methionine and choline deficient diet-induced non alcoholic steatohepatitis in mice

AU - Kammoun, Helene L.

AU - Allen, Tamara Louise

AU - Henstridge, Darren Colin

AU - Kraakman, Michael James

AU - Peijs, Lone

AU - Rose-John, Stefan

AU - Febbraio, Mark Anthony

PY - 2017/6/20

Y1 - 2017/6/20

N2 - Non-alcoholic steatohepatitis (NASH) is a liver disease with the potential to lead to cirrhosis and hepatocellular carcinoma. Interleukin-6 (IL-6) has been implicated in the pathogenesis of NASH, with the so-called IL-6 ‘trans-signaling’ cascade being responsible for the proinflammatory actions of this cytokine. We aimed to block IL-6 ‘trans-signaling’, using a transgenic mouse that overexpresses human soluble glycoprotein130 (sgp130Fc Tg mice) fed a commonly used dietary model of inducing NASH (methionine and choline deficient-diet; MCD diet) and hypothesized that markers of NASH would be ameliorated in such mice. Sgp130Fc Tg and littermate control mice were fed a MCD or control diet for 4 weeks. The MCD diet induced many hallmarks of NASH including hepatomegaly, steatosis, and liver inflammation. However, in contrast with other mouse models and, indeed, human NASH, the MCD diet model did not increase the mRNA or protein expression of IL-6. Not surprisingly, therefore, markers of MCD diet-induced NASH were unaffected by sgp130Fc transgenic expression. While the MCD diet model induces many pathophysiological markers of NASH, it does not induce increased IL-6 expression in the liver, a key hallmark of human NASH. We, therefore, caution the use of the MCD diet as a viable mouse model of NASH.

AB - Non-alcoholic steatohepatitis (NASH) is a liver disease with the potential to lead to cirrhosis and hepatocellular carcinoma. Interleukin-6 (IL-6) has been implicated in the pathogenesis of NASH, with the so-called IL-6 ‘trans-signaling’ cascade being responsible for the proinflammatory actions of this cytokine. We aimed to block IL-6 ‘trans-signaling’, using a transgenic mouse that overexpresses human soluble glycoprotein130 (sgp130Fc Tg mice) fed a commonly used dietary model of inducing NASH (methionine and choline deficient-diet; MCD diet) and hypothesized that markers of NASH would be ameliorated in such mice. Sgp130Fc Tg and littermate control mice were fed a MCD or control diet for 4 weeks. The MCD diet induced many hallmarks of NASH including hepatomegaly, steatosis, and liver inflammation. However, in contrast with other mouse models and, indeed, human NASH, the MCD diet model did not increase the mRNA or protein expression of IL-6. Not surprisingly, therefore, markers of MCD diet-induced NASH were unaffected by sgp130Fc transgenic expression. While the MCD diet model induces many pathophysiological markers of NASH, it does not induce increased IL-6 expression in the liver, a key hallmark of human NASH. We, therefore, caution the use of the MCD diet as a viable mouse model of NASH.

KW - diet

KW - mouse models

KW - inflammation

KW - cholines

KW - macrophages

KW - methionine

KW - fats

KW - nutritional deficiencies

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M3 - Article

VL - 12

JO - PLoS ONE

JF - PLoS ONE

SN - 1932-6203

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ER -