Increased cytochrome<i>P</i>-450 2E1 expression sensitizes hepatocytes to c-Jun-mediated cell death from TNF-α

Liu, Hailing; Jones, Brett E.; Bradham, Cynthia A.; Czaja, Mark J.

doi:10.1152/ajpgi.00304.2001

Cited by 82 publications

(77 citation statements)

References 47 publications

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“…144 Moreover, studies in other cell types using inhibitors of the JNK pathway also revealed a proapoptotic function of the JNK pathway in TNF-induced cell death. [262][263][264][265][266][267][268] The different roles of JNK in TNF-induced apoptosis could be partly related to celltype-specific effects, but may also mirror that TNF engages JNK by more than one pathway. Indeed, especially under apoptotic conditions, TNF activates JNK, but also p38, with biphasic kinetics.…”

Section: Molecular Mechanisms Of Tnf-induced Cell Deathmentioning

confidence: 99%

Tumor necrosis factor signaling

2003

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A single mouse click on the topic tumor necrosis factor (TNF) in PubMed reveals about 50 000 articles providing one or the other information about this pleiotropic cytokine or its relatives. This demonstrates the enormous scientific and clinical interest in elucidating the biology of a molecule (or rather a large family of molecules), which began now almost 30 years ago with the description of a cytokine able to exert antitumoral effects in mouse models. Although our understanding of the multiple functions of TNF in vivo and of the respective underlying mechanisms at a cellular and molecular level has made enormous progress since then, new aspects are steadily uncovered and it appears that still much needs to be learned before we can conclude that we have a full comprehension of TNF biology. This review shortly covers some general aspects of this fascinating molecule and then concentrates on the molecular mechanisms of TNF signal transduction. In particular, the multiple facets of crosstalk between the various signalling pathways engaged by TNF will be addressed.

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Section: Molecular Mechanisms Of Tnf-induced Cell Deathmentioning

confidence: 99%

Tumor necrosis factor signaling

2003

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“…The ethanol sensitization of TNFα toxicity in E47 cells and hepatocytes from chronic ethanol fed rats also depended on P38 MAPK signaling since SB203580, a P38 MAPK inhibitor, prevented this enhanced toxicity (172). In a RALA hepatocyte cell line model, Czaja and collaborators showed that hepatocytes with increased expression of CYP2E1 were sensitized to TNFα mediated cell death (211). Toxicity was a mixture of necrosis and apoptosis, was associated with prolonged activation of JNK and phosphorylation of c-Jun, and could be prevented by a dominant negative c-Jun construct (211).…”

Section: Lps/tnfα-cyp2e1 Interactionsmentioning

confidence: 99%

“…In a RALA hepatocyte cell line model, Czaja and collaborators showed that hepatocytes with increased expression of CYP2E1 were sensitized to TNFα mediated cell death (211). Toxicity was a mixture of necrosis and apoptosis, was associated with prolonged activation of JNK and phosphorylation of c-Jun, and could be prevented by a dominant negative c-Jun construct (211). These results suggest that increased oxidant stress from CYP2E1 may sensitize isolated hepatocytes to TNFα-induced toxicity.…”

Section: Lps/tnfα-cyp2e1 Interactionsmentioning

confidence: 99%

CYP2E1 and oxidative liver injury by alcohol

Cederbaum

2008

Free Radical Biology and Medicine

659

534

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Ethanol-induced oxidative stress appears to play a major role in mechanisms by which ethanol causes liver injury. Many pathways have been suggested to contribute to the ability of ethanol to induce a state of oxidative stress. One central pathway appears to be the induction of cytochrome P450 2E1 (CYP2E1) by ethanol. CYP2E1 metabolizes and activates many toxicological substrates, including ethanol, to more reactive, toxic products. Levels of CYP2E1 are elevated under a variety of physiological and pathophysiological conditions, and after acute and chronic alcohol treatment. CYP2E1 is also an effective generator of reactive oxygen species such as the superoxide anion radical and hydrogen peroxide, and in the presence of iron catalysts, produces powerful oxidants such as the hydroxyl radical. This Review Article summarizes some of the biochemical and toxicological properties of CYP2E1, and briefly describes the use of cell lines developed to constitutively express CYP2E1 in assessing the actions of CYP2E1. Possible therapeutic implications for treatment of alcoholic liver injury by inhibition of CYP2E1 or CYP2E1-dependent oxidative stress will be discussed, followed by some future directions which may help to understand the actions of CYP2E1 and its role in alcoholic liver injury.

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“…studies have demonstrated that CYP2E1 overexpression causes an activation of JNK mitogen-activated protein kinase (45). JNK is known to phosphorylate inhibitory IRS serine residues in other cell types and in nonhepatic and hepatic tissues (14,20).…”

Section: Decreased Insulin Signaling In S-cyp Cells Is Partially Revementioning

confidence: 99%

Hepatocyte CYP2E1 Overexpression and Steatohepatitis Lead to Impaired Hepatic Insulin Signaling

Schattenberg

Wang

Singh

et al. 2005

Journal of Biological Chemistry

Self Cite

179

134

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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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Increased cytochromeP-450 2E1 expression sensitizes hepatocytes to c-Jun-mediated cell death from TNF-α

Abstract: Liu, Hailing, Brett E. Jones, Cynthia Bradham, and Mark J. Czaja. Increased cytochrome P-450 2E1 expression sensitizes hepatocytes to c-Jun-mediated cell death from TNF-␣.

Cited by 82 publications

References 47 publications

Tumor necrosis factor signaling

Tumor necrosis factor signaling

CYP2E1 and oxidative liver injury by alcohol

Hepatocyte CYP2E1 Overexpression and Steatohepatitis Lead to Impaired Hepatic Insulin Signaling

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