Epidermal Growth Factor Protects the Liver Against Alcohol‐Induced Injury and Sensitization to Bacterial Lipopolysaccharide

Deaciuc, Ion V.; D’Souza, Nympha B.; Burikhanov, Ravshan; Lee, Eun Y.; Tarba, Corneliu; McClain, Craig J.; Villiers, Willem J.S. de

doi:10.1111/j.1530-0277.2002.tb02616.x

Cited by 30 publications

(19 citation statements)

References 44 publications

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“…Further, loss of EGFR function in humans and mice is implicated in the development of steatosis (Collin de l’Hortet and others 2014; Scheving and others 2014). EGFR activation was shown to be hepatoprotective against chemical-induced liver injury and EGF supplementation attenuated alcohol-induced liver disease (Deaciuc and others 2002; Scheving and others 2015). Loss of EGFR function has also been implicated in diabetes, as it diminishes insulin production, islet cell mass, and proliferation (Bernal-Mizrachi and others 2014; Miettinen and others 2008).…”

Section: Discussionmentioning

confidence: 99%

“…Akt and mTOR are effector kinases downstream of EGFR that regulate lipid metabolism, and glycogen synthesis (Caron and others 2015; Taniguchi and others 2006). Decreased EGFR signaling has been implicated in metabolic diseases such as type II diabetes (Bernal-Mizrachi and others 2014; Miettinen and others 2008) and NASH (Collin de l’Hortet and others 2014; Deaciuc and others 2002; Komposch and Sibilia 2016; Scheving and others 2014; Scheving and others 2015), both of which have been associated with PCB exposures (Cave and others 2010; Li and others 2013; Taylor and others 2013; Wahlang and others 2016; Wahlang and others 2014b; Yu and others 1997). Thus, we hypothesised that if PCBs antagonised EGFR like phenobarbital, this mechanism could account for both indirect CAR activation and the associated ‘off target’ effects contributing to PCB-related NASH.…”

Section: Introductionmentioning

confidence: 99%

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Polychlorinated biphenyls disrupt hepatic epidermal growth factor receptor signaling

Hardesty

Wahlang

Falkner³

et al. 2017

Xenobiotica

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Polychlorinated biphenyls (PCBs) are persistent environmental pollutants that disrupt hepatic xenobiotic and intermediary metabolism, leading to metabolic syndrome and nonalcoholic steatohepatitis (NASH).Since phenobarbital indirectly activates Constitutive Androstane Receptor (CAR) by antagonizing growth factor binding to the epidermal growth factor receptor (EGFR), we hypothesized that PCBs may also diminish EGFR signaling.The effects of the PCB mixture Aroclor 1260 on the protein phosphorylation cascade triggered by EGFR activation were determined in murine (in vitro and in vivo) and human models (in vitro). EGFR tyrosine residue phosphorylation was decreased by PCBs in all models tested.The IC50 values for Aroclor 1260 concentrations that decreased Y1173 phosphorylation of EGFR were similar in murine AML-12 and human HepG2 cells (~2–4 μg/mL). Both dioxin and non-dioxin-like PCB congeners decreased EGFR phosphorylation in cell culture.PCB treatment reduced phosphorylation of downstream EGFR effectors including Akt and mTOR, as well as other phosphoprotein targets including STAT3 and c-RAF in vivo.PCBs diminish EGFR signaling in human and murine hepatocyte models and may dysregulate critical phosphoprotein regulators of energy metabolism and nutrition, providing a new mechanism of action in environmental diseases.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Polychlorinated biphenyls disrupt hepatic epidermal growth factor receptor signaling

Hardesty

Wahlang

Falkner³

et al. 2017

Xenobiotica

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“…The EGF-R is highly expressed in the hepatocyte and seems to be a relevant mediator of survival and proliferative responses (18 -20, 25-27). Activation of the EGF-R by EGF administration or the overexpression of TGF␣ in transgenic mice has been shown to efficiently protect hepatocytes from apoptotic cell death (19,21). However, the expression profiles of these and other EGF-R ligands during acute liver damage induced by Fas ligation have not been defined.…”

Section: Discussionmentioning

confidence: 99%

Novel Role for Amphiregulin in Protection from Liver Injury

Berasain

Garcı́a-Trevijano

Castillo

et al. 2005

Journal of Biological Chemistry

119

123

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Clinically, the Fas and Fas ligand system plays a central role in the development of hepatocyte apoptosis, a process contributing to a broad spectrum of liver diseases. Therefore, the development of therapies aimed at the inhibition of hepatocyte apoptosis is a major issue. Activation of the epidermal growth factor receptor has been shown to convey survival signals to the hepatocyte. To learn about the endogenous response of epidermal growth factor receptor ligands during Fas-mediated liver injury we investigated the expression of epidermal growth factor, transforming growth factor ␣, heparinbinding epidermal growth factor-like growth factor, betacellulin, epiregulin, and amphiregulin in the liver of mice challenged with Fas-agonist antibody. Amphiregulin expression, barely detectable in healthy liver, was significantly up-regulated. Amphiregulin administration abrogated Fas-mediated liver injury in mice and showed direct anti-apoptotic effects in primary hepatocytes. Amphiregulin activated the Akt and signal transducer and activator of transcription-3 survival pathways, and up-regulated Bcl-xL expression. Amphiregulin knock-out mice showed signs of chronic liver damage in the absence of any noxious treatment, and died faster than wild type mice in response to lethal doses of Fas-agonist antibody. In contrast, these mice were more resistant against sublethal liver damage, supporting the hypothesis that chronic liver injury can precondition hepatocytes inducing resistance to subsequent cell death. These results show that amphiregulin is a protective factor induced in response to liver damage and that it may be therapeutic in liver diseases.

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“…EGF also contributes to regeneration after liver injury through the EGFR/STAT signaling pathway and protects the liver against both alcohol-induced liver injury and liver sensitization to bacterial lipopolysaccharide through downregulation of apoptosis (123,583).…”

Section: Role Of Egfr In the Livermentioning

confidence: 99%

Expression and Function of the Epidermal Growth Factor Receptor in Physiology and Disease

Chen

Zeng

Forrester

et al. 2016

Physiological Reviews

209

156

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The epidermal growth factor receptor (EGFR) is the prototypical member of a family of membrane-associated intrinsic tyrosine kinase receptors, the ErbB family. EGFR is activated by multiple ligands, including EGF, transforming growth factor (TGF)-α, HB-EGF, betacellulin, amphiregulin, epiregulin, and epigen. EGFR is expressed in multiple organs and plays important roles in proliferation, survival, and differentiation in both development and normal physiology, as well as in pathophysiological conditions. In addition, EGFR transactivation underlies some important biologic consequences in response to many G protein-coupled receptor (GPCR) agonists. Aberrant EGFR activation is a significant factor in development and progression of multiple cancers, which has led to development of mechanism-based therapies with specific receptor antibodies and tyrosine kinase inhibitors. This review highlights the current knowledge about mechanisms and roles of EGFR in physiology and disease.

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Epidermal Growth Factor Protects the Liver Against Alcohol‐Induced Injury and Sensitization to Bacterial Lipopolysaccharide

Abstract: EGF protects the liver against both alcohol-induced liver damage and liver sensitization to bacterial LPS through down-regulation of apoptosis.

Cited by 30 publications

References 44 publications

Polychlorinated biphenyls disrupt hepatic epidermal growth factor receptor signaling

Polychlorinated biphenyls disrupt hepatic epidermal growth factor receptor signaling

Novel Role for Amphiregulin in Protection from Liver Injury

Expression and Function of the Epidermal Growth Factor Receptor in Physiology and Disease

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