Epidermal growth factor signaling protects from cholestatic liver injury and fibrosis

Svinka, Jasmin; Pflügler, Sandra; Mair, Markus; Marschall, Hanns‐Ulrich; Hengstler, Jan G.; Stiedl, Patricia; Poli, Valeria; Casanova, Emilio; Timelthaler, Gerald; Sibilia, Maria; Eferl, Robert

doi:10.1007/s00109-016-1462-8

Cited by 23 publications

(26 citation statements)

References 32 publications

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“…EGFR signaling is essential for hepatic defense against many noxius stimuli, including cholestasis . Because AREG expression is up‐regulated in human and experimental cholestasis, we investigated its role using Areg –/– mice in the BDL and ANIT models.…”

Section: Resultsmentioning

confidence: 99%

“…A similar dichotomy exists for the epidermal growth factor receptor (EGFR), a transmembrane tyrosine kinase expressed at very high levels on the surface of hepatocytes . Interestingly, the EGFR has been recently shown to provide critical hepatoprotective signaling also in cholestatic liver disease . Indeed, in Mdr2 knockout mice ( Mdr2 –/– ), a well‐characterized mouse model of BA‐mediated liver injury, elimination of EGFR results in more‐serious manifestations of cholestasis, parenchymal damage, and fibrosis.…”

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confidence: 99%

“…However, the liver has an extraordinary regenerative capacity aimed at restoration of damaged parenchyma and hepatic function that is also triggered during cholestasis‐associated injury . Understanding the molecular and cellular mechanisms of liver regeneration (LR) is relevant not only for the elucidation of potential hepatoprotective strategies, but also because the protracted activation of reparative pathways is strongly linked to liver fibrogenesis and tumorigenesis . The Janus‐faced nature of the effectors of LR is illustrated by BAs themselves, which are essential for triggering parenchymal mass restoration, but also contribute to cholestatic liver injury, fibrosis, and carcinogenesis .…”

mentioning

confidence: 99%

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The Epidermal Growth Factor Receptor Ligand Amphiregulin Protects From Cholestatic Liver Injury and Regulates Bile Acids Synthesis

et al. 2019

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Intrahepatic accumulation of bile acids (BAs) causes hepatocellular injury. Upon liver damage, a potent protective response is mounted to restore the organ’s function. Epidermal growth factor receptor (EGFR) signaling is essential for regeneration after most types of liver damage, including cholestatic injury. However, EGFR can be activated by a family of growth factors induced during liver injury and regeneration. We evaluated the role of the EGFR ligand, amphiregulin (AREG), during cholestatic liver injury and regulation of AREG expression by BAs. First, we demonstrated increased AREG levels in livers from patients with primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC). In two murine models of cholestatic liver injury, bile duct ligation (BDL) and alpha‐naphthyl‐isothiocyanate (ANIT) gavage, hepatic AREG expression was markedly up‐regulated. Importantly, Areg–/– mice showed aggravated liver injury after BDL and ANIT administration compared to Areg+/+ mice. Recombinant AREG protected from ANIT and BDL‐induced liver injury and reduced BA‐triggered apoptosis in liver cells. Oral BA administration induced ileal and hepatic Areg expression, and, interestingly, cholestyramine feeding reduced postprandial Areg up‐regulation in both tissues. Most interestingly, Areg–/– mice displayed high hepatic cholesterol 7 α‐hydroxylase (CYP7A1) expression, reduced serum cholesterol, and high BA levels. Postprandial repression of Cyp7a1 was impaired in Areg–/– mice, and recombinant AREG down‐regulated Cyp7a1 mRNA in hepatocytes. On the other hand, BAs promoted AREG gene expression and protein shedding in hepatocytes. This effect was mediated through the farnesoid X receptor (FXR), as demonstrated in Fxr–/– mice, and involved EGFR transactivation. Finally, we show that hepatic EGFR expression is indirectly induced by BA‐FXR through activation of suppressor of cytokine signaling‐3 (SOC3). Conclusion: AREG‐EGFR signaling protects from cholestatic injury and participates in the physiological regulation of BA synthesis.

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Section: Resultsmentioning

confidence: 99%

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confidence: 99%

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The Epidermal Growth Factor Receptor Ligand Amphiregulin Protects From Cholestatic Liver Injury and Regulates Bile Acids Synthesis

et al. 2019

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“…Cholangiocytes from human PSC samples exhibited increased phospho‐EGFR compared to normal livers and other liver diseases . In vivo , hepatocyte/cholangiocyte‐specific ablation of EGFR in Mdr2 knockout mice ( Mdr2 –/– ), led to an aggravation of liver fibrosis, along with a more prominent cholangiocyte proliferation compared to Mdr2 –/– control mice, suggesting that cholangiocyte proliferation is independent of EGFR . ErbB2 was overexpressed in a small cohort of human samples of PSC, suggesting that it could represent an early dysfunctional event linked to human cholangiocarcinogenesis in this disease .…”

Section: Erbb Receptors In Non‐malignant Cholangiopathiesmentioning

confidence: 99%

Role of ErbB/HER family of receptor tyrosine kinases in cholangiocyte biology

2017

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The ErbB/HER family comprises four distinct tyrosine kinase receptors, EGFR/ErbB1/HER1, ErbB2/HER2, ErbB3/ HER3, and ErbB4/HER4, which trigger intracellular signals at the origin of essential cellular functions, including differentiation, proliferation, survival, and migration. Epithelial cells, named cholangiocytes, that line intrahepatic and extrahepatic bile ducts, contribute substantially to biliary secretory functions and bile transport. Although ErbB receptors have been widely studied in cholangiocarcinoma (CCA), a malignancy of the biliary tract, knowledge of these receptors in biliary epithelium physiology and in non-malignant cholangiopathies is far from complete. Current knowledge suggests a role for epidermal growth factor receptor (EGFR) in cholangiocyte specification and proliferation, and in hepatocyte transdifferentiation into cholangiocytes during liver regeneration to restore biliary epithelium integrity. High expression and activation of EGFR and/or ErbB2 were recently demonstrated in biliary lithiasis and primary sclerosing cholangitis, two cholangiopathies regarded as risk factors for CCA. In CCA, ErbB receptors are frequently overexpressed, leading to tumor progression and low prognosis. Anti-ErbB therapies were efficient only in preclinical trials and have suggested the existence of resistance mechanisms with the need to identify predictive factors of therapy response. This review aims to compile the current knowledge on the functions of ErbB receptors in physiology and physiopathology of the biliary epithelium. (HEPATOLOGY 2017; 00:000-000). ErbB/HER FamilyThe ErbB family of receptor tyrosine kinases comprises epidermal growth factor (EGF) receptor (EGFR; ErbB1/HER1), ErbB2 (HER2), ErbB3 (HER3), and ErbB4 (HER4; Fig. 1). These plasma membrane receptors are composed of an extracellular ligand-binding domain, a transmembrane domain, and an intracellular domain with a conserved tyrosine kinase (TK) domain, with the exception of ErbB3 which holds an inactive TK domain. They bind specific ligands belonging to the EGF family, with the exception of ErbB2 which has no known ligand. Thus, ErbB2 and ErbB3 are activated through heterodimerization with other family members. ErbB ligands are produced as transmembrane precursors and processed

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“…Epidermal growth factor receptor (EGFR) pathway represents an important signaling pathway in the liver as it protects hepatocytes from apoptosis, 94 and it is necessary for hepatocyte division. 95 Epidermal growth factor (EGF), amphiregulin, heparin-binding EGF (HB-EGF), TGFa, epiregulin, and betacellulin are all ligands of EGFR and their bioavailability is provided by ADAM proteases.…”

Section: Regulator Of Growth Factor Signaling In the Livermentioning

confidence: 99%

Metalloproteinases in liver fibrosis: current insights

Zbodakova¹,

Chalupský²,

Turečková³

et al. 2017

MNM

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Liver fibrosis is defined by excessive deposition of extracellular matrix. The fibrotic conditions result from the imbalance between synthesis and deposition of fibrous tissues and decomposition of these matrix proteins. This process can be reversed as a regular part of the healing process after hepatic damage or can become chronic. When the protein matrix synthesis predominates and the decomposition is suppressed, fibrosis will progress into irreversible cirrhosis or steatosis. Among the molecular players involved in fibrotic liver diseases, metalloproteinases of matrix metalloproteinase (MMP) and a disintegrin and metalloproteinase (ADAM) families are critical in the development of liver fibrosis and its resolution. Previously, MMPs were recognized as extracellular matrix degrading enzymes. Currently, they are also known as mediators in a variety of processes related to immunity and tissue repair. In this article, we have reviewed the models of liver fibrosis and findings on MMPs and ADAMs in hepatic fibrosis conditions.

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Epidermal growth factor signaling protects from cholestatic liver injury and fibrosis

Cited by 23 publications

References 32 publications

The Epidermal Growth Factor Receptor Ligand Amphiregulin Protects From Cholestatic Liver Injury and Regulates Bile Acids Synthesis

The Epidermal Growth Factor Receptor Ligand Amphiregulin Protects From Cholestatic Liver Injury and Regulates Bile Acids Synthesis

Role of ErbB/HER family of receptor tyrosine kinases in cholangiocyte biology

Metalloproteinases in liver fibrosis: current insights

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