title: Hepatocyte CYP2E1 overexpression and steatohepatitis lead to impaired hepatic insulin signaling.
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.
authors.affiliation: Department of Medicine and Marion Bessin Liver Research Center, Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, New York 10461, USA.
authors.forename: Jörn M
authors.initials: JM
authors.lastname: Schattenberg
authors.forename: Yongjun
authors.initials: Y
authors.lastname: Wang
authors.forename: Rajat
authors.initials: R
authors.lastname: Singh
authors.forename: Raina M
authors.initials: RM
authors.lastname: Rigoli
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Czaja
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D015152:Blotting, Northern; D015153:Blotting, Western; D002460:Cell Line; D002794:Choline / Q000737:chemistry; D019392:Cytochrome P-450 CYP2E1 / Q000096:biosynthesis* / Q000737:chemistry*; D004268:DNA-Binding Proteins / Q000378:metabolism; D015536:Down-Regulation; D005234:Fatty Liver / Q000378:metabolism; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D005947:Glucose / Q000378:metabolism; D005979:Glutathione Peroxidase; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D006505:Hepatitis / Q000378:metabolism*; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D047468:Immunoprecipitation; D007328:Insulin / Q000378:metabolism*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D048670:MAP Kinase Kinase 4; D008715:Methionine / Q000737:chemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D009419:Nerve Tissue Proteins; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D012313:RNA / Q000378:metabolism; D051381:Rats; D012694:Serine / Q000737:chemistry; D015398:Signal Transduction; D013347:Subcellular Fractions / Q000378:metabolism; D013997:Time Factors; D014157:Transcription Factors / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D004268:DNA-Binding Proteins; C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D007328:Insulin; D009419:Nerve Tissue Proteins; D011506:Proteins; D011518:Proto-Oncogene Proteins; D014157:Transcription Factors; C014149:phosphoenolpyruvate carboxykinase ferroactivator protein, rat; C074639:Foxo1 protein, rat; D014443:Tyrosine; D012694:Serine; D012313:RNA; D008715:Methionine; D005979:Glutathione Peroxidase; D019392:Cytochrome P-450 CYP2E1; C494918:AKT1 protein, human; C494920:Akt1 protein, rat; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D048031:JNK Mitogen-Activated Protein Kinases; D038362:Glycogen Synthase Kinase 3; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases; D005947:Glucose; D002794:Choline