Experimental Nonalcoholic Steatohepatitis and Liver Fibrosis Are Ameliorated by Pharmacologic Activation of Nrf2 (NF-E2 p45-Related Factor 2)

Ritu S. Sharma, David J. Harrison, Dorothy Kisielewski, Diane M. Cassidy, Alison D. McNeilly, Jennifer R. Gallagher, Shaun V. Walsh, Tadashi Honda, Rory J. McCrimmon, Albena T. Dinkova-Kostova, Michael L.J. Ashford, John F. Dillon, John D. Hayes

Research output: Contribution to journalArticle

Abstract

Background & Aims: Nonalcoholic steatohepatitis (NASH) is associated with oxidative stress. We surmised that pharmacologic activation of NF-E2 p45-related factor 2 (Nrf2) using the acetylenic tricyclic bis(cyano enone) TBE-31 would suppress NASH because Nrf2 is a transcriptional master regulator of intracellular redox homeostasis. Methods: Nrf2+/+ and Nrf2-/- C57BL/6 mice were fed a high-fat plus fructose (HFFr) or regular chow diet for 16 weeks or 30 weeks, and then treated for the final 6 weeks, while still being fed the same HFFr or regular chow diets, with either TBE-31 or dimethyl sulfoxide vehicle control. Measures of whole-body glucose homeostasis, histologic assessment of liver, and biochemical and molecular measurements of steatosis, endoplasmic reticulum (ER) stress, inflammation, apoptosis, fibrosis, and oxidative stress were performed in livers from these animals. Results: TBE-31 treatment reversed insulin resistance in HFFr-fed wild-type mice, but not in HFFr-fed Nrf2-null mice. TBE-31 treatment of HFFr-fed wild-type mice substantially decreased liver steatosis and expression of lipid synthesis genes, while increasing hepatic expression of fatty acid oxidation and lipoprotein assembly genes. Also, TBE-31 treatment decreased ER stress, expression of inflammation genes, and markers of apoptosis, fibrosis, and oxidative stress in the livers of HFFr-fed wild-type mice. By comparison, TBE-31 did not decrease steatosis, ER stress, lipogenesis, inflammation, fibrosis, or oxidative stress in livers of HFFr-fed Nrf2-null mice. Conclusions: Pharmacologic activation of Nrf2 in mice that had already been rendered obese and insulin resistant reversed insulin resistance, suppressed hepatic steatosis, and mitigated against NASH and liver fibrosis, effects that we principally attribute to inhibition of ER, inflammatory, and oxidative stress.

Original languageEnglish (US)
Pages (from-to)367-398
Number of pages32
JournalCMGH
Volume5
Issue number3
DOIs
StatePublished - Mar 1 2018
Externally publishedYes

Fingerprint

NF-E2-Related Factor 2
Fructose
Liver Cirrhosis
Fats
Endoplasmic Reticulum Stress
Oxidative Stress
Liver
Fibrosis
Inflammation
Insulin Resistance
Homeostasis
Apoptosis
Body Weights and Measures
Diet
Lipogenesis
Fatty Liver
Dimethyl Sulfoxide
Non-alcoholic Fatty Liver Disease
Inbred C57BL Mouse
Genes

Keywords

  • NASH
  • Nrf2
  • TBE-31

ASJC Scopus subject areas

  • Hepatology
  • Gastroenterology

Cite this

Sharma, R. S., Harrison, D. J., Kisielewski, D., Cassidy, D. M., McNeilly, A. D., Gallagher, J. R., ... Hayes, J. D. (2018). Experimental Nonalcoholic Steatohepatitis and Liver Fibrosis Are Ameliorated by Pharmacologic Activation of Nrf2 (NF-E2 p45-Related Factor 2). CMGH, 5(3), 367-398. https://doi.org/10.1016/j.jcmgh.2017.11.016

Experimental Nonalcoholic Steatohepatitis and Liver Fibrosis Are Ameliorated by Pharmacologic Activation of Nrf2 (NF-E2 p45-Related Factor 2). / Sharma, Ritu S.; Harrison, David J.; Kisielewski, Dorothy; Cassidy, Diane M.; McNeilly, Alison D.; Gallagher, Jennifer R.; Walsh, Shaun V.; Honda, Tadashi; McCrimmon, Rory J.; Dinkova-Kostova, Albena T.; Ashford, Michael L.J.; Dillon, John F.; Hayes, John D.

In: CMGH, Vol. 5, No. 3, 01.03.2018, p. 367-398.

Research output: Contribution to journalArticle

Sharma, RS, Harrison, DJ, Kisielewski, D, Cassidy, DM, McNeilly, AD, Gallagher, JR, Walsh, SV, Honda, T, McCrimmon, RJ, Dinkova-Kostova, AT, Ashford, MLJ, Dillon, JF & Hayes, JD 2018, 'Experimental Nonalcoholic Steatohepatitis and Liver Fibrosis Are Ameliorated by Pharmacologic Activation of Nrf2 (NF-E2 p45-Related Factor 2)', CMGH, vol. 5, no. 3, pp. 367-398. https://doi.org/10.1016/j.jcmgh.2017.11.016
Sharma, Ritu S. ; Harrison, David J. ; Kisielewski, Dorothy ; Cassidy, Diane M. ; McNeilly, Alison D. ; Gallagher, Jennifer R. ; Walsh, Shaun V. ; Honda, Tadashi ; McCrimmon, Rory J. ; Dinkova-Kostova, Albena T. ; Ashford, Michael L.J. ; Dillon, John F. ; Hayes, John D. / Experimental Nonalcoholic Steatohepatitis and Liver Fibrosis Are Ameliorated by Pharmacologic Activation of Nrf2 (NF-E2 p45-Related Factor 2). In: CMGH. 2018 ; Vol. 5, No. 3. pp. 367-398.
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AU - Kisielewski, Dorothy

AU - Cassidy, Diane M.

AU - McNeilly, Alison D.

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