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Reply to 'TNF-α is not the cause of fatty liver disease in obese diabetic mice'

Nature Medicine volume 7, pages 2–3 (2001)Cite this article

Diehl replies

Memon and colleagues report that hepatic lipids and serum aminotransferases are similar in ob/ob wild-type mice and ob/ob mice that are genetically deficient in both TNF receptors, apparently refuting our hypothesis that increases in hepatic TNF-α contribute to the pathogenesis of FLD. Recently, they also noted increased UCP-2 mRNA levels in the livers of TNF-α receptor-deficient ob/ob mice4, casting further doubt on our suggestion that TNF-related induction UCP-2 compromises hepatocyte viability in fatty livers. It is important, however, to emphasize that several issues remain unresolved.

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References

  1. Lin, H.Z. et al. Metformin reverse fatty liver disease in obese, leptin-deficient mice. Nature Med. 6, 998–1003 (2000).

    Article  CAS  Google Scholar 

  2. Uysal, K.T., Wiesbrock, S.M., Marino, M.W. & Hotamisligil G.S. Protection from obesity-induced insulin resistance in mice lacking TNF-α function. Nature 389, 610–614 (1997).

    Article  CAS  Google Scholar 

  3. Uysal, K.T., Wiesbrock, S.M. & Hotamisligil, G.S. Functional analysis of tumor necrosis factor (TNF) receptors in TNF-α mediated insulin resistance in genetic obesity. Endocrinology 139, 4832–4838 (1998).

    Article  CAS  Google Scholar 

  4. Memon, R.A. et al. Up regulation of uncoupling protein 2 mRNA in genetic obesity: lack of an essential role for leptin, hyperphagia, increased tissue lipid content and TNF-α. Biochem. Biophys. Acta. 1484, 41–50 (2000).

    CAS  PubMed  Google Scholar 

  5. Yang, S.Q., Lin, H.Z., Lane, M.D., Clemens, M. & Diehl, A.M. Obesity increases sensitivity to endotoxin liver injury: implications for pathogenesis of steatohepatitis. Proc. Natl. Acad. Sci. USA 94, 2557–2562 (1997).

    Article  CAS  Google Scholar 

  6. Matteoni, C., Younossi, Z.M. & McCullough, A. Nonalcoholic fatty liver disease: A spectrum of clinical pathological severity. Gastroenterology 116, 1413–1419 (1999).

    Article  CAS  Google Scholar 

  7. Yin, M. et al. Essential role of tumor necrosis factor alpha in alcohol-induced liver injury in mice. Gastroenterology 117, 942–952 (1999).

    Article  CAS  Google Scholar 

  8. Garcia-Ruiz, C., Colell, A., Morales, A., Kaplowitz, N. & Fernandez-Checa, J.C. Role of oxidative stress generated from the mitochondrial electron transport chain and mitochondrial glutathione status in loss of mitochondrial function and activation of transcription factor nuclear-κB: Studies with isolated mitochondria and rat hepatocytes. Mol. Pharmacol. 48, 825834 (1995)

    Google Scholar 

  9. Yang, S.Q. et al. Mitochondrial adaptations to obesity-related oxidant stress. Arch. Biochem. Biophys. 378, 259–268 (2000).

    Article  CAS  Google Scholar 

  10. Chavin, K. et al. Obesity induces expression of uncoupling protein-2 in hepatocytes and promotes liver ATP depletion. J. Biol. Chem. 254, 5692–5700 (1999).

    Article  Google Scholar 

  11. Larrouy, D. et al. Kupffer cells are a dominant type of uncoupling protein-2 expression in rat liver. Biochem. Biophys. Res. Commun. 235, 760–764 (1997).

    Article  CAS  Google Scholar 

  12. Cortez-Pinto, H. et al. Bacterial lipopolysaccharide induces uncoupling protein-2 in hepatocytes via a tumor necrosis alpha-dependent mechanism. Biochem. Biophys. Res. Commun. 251, 313–319 (1998).

    Article  CAS  Google Scholar 

  13. Lee, F.-Y. et al. Phenotypic abnormalities in macrophages from leptin-deficient, obese mice. Am. J. Physiol. Cell. Physiol. 276, C386–C394 (1999).

    Article  CAS  Google Scholar 

  14. Skulachev, V.P. Role of uncoupled and non-coupled oxidations in the maintenance of safely low levels of oxygen and its one electron reductants. Quarterly Rev. Biophys. 29, 169–202 (1996).

    Article  CAS  Google Scholar 

  15. Leist, M. et al. Murine hepatocyte apoptosis induced in vitro and in vivo by TNF-α requires transcriptional arrest. J. Immunol. 153, 1778–1788. 1994

    CAS  PubMed  Google Scholar 

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  1. The Johns Hopkins University School of Medicine, Baltimore, Marlyland, USA

    Anna Mae Diehl

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Mae Diehl, A. Reply to 'TNF-α is not the cause of fatty liver disease in obese diabetic mice'. Nat Med 7, 2–3 (2001). https://doi.org/10.1038/83319

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