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Cited by 194Liver Disease Diagnosis and TreatmentLiver physiology and pathologyDrug-Induced Hepatotoxicity and Protection

The DOI matches its Crossref record; 61 of the 61 references it cites were found in a registry or an index.

Hepatocyte CYP2E1 Overexpression and Steatohepatitis Lead to Impaired Hepatic Insulin Signaling

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Schattenberg, Jörn M., Wang, Yongjun, Singh, Rajat, Rigoli, Raina M., Czaja, Mark J.·2005·Journal of Biological Chemistry
DOI 10.1074/jbc.m410310200
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Abstract

Insulin resistance and increased cytochrome P450 2E1 (CYP2E1) expression are both associated with and mechanistically implicated in the development of nonalcoholic fatty liver disease. Although currently viewed as distinct factors, insulin resistance and CYP2E1 expression may be interrelated through the ability of CYP2E1-induced oxidant stress to impair hepatic insulin signaling. To test this possibility, the effects of in vitro and in vivo CYP2E1 overexpression on hepatocyte insulin signaling were examined. CYP2E1 overexpression in a hepatocyte cell line decreased tyrosine phosphorylation of insulin receptor substrate (IRS)-1 and IRS-2 in response to insulin. CYP2E1 overexpression was also associated with increased inhibitory serine 307 and 636/639 IRS-1 phosphorylation. In parallel, the effects of insulin on Akt activation, glycogen synthase kinase 3, and FoxO1a phosphorylation, and glucose secretion were all significantly decreased in CYP2E1 overexpressing cells. This inhibition of insulin signaling by CYP2E1 overexpression was partially c-Jun N-terminal kinase dependent. In the methionine- and choline-deficient diet mouse model of steatohepatitis with CYP2E1 overexpression, insulin-induced IRS-1, IRS-2, and Akt phosphorylation were similarly decreased. These findings indicate that increased hepatocyte CYP2E1 expression and the presence of steatohepatitis result in the down-regulation of insulin signaling, potentially contributing to the insulin resistance associated with nonalcoholic fatty liver disease.

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  1. Chou, 1983, Mol. Cell. Biol., 3, 1013
  2. Liu, 2002, Am. J. Physiol., 282, G257
  3. Boden, 2001, Am. J. Physiol., 280, E23
  4. Barthel, 2003, Am. J. Physiol., 285, E685
  5. Altomonte, 2003, Am. J. Physiol., 285, E718

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Metadata

Authors
Schattenberg, J. M., Wang, Y., Singh, R., Rigoli, R. M., & Czaja, M. J.
Affiliations
Albert Einstein College of Medicine (US)
Corresponding author
Czaja, Mark J.
ORCID
Venue
Journal of Biological Chemistry
Publisher
Elsevier BV
Published
2005-03
Volume
280
Issue
11
Pages
9887-9894
ISSN
0021-9258 (ISSN-L)
DOI
10.1074/jbc.m410310200
OpenAlex
W2070680921
Cited by
194
References
60
Citations by year
2025: 1 · 2024: 4 · 2023: 1 · 2022: 4 · 2021: 8 · 2020: 2 · 2019: 6 · 2018: 4 · 2017: 12 · 2016: 13 · 2015: 11 · 2014: 12 · 2013: 8 · 2012: 8
FWCI
15.06
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Biological Chemistry (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
National Institute of Diabetes and Digestive and Kidney Diseases (DK-61498, P30DK041296, DK41296, R01DK061498)
Topics
  • Health Sciences › Medicine › Hepatology › Liver Disease Diagnosis and Treatment
  • Health Sciences › Medicine › Hepatology › Liver physiology and pathology
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
Keywords
CYP2E1, insulin resistance, non-alcoholic fatty liver disease, steatohepatitis, IRS-1, insulin receptor substrate 2, Akt phosphorylation, glycogen synthase kinase-3, FOXO1, c-Jun N-terminal kinase, oxidative stress, methionine-choline-deficient diet
MeSH terms
Forkhead Box Protein O1, Adenoviridae, Animals, Cell Line, Choline, DNA-Binding Proteins, Fatty Liver, Glucose, Glutathione Peroxidase, Hepatitis, Humans, Insulin, Methionine, Mice, Inbred C57BL, Nerve Tissue Proteins, Phosphorylation, Proteins, Proto-Oncogene Proteins, RNA, Serine, Subcellular Fractions, Time Factors, Transcription Factors, Tyrosine, Blotting, Northern, Blotting, Western, Signal Transduction, Down-Regulation, Up-Regulation, Protein Serine-Threonine Kinases, Protein Structure, Tertiary, Cytochrome P-450 CYP2E1, Mitogen-Activated Protein Kinase Kinases, Hepatocytes, Glycogen Synthase Kinase 3, Immunoprecipitation, JNK Mitogen-Activated Protein Kinases, MAP Kinase Kinase 4, Proto-Oncogene Proteins c-akt, Mice, Rats, Forkhead Transcription Factors

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