Evidence map›Paper›PMID 29552625›Full record

ArticleCellular and molecular gastroenterology and hepatology2018

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 and 3 more

Open access · goldAbstract read
In one paragraph

Article in Cellular and molecular gastroenterology and hepatology, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 113 papers.

0numbers the graph read from it
0cells of the map it votes in
113citing papers in PubMed
11.0field-weighted citation impact, top 1% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

113 citing papers in PubMed, 207 citations in OpenAlex.

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53 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

13 authors at 4 institutions in 2 countries.

Ritu S SharmaDivision of Cancer Research, Ninewells Hospital and Medical School, University of Dundee, Dundee, Scotland, United Kingdom.
David J HarrisonSchool of Medicine, University of St Andrews, St Andrews, Scotland, United Kingdom.
Dorothy KisielewskiDivision of Cancer Research, Ninewells Hospital and Medical School, University of Dundee, Dundee, Scotland, United Kingdom.
Diane M CassidyDivision of Cancer Research, Ninewells Hospital and Medical School, University of Dundee, Dundee, Scotland, United Kingdom.
Alison D McNeillyDivision of Molecular and Clinical Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee, Scotland, United Kingdom.
Jennifer R GallagherDivision of Molecular and Clinical Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee, Scotland, United Kingdom.
Shaun V WalshDepartment of Pathology, Ninewells Hospital and Medical School, Tayside NHS Trust, Dundee, Scotland, United Kingdom.
Tadashi HondaDepartment of Chemistry and Institute of Chemical Biology & Drug Discovery, Stony Brook University, Stony Brook, New York.
Rory J McCrimmonDivision of Molecular and Clinical Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee, Scotland, United Kingdom.
Albena T Dinkova-KostovaDivision of Cancer Research, Ninewells Hospital and Medical School, University of Dundee, Dundee, Scotland, United Kingdom.
Michael L J AshfordDivision of Molecular and Clinical Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee, Scotland, United Kingdom.
John F DillonDivision of Molecular and Clinical Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee, Scotland, United Kingdom.
John D HayesDivision of Cancer Research, Ninewells Hospital and Medical School, University of Dundee, Dundee, Scotland, United Kingdom.
University of Dundee · GBNinewells Hospital · GBStony Brook University · USUniversity of St Andrews · GB

Funding

Medical Research Council MR/J001465/1Medical Research Council MR/N009851/1
6 · The paper itself

Abstract

BACKGROUND &

aimsNonalcoholic 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

resultsTBE-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.

conclusionsPharmacologic 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.

Indexed as

ACACA, acetyl-CoA carboxylase alphaACLY, ATP citrate lyaseACOT7, acetyl-CoA thioesterase 7ACOX2, acetyl-CoA oxidase 2ADRP, adipose differentiation-related proteinAP-1, activator protein 1ApoB, apolipoprotein BATF4, activating transcription factor-4ATF6, activating transcription factor-6BCL-2, B-cell lymphomaBIP, binding immunoglobulin proteinCAT, catalaseCD36, cluster of differentiation 36CDDO, 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acidC/EBP, CCAAT/enhancer-binding proteinCES1G, carboxylesterase 1gCHOP, C/EBP homologous proteinChREBP, carbohydrate-responsive element-binding proteinCOL1A1, collagen, type I, alpha-1COX2, cyclooxygenase-2CPT1A, carnitine palmitoyltransferase 1aDGAT2, diacylglycerol acyltransferase-2DMSO, dimethyl sulfoxideeIf2α, eukaryotic translation initiation factor 2AER, endoplasmic reticulumFASN, fatty acid synthaseFXR, farnesoid X receptorGCLC, glutamate-cysteine ligase catalyticGCLM, glutamate-cysteine ligase modifierGPX2, glutathione peroxidase-2GSH, reduced glutathioneGSSG, oxidized glutathioneGSTA4, glutathione S-transferase Alpha-4GSTM1, glutathione S-transferase Mu-1GTT, glucose tolerance testH&E, hematoxylin and eosinHF30Fr, high-fat diet with 30% fructose in drinking waterHF55Fr, high-fat diet with 55% fructose in drinking waterHFFr, high-fat diet with fructose in drinking waterHF, high-fatHMOX1, heme oxygenase-1IKK, IκB kinaseIRE1α, inositol requiring kinase-1αITT, insulin tolerance testIκB, inhibitor of NF-κBJNK1, c-Jun N-terminal kinase 1Keap1, Kelch-like ECH-associated protein-1LXRα, liver X receptor αMCD, methionine- and choline-deficientMCP-1, monocyte chemotactic protein-1MGPAT, mitochondrial glycerol-3-phosphate acetyltransferaseMPO, myeloperoxidaseMTTP, microsomal triglyceride transfer proteinNAFLD, non-alcoholic fatty liver diseaseNASHNASH, nonalcoholic steatohepatitisNAS, NAFLD activity scoreNF-κB, nuclear factor-κBNOS2, nitric oxide synthase-2NQO1, NAD(P)H:quinone oxidoreductase 1Nrf2Nrf2, NF-E2 p45-related factor 2p58IPK, p58 inhibitor of the PKR kinasePARP, poly ADP ribose polymerasePCR, polymerase chain reactionPDI, protein disulfide isomerasePERK, PRK-like endoplasmic reticulum kinasePPARα, peroxisome proliferator-activated receptor αPPARγ, peroxisome proliferator-activated receptor γPRDX6, peroxiredoxin 6PTGR1, prostaglandin reductase-1PTT, pyruvate tolerance testqRT-PCR, quantitative reverse transcriptase PCRRC, regular chowSCAD, short-chain acyl-CoA dehydrogenaseSCD1, stearoyl-CoA desaturase-1SFN, sulforaphaneSHP, small heterodimer partnerSLC7A11, solute carrier family 7 member 11SREBP-1c, sterol regulatory element-binding protein-1cTBE-31TGFβ, transforming growth factor beta-1TNF-α, tumor necrosis factor-αTXN1, thioredoxin-1TXNRD1, thioredoxin reductase-1UPR, unfolded protein responseXBP1, X-box binding protein-1α-SMA, alpha smooth muscle actin

Identifiers

PMID29552625
PMCPMC5852394
OpenAlexW2775505129

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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.