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

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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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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: Schattenberg, Jörn M.
Wang, Yongjun
Singh, Rajat
Czaja, Mark J.
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: hybrid
doi.org
Licence: cc-by
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
creativecommons.org/licenses/by/4.0/ (vor, 5707 d)
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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Hepatocyte CYP2E1 Overexpression and Steatohepatitis Lead to Impaired Hepatic Insulin Signaling

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