Steatohepatitis/Metabolic Liver Disease

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Increased tumor necrosis factor α–converting enzyme activity induces insulin resistance and hepatosteatosis in mice†

  1. Loredana Fiorentino1,‡,
  2. Alessia Vivanti1,‡,
  3. Michele Cavalera1,
  4. Valeria Marzano1,2,
  5. Maurizio Ronci1,2,
  6. Marta Fabrizi1,
  7. Stefano Menini3,
  8. Giuseppe Pugliese3,
  9. Rossella Menghini1,
  10. Rama Khokha4,
  11. Renato Lauro1,
  12. Andrea Urbani1,2,
  13. Massimo Federici1,§,*

Article first published online: 25 AUG 2009

DOI: 10.1002/hep.23250

Issue

Hepatology

Hepatology

Volume 51, Issue 1, pages 103–110, January 2010

Additional Information

How to Cite

Fiorentino, L., Vivanti, A., Cavalera, M., Marzano, V., Ronci, M., Fabrizi, M., Menini, S., Pugliese, G., Menghini, R., Khokha, R., Lauro, R., Urbani, A. and Federici, M. (2010), Increased tumor necrosis factor α–converting enzyme activity induces insulin resistance and hepatosteatosis in mice. Hepatology, 51: 103–110. doi: 10.1002/hep.23250

Author Information

  1. 1

    Department of Internal Medicine, University of Rome Tor Vergata, Rome, Italy

  2. 2

    S. Lucia Research Institute, Rome, Italy

  3. 3

    Department of Clinical Sciences, Sapienza University of Rome, Rome, Italy

  4. 4

    Ontario Cancer Institute, University of Toronto, Toronto, Ontario, Canada

  1. ‡

    These authors contributed equally to this work.

  2. §

    fax: (39)-0672596890.

*Department of Internal Medicine, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy

  1. †

    Potential conflict of interest: Nothing to report.

  2. ‡

    These authors contributed equally to this work.

  3. §

    fax: (39)-0672596890.

Publication History

  1. Issue published online: 23 DEC 2009
  2. Article first published online: 25 AUG 2009
  3. Accepted manuscript online: 25 AUG 2009 12:00AM EST
  4. Manuscript Accepted: 12 AUG 2009
  5. Manuscript Received: 1 APR 2009

Funded by

  • Telethon. Grant Number: GGP-08065
  • Juvenile Diabetes Research Foundation. Grant Number: Research Grant 1-2007-665
  • Società Italiana di Diabetologia (Italian Society of Diabetology). Grant Number: Research Grant 2007
  • Italian Ministry of University. Grant Number: PRIN 2006/2008
  • Ministry of Health Research Grants
  • Fondazione Roma

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Abstract

Tumor necrosis factor α–converting enzyme (TACE, also known as ADAM17) was recently involved in the pathogenesis of insulin resistance. We observed that TACE activity was significantly higher in livers of mice fed a high-fat diet (HFD) for 1 month, and this activity was increased in liver > white adipose tissue > muscle after 5 months compared with chow control. In mouse hepatocytes, C2C12 myocytes, and 3T3F442A adipocytes, TACE activity was triggered by palmitic acid, lipolysaccharide, high glucose, and high insulin. TACE overexpression significantly impaired insulin-dependent phosphorylation of AKT, GSK3, and FoxO1 in mouse hepatocytes. To test the role of TACE activation in vivo, we used tissue inhibitor of metalloproteinase 3 (Timp3) null mice, because Timp3 is the specific inhibitor of TACE and Timp3−/− mice have higher TACE activity compared with wild-type (WT) mice. Timp3−/− mice fed a HFD for 5 months are glucose-intolerant and insulin-resistant; they showed macrovesicular steatosis and ballooning degeneration compared with WT mice, which presented only microvesicular steatosis. Shotgun proteomics analysis revealed that Timp3−/− liver showed a significant differential expression of 38 proteins, including lower levels of adenosine kinase, methionine adenosysltransferase I/III, and glycine N-methyltransferase and higher levels of liver fatty acid-binding protein 1. These changes in protein levels were also observed in hepatocytes infected with adenovirus encoding TACE. All these proteins play a role in fatty acid uptake, triglyceride synthesis, and methionine metabolism, providing a molecular explanation for the increased hepatosteatosis observed in Timp3−/− compared with WT mice. Conclusion: We have identified novel mechanisms, governed by the TACE–Timp3 interaction, involved in the determination of insulin resistance and liver steatosis during overfeeding in mice. (HEPATOLOGY 2009.)

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