Tags

Type your tag names separated by a space and hit enter

Experimental Nonalcoholic Steatohepatitis and Liver Fibrosis Are Ameliorated by Pharmacologic Activation of Nrf2 (NF-E2 p45-Related Factor 2).
Cell Mol Gastroenterol Hepatol. 2018 Mar; 5(3):367-398.CM

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.

Authors+Show Affiliations

Division of Cancer Research, Ninewells Hospital and Medical School, University of Dundee, Dundee, Scotland, United Kingdom.School of Medicine, University of St Andrews, St Andrews, Scotland, United Kingdom.Division of Cancer Research, Ninewells Hospital and Medical School, University of Dundee, Dundee, Scotland, United Kingdom.Division of Cancer Research, Ninewells Hospital and Medical School, University of Dundee, Dundee, Scotland, United Kingdom. Division of Molecular and Clinical Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee, Scotland, United Kingdom.Division of Molecular and Clinical Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee, Scotland, United Kingdom.Division of Molecular and Clinical Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee, Scotland, United Kingdom.Department of Pathology, Ninewells Hospital and Medical School, Tayside NHS Trust, Dundee, Scotland, United Kingdom.Department of Chemistry and Institute of Chemical Biology & Drug Discovery, Stony Brook University, Stony Brook, New York.Division of Molecular and Clinical Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee, Scotland, United Kingdom.Division of Cancer Research, Ninewells Hospital and Medical School, University of Dundee, Dundee, Scotland, United Kingdom.Division of Molecular and Clinical Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee, Scotland, United Kingdom.Division of Molecular and Clinical Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee, Scotland, United Kingdom.Division of Cancer Research, Ninewells Hospital and Medical School, University of Dundee, Dundee, Scotland, United Kingdom.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

29552625

Citation

Sharma, Ritu S., et al. "Experimental Nonalcoholic Steatohepatitis and Liver Fibrosis Are Ameliorated By Pharmacologic Activation of Nrf2 (NF-E2 p45-Related Factor 2)." Cellular and Molecular Gastroenterology and Hepatology, vol. 5, no. 3, 2018, pp. 367-398.
Sharma RS, Harrison DJ, Kisielewski D, et al. Experimental Nonalcoholic Steatohepatitis and Liver Fibrosis Are Ameliorated by Pharmacologic Activation of Nrf2 (NF-E2 p45-Related Factor 2). Cell Mol Gastroenterol Hepatol. 2018;5(3):367-398.
Sharma, R. S., Harrison, D. J., Kisielewski, D., Cassidy, D. M., McNeilly, A. D., Gallagher, J. R., Walsh, S. V., Honda, T., McCrimmon, R. J., Dinkova-Kostova, A. T., Ashford, M. L. J., Dillon, J. F., & Hayes, J. D. (2018). Experimental Nonalcoholic Steatohepatitis and Liver Fibrosis Are Ameliorated by Pharmacologic Activation of Nrf2 (NF-E2 p45-Related Factor 2). Cellular and Molecular Gastroenterology and Hepatology, 5(3), 367-398. https://doi.org/10.1016/j.jcmgh.2017.11.016
Sharma RS, et al. Experimental Nonalcoholic Steatohepatitis and Liver Fibrosis Are Ameliorated By Pharmacologic Activation of Nrf2 (NF-E2 p45-Related Factor 2). Cell Mol Gastroenterol Hepatol. 2018;5(3):367-398. PubMed PMID: 29552625.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Experimental Nonalcoholic Steatohepatitis and Liver Fibrosis Are Ameliorated by Pharmacologic Activation of Nrf2 (NF-E2 p45-Related Factor 2). AU - Sharma,Ritu S, AU - Harrison,David J, AU - Kisielewski,Dorothy, AU - Cassidy,Diane M, AU - McNeilly,Alison D, AU - Gallagher,Jennifer R, AU - Walsh,Shaun V, AU - Honda,Tadashi, AU - McCrimmon,Rory J, AU - Dinkova-Kostova,Albena T, AU - Ashford,Michael L J, AU - Dillon,John F, AU - Hayes,John D, Y1 - 2017/12/13/ PY - 2017/08/14/received PY - 2017/11/30/accepted PY - 2018/3/20/entrez PY - 2018/3/20/pubmed PY - 2018/3/20/medline KW - ACACA, acetyl-CoA carboxylase alpha KW - ACLY, ATP citrate lyase KW - ACOT7, acetyl-CoA thioesterase 7 KW - ACOX2, acetyl-CoA oxidase 2 KW - ADRP, adipose differentiation-related protein KW - AP-1, activator protein 1 KW - ATF4, activating transcription factor-4 KW - ATF6, activating transcription factor-6 KW - ApoB, apolipoprotein B KW - BCL-2, B-cell lymphoma KW - BIP, binding immunoglobulin protein KW - C/EBP, CCAAT/enhancer-binding protein KW - CAT, catalase KW - CD36, cluster of differentiation 36 KW - CDDO, 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid KW - CES1G, carboxylesterase 1g KW - CHOP, C/EBP homologous protein KW - COL1A1, collagen, type I, alpha-1 KW - COX2, cyclooxygenase-2 KW - CPT1A, carnitine palmitoyltransferase 1a KW - ChREBP, carbohydrate-responsive element-binding protein KW - DGAT2, diacylglycerol acyltransferase-2 KW - DMSO, dimethyl sulfoxide KW - ER, endoplasmic reticulum KW - FASN, fatty acid synthase KW - FXR, farnesoid X receptor KW - GCLC, glutamate-cysteine ligase catalytic KW - GCLM, glutamate-cysteine ligase modifier KW - GPX2, glutathione peroxidase-2 KW - GSH, reduced glutathione KW - GSSG, oxidized glutathione KW - GSTA4, glutathione S-transferase Alpha-4 KW - GSTM1, glutathione S-transferase Mu-1 KW - GTT, glucose tolerance test KW - H&E, hematoxylin and eosin KW - HF, high-fat KW - HF30Fr, high-fat diet with 30% fructose in drinking water KW - HF55Fr, high-fat diet with 55% fructose in drinking water KW - HFFr, high-fat diet with fructose in drinking water KW - HMOX1, heme oxygenase-1 KW - IKK, IκB kinase KW - IRE1α, inositol requiring kinase-1α KW - ITT, insulin tolerance test KW - IκB, inhibitor of NF-κB KW - JNK1, c-Jun N-terminal kinase 1 KW - Keap1, Kelch-like ECH-associated protein-1 KW - LXRα, liver X receptor α KW - MCD, methionine- and choline-deficient KW - MCP-1, monocyte chemotactic protein-1 KW - MGPAT, mitochondrial glycerol-3-phosphate acetyltransferase KW - MPO, myeloperoxidase KW - MTTP, microsomal triglyceride transfer protein KW - NAFLD, non-alcoholic fatty liver disease KW - NAS, NAFLD activity score KW - NASH KW - NASH, nonalcoholic steatohepatitis KW - NF-κB, nuclear factor-κB KW - NOS2, nitric oxide synthase-2 KW - NQO1, NAD(P)H:quinone oxidoreductase 1 KW - Nrf2 KW - Nrf2, NF-E2 p45-related factor 2 KW - PARP, poly ADP ribose polymerase KW - PCR, polymerase chain reaction KW - PDI, protein disulfide isomerase KW - PERK, PRK-like endoplasmic reticulum kinase KW - PPARα, peroxisome proliferator-activated receptor α KW - PPARγ, peroxisome proliferator-activated receptor γ KW - PRDX6, peroxiredoxin 6 KW - PTGR1, prostaglandin reductase-1 KW - PTT, pyruvate tolerance test KW - RC, regular chow KW - SCAD, short-chain acyl-CoA dehydrogenase KW - SCD1, stearoyl-CoA desaturase-1 KW - SFN, sulforaphane KW - SHP, small heterodimer partner KW - SLC7A11, solute carrier family 7 member 11 KW - SREBP-1c, sterol regulatory element-binding protein-1c KW - TBE-31 KW - TGFβ, transforming growth factor beta-1 KW - TNF-α, tumor necrosis factor-α KW - TXN1, thioredoxin-1 KW - TXNRD1, thioredoxin reductase-1 KW - UPR, unfolded protein response KW - XBP1, X-box binding protein-1 KW - eIf2α, eukaryotic translation initiation factor 2A KW - p58IPK, p58 inhibitor of the PKR kinase KW - qRT-PCR, quantitative reverse transcriptase PCR KW - α-SMA, alpha smooth muscle actin SP - 367 EP - 398 JF - Cellular and molecular gastroenterology and hepatology JO - Cell Mol Gastroenterol Hepatol VL - 5 IS - 3 N2 - 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. SN - 2352-345X UR - https://www.unboundmedicine.com/medline/citation/29552625/Experimental_Nonalcoholic_Steatohepatitis_and_Liver_Fibrosis_Are_Ameliorated_by_Pharmacologic_Activation_of_Nrf2__NF_E2_p45_Related_Factor_2__ L2 - https://linkinghub.elsevier.com/retrieve/pii/S2352-345X(17)30180-7 DB - PRIME DP - Unbound Medicine ER -