CoChat
Sign Up
Cited by 61Liver Disease Diagnosis and TreatmentGenomics, phytochemicals, and oxidative stressLiver physiology and pathology

Hepatocyte-specific Keap1 deletion reduces liver steatosis but not inflammation during non-alcoholic steatohepatitis development

Ramadori, Pierluigi, Drescher, Hannah, Erschfeld, Stephanie, Schumacher, Fabienne, Berger, Cordula, Fragoulis, Athanassios, Schenkel, Julia, Kensler, Thomas W., Wruck, Christoph J., Trautwein, Christian, Kroy, Daniela C., Streetz, Konrad L.·2016·Free Radical Biology and Medicine
DOI 10.1016/j.freeradbiomed.2015.12.014
Open this paper in CoChat — free account

Abstract

Generation of reactive oxygen species (ROS) in response to fatty acids accumulation has been classically proposed as a possible "second hit" triggering progression from simple steatosis to non-alcoholic steatohepatitis (NASH). In this study we challenged hepatocyte-specific Keap1 knockout mice (Keap1(Δhepa)) and littermate Cre- controls (Keap1(fx/fx)) with two different diet models of NASH in order to evaluate the effects of the anti-oxidant transcription factor Nrf2 over-activation on hepatic metabolism and disease progression. After 4 weeks of MCD diet the liver/body weight ratio of Keap1(Δhepa) mice was significantly higher compared to littermate controls with no differences in total body weight. Strikingly, liver histology revealed a dramatic reduction of lipid droplets confirmed by a decreased content of intra-hepatic triglycerides in Keap1(Δhepa) compared to controls. In parallel to reduced expression of genes involved in lipid droplet formation, protein expression of Liver X Receptor (LXRα/β) and Peroxisome proliferator-activated receptor α (PPARα) was significantly decreased. In contrast, genes involved in mitochondrial lipid catabolism were markedly up-regulated in Keap1(Δhepa) livers. A similar phenotype characterized by inhibition of lipogenesis in favor of increased mitochondrial catabolic activity was also observed after 13 weeks of western diet administration. MCD-induced apoptosis was significantly dampened in Keap1(Δhepa) compared to Keap1(fx/fx) as detected b…

Integrity signals

Registry

Crossref · 10.1016/j.freeradbiomed.2015.12.014

Cites

Statistics

Recomputing p-values needs the paper’s full text.

Claims the paper makes

This paper’s full text isn’t openly available, so its claims and self-check weren’t run. The registry and citation checks still apply.

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Several genes were previously connected with fatty liver disease such as Nr3c1, Nr3c2, Zbtb16, Dnmt1, and Keap1, but most of the top genes had no connections with liver disease or NASH.

    “Several genes were previously connected with fatty liver disease such as the glucocorticoid receptor Nr3c128,29, the mineralocorticoid receptor Nr3c230,31, the transcription factor Zbtb1632, the DNA methyltransferase Dnmt133, and the E3 ubiquitin ligase adaptor Keap134,35, but most of the top genes had no connections with liver disease or NASH.”

    From Positive selection of somatically mutated clones identifies adaptive pathways in metabolic liver disease (2023) · cites this paper as [35]

The citation lists haven’t been fetched yet

References 45 · Cited by 61

Research works printed but not linked: 39

  1. Day, 1998, Steatohepatitis: a tale of two “hits”?, Gastroenterology, 114, 842, 10.1016/S0016-5085(98)70599-2 · DOI · Paper page
  2. Begriche, 2013, Mitochondrial adaptations and dysfunctions in nonalcoholic fatty liver disease, Hepatology, 58, 1497, 10.1002/hep.26226 · DOI · Paper page
  3. Nan, 2009, Antioxidants vitamin E and 1-aminobenzotriazole prevent experimental non-alcoholic steatohepatitis in mice, Scand. J. Gastroenterol., 15, 1
  4. Kensler, 2007, Cell survival responses to environmental stresses via the Keap1-Nrf2-ARE pathway, Annu. Rev. Pharmacol. Toxicol., 47, 89, 10.1146/annurev.pharmtox.46.120604.141046 · DOI · Paper page
  5. Taguchi, 2011, Molecular mechanisms of the Keap1-Nrf2 pathway in stress response and cancer evolution, Genes. Cells, 16, 123, 10.1111/j.1365-2443.2010.01473.x · DOI · Paper page
  6. Okawa, 2006, Hepatocyte-specific deletion of the keap1 gene activates Nrf2 and confers potent resistance against acute drug toxicity, Biochem. Biophys. Res. Commun., 339, 79, 10.1016/j.bbrc.2005.10.185 · DOI
  7. Ke, 2013, KEAP1-NRF2 complex in ischemia-induced hepatocellular damage of mouse liver transplants, J. Hepatol., 59, 1200, 10.1016/j.jhep.2013.07.016 · DOI
  8. Wu, 2012, Role of Nrf2 in preventing ethanol-induced oxidative stress and lipid accumulation, Toxicol. Appl. Pharmacol., 262, 321, 10.1016/j.taap.2012.05.010 · DOI
  9. Wang, 2013, Nrf2 deletion causes “benign” simple steatosis to develop into nonalcoholic steatohepatitis in mice fed a high-fat diet, Lipids Health Dis., 12, 165, 10.1186/1476-511X-12-165 · DOI
  10. More, 2013, Keap1 knockdown increases markers of metabolic syndrome after long-term high fat diet feeding, Free. Radic. Biol. Med., 61, 85, 10.1016/j.freeradbiomed.2013.03.007 · DOI
  11. Kroy, 2014, Hepatocyte specific deletion of c-Met leads to the development of severe non-alcoholic steatohepatitis in mice, JHepatol, 61, 883, 10.1016/j.jhep.2014.05.019 · DOI
  12. Kaldenbach, 2012, Hepatocyte growth factor/c-Met signalling is important for the selection of transplanted hepatocytes, Gut, 61, 1209, 10.1136/gutjnl-2011-301345 · DOI
  13. Rizki, 2006, Mice fed a lipogenic methionine-choline-deficient diet develop hypermetabolism coincident with hepatic suppression of SCD-1, J. Lipid Res., 47, 2280, 10.1194/jlr.M600198-JLR200 · DOI
  14. Lee, 2014, Activation of the Nrf2-ARE pathway in hepatocytes protects against steatosis in nutritionally induced non-alcoholic steatohepatitis in mice, Toxicol. Sci., 142, 361, 10.1093/toxsci/kfu184 · DOI
  15. Pang, 2014, and Nrf2 couples proline catabolism with lipid metabolism during nutrient deprivation, Nat. Commun., 5, 5048, 10.1038/ncomms6048 · DOI
  16. Xu, 2013, Keap1-knockdown decreases fasting-induced fatty liver via altered lipid metabolism and decreased fatty acid mobilization from adipose tissue, PLOS One, 8, e79841, 10.1371/journal.pone.0079841 · DOI
  17. Kay, 2011, Nrf2 inhibits LXRα-dependent hepatic lipogenesis by competing with FXR for acetylase binding, Antioxid. Redox Signal, 15, 2135, 10.1089/ars.2010.3834 · DOI
  18. Chowdhry, 2010, Loss of Nrf2 markedly exacerbates nonalcoholic steatohepatitis, Free. Radic. Biol. Med., 48, 357, 10.1016/j.freeradbiomed.2009.11.007 · DOI
  19. Xu, 2012, Enhanced Nrf2 activity worsens insulin resistance, impairs lipid accumulation in adipose tissue, and increases hepatic steatosis in leptin-deficient mice, Diabetes, 61, 3208, 10.2337/db11-1716 · DOI
  20. Chartoumpekis, 2013, New player on an old field; the keap1/Nrf2 pathway as a target for treatment of type 2 diabetes and metabolic syndrome, Curr. Diabetes Rev., 9, 137
  21. Kulkarni, 2014, Fasting induces nuclear factor E2-related factor 2 and ATP-binding Cassette transporters via protein kinase A and Sirtuin-1 in mouse and human, Antioxid. Redox Signal, 20, 15, 10.1089/ars.2012.5082 · DOI
  22. Zhang, 2012, Liver LXRα expression is crucial for whole body cholesterol homeostasis and reverse cholesterol transport in mice, J. Clin. Invest, 122, 1688, 10.1172/JCI59817 · DOI
  23. Ludtmann, 2014, Nrf2 affects the efficiency of mitochondrial fatty acid oxidation, Biochem. J., 457, 415, 10.1042/BJ20130863 · DOI
  24. Cortez-Pinto, 2009, Uncoupling proteins and non-alcoholic fatty liver disease, J. Hepatol., 50, 857, 10.1016/j.jhep.2009.02.019 · DOI
  25. Chavin, 1999, Obesity induces expression of uncoupling protein-2 in hepatocytes and promotes liver ATP depletion, J. Biol. Chem., 274, 5692, 10.1074/jbc.274.9.5692 · DOI
  26. Rashid, 1999, Mitochondrial proteins that regulate apoptosis and necrosis are induced in mouse fatty liver, Hepatology, 29, 1131, 10.1002/hep.510290428 · DOI
  27. Wang, 2012, The mitochondrial phosphatase PGAM5 functions at the convergence point of multiple necrotic death pathways, Cell, 148, 228, 10.1016/j.cell.2011.11.030 · DOI · Paper page
  28. Temkin, 2006, Inhibition of ADP/ATP exchange in receptor-interacting protein-mediated necrosis, Mol. Cell. Biol., 26, 2215, 10.1128/MCB.26.6.2215-2225.2006 · DOI
  29. Kang, 2015, Regulation of NKT cell-mediated immune responses to tumours and liver inflammation by mitochondrial PGAM5-Drp1 signalling, Nat. Commun., 6, 8371, 10.1038/ncomms9371 · DOI
  30. Niture, 2012, Nrf2 protein up-regulates antiapoptotic protein Bcl-2 and prevents cellular apoptosis, J. Biol. Chem., 287, 9873, 10.1074/jbc.M111.312694 · DOI
  31. Cazanave, 2014, Degradation of Keap1 activates BH3-only proteins Bim and PUMA during hepatocyte lipoapoptosis, Cell. Death Differ., 21, 1303, 10.1038/cdd.2014.49 · DOI
  32. Tian, 2012, Keap1: one stone kills three birds Nrf2, IKKβ and Bcl-2/Bcl-xL, Cancer Lett., 325, 26, 10.1016/j.canlet.2012.06.007 · DOI
  33. Beyer, 2008, Impaired liver regeneration in Nrf2 knockout mice: role of ROS-mediated insulin/IGF-1 resistance, EMBO J., 27, 212, 10.1038/sj.emboj.7601950 · DOI
  34. Osburn, 2008, Genetic or pharmacologic amplification of Nrf2 signaling inhibits acute inflammatory liver injury in mice, Toxicol. Sci., 104, 218, 10.1093/toxsci/kfn079 · DOI
  35. Taguchi, 2010, Genetic analysis of cytoprotective functions supported by graded expression of Keap1, Mol. Cell. Biol., 30, 3016, 10.1128/MCB.01591-09 · DOI
  36. Bryan, 2013, The Nrf2 cell defence pathway: Keap1-dependent and -independent mechanisms of regulation, Biochem. Pharmacol., 85, 705, 10.1016/j.bcp.2012.11.016 · DOI
  37. Kim, 2010, Suppression of NF-kappaB signaling by KEAP1 regulation of IKKbeta activity through autophagic degradation and inhibition of phosphorylation, Cell. Signal, 22, 1645, 10.1016/j.cellsig.2010.06.004 · DOI
  38. Hardwick, 2010, Diversity in antioxidant response enzymes in progressive stages of human nonalcoholic fatty liver disease, Drug. Metab. Dispos., 38, 2293, 10.1124/dmd.110.035006 · DOI
  39. Takahashi, 2014, Does hepatic oxidative stress enhance activation of Nuclear Factor-E2-Related Factor in patients with Nonalcoholic Steatohepatitis?, Antiox Redox Signal, 20, 538, 10.1089/ars.2013.5470 · DOI

Authors
Ramadori, P., Drescher, H., Erschfeld, S., Schumacher, F., Berger, C., Fragoulis, A., Schenkel, J., Kensler, T. W., Wruck, C. J., Trautwein, C., Kroy, D. C., & Streetz, K. L.
Affiliations
  • Universitätsklinikum Aachen (DE)
  • University of Pittsburgh (US)
Corresponding author
  • Ramadori, Pierluigi
  • Streetz, Konrad L.
ORCID
Venue
Free Radical Biology and Medicine
Publisher
Elsevier BV
Published
2016-02
Volume
91
Pages
114-126
ISSN
0891-5849 (ISSN-L)
DOI
10.1016/j.freeradbiomed.2015.12.014
OpenAlex
W2218597301
Cited by
61
References
45
Citations by year
2026: 2 · 2025: 5 · 2024: 7 · 2023: 5 · 2022: 8 · 2021: 4 · 2020: 5 · 2019: 3 · 2018: 10 · 2017: 8 · 2016: 4
FWCI
5.75
Type
journal article
Language
en
Open access
closed
Licence
Locations
  • Free Radical Biology and Medicine (publishedVersion)
  • PubMed (publishedVersion)
  • RWTH Publications (RWTH Aachen) (submittedVersion)
Funders
Deutsche Forschungsgemeinschaft DFG (SFB/TRR57)
Topics
  • Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics, phytochemicals, and oxidative stress
  • Health Sciences › Medicine › Hepatology › Liver physiology and pathology
Keywords
Keap1, Nrf2, nonalcoholic steatohepatitis, hepatic steatosis, hepatocyte-specific knockout, lipid droplets, de novo lipogenesis, liver X receptor, PPARα, reactive oxygen species, apoptosis, liver inflammation, fibrosis, methionine-choline-deficient diet, oxidative stress
MeSH terms
Kelch-Like ECH-Associated Protein 1, Animals, Cells, Cultured, Cholesterol, Liver, Male, Mice, Inbred C57BL, Organ Size, Oxidation-Reduction, Apoptosis, Mice, Knockout, Active Transport, Cell Nucleus, Hepatocytes, Lipid Metabolism, NF-E2-Related Factor 2, Non-alcoholic Fatty Liver Disease

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review