Gastroenterology

Gastroenterology

Volume 128, Issue 2, February 2005, Pages 424-432
Gastroenterology

Basic-liver, pancreas, and biliary tract
Amphiregulin: An early trigger of liver regeneration in mice

https://doi.org/10.1053/j.gastro.2004.11.006Get rights and content

Background & Aims: Liver regeneration is a unique response directed to restore liver mass after resection or injury. The survival and proliferative signals triggered during this process are conveyed by a complex network of cytokines and growth factors acting in an orderly manner. Activation of the epidermal growth factor receptor is thought to play an important role in liver regeneration. Amphiregulin is a member of the epidermal growth factor family whose expression is not detectable in healthy liver. We have investigated the expression of amphiregulin in liver injury and its role during liver regeneration after partial hepatectomy. Methods: Amphiregulin gene expression was examined in healthy and cirrhotic human and rat liver, in rodent liver regeneration after partial hepatectomy, and in primary hepatocytes. The proliferative effects and intracellular signaling of amphiregulin were studied in isolated hepatocytes. The in vivo role of amphiregulin in liver regeneration after partial hepatectomy was analyzed in amphiregulin-null mice. Results: Amphiregulin gene expression is detected in chronically injured human and rat liver and is rapidly induced after partial hepatectomy in rodents. Amphiregulin expression is induced in isolated hepatocytes by interleukin 1β and prostaglandin E2, but not by hepatocyte growth factor, interleukin 6, or tumor necrosis factor α. We show that amphiregulin behaves as a primary mitogen for isolated hepatocytes, acting through the epidermal growth factor receptor. Finally, amphiregulin-null mice display impaired proliferative responses after partial liver resection. Conclusions: Our findings indicate that amphiregulin is an early-response growth factor that may contribute to the initial phases of liver regeneration.

Section snippets

Patients

Liver tissue samples were from 2 groups of subjects. The first group comprised control individuals (n = 26; 19 men; mean age, 50.8 years; range, 18–73 years) with normal or minimal changes in the liver. We collected tissue samples at surgery (16 cases) of digestive tumors or from percutaneous liver biopsy performed because of mild alteration of liver function tests (10 cases). The second group comprised subjects with liver cirrhosis (n = 29; 24 men; mean age, 56 years; range, 36–77 years) that

Amphiregulin gene expression is induced in human and experimental liver injury

We have previously shown that expression of the transcription factor WT1 is induced in almost all tested samples of cirrhotic human liver and always in CCl4-induced cirrhosis in rats.5 The fact that AR is a major transcriptional target for WT17 led us to examine the expression of this growth factor in the liver of cirrhotic patients. Although real-time PCR analysis showed barely detectable levels of AR expression in healthy human liver, AR gene expression was observed in approximately 75% of

Discussion

The loss of functional liver mass induced by toxins, viral infections, or tissue resection triggers a well-orchestrated regenerative response that involves a number of cytokines, growth factors, hormones, and metabolites.1, 2, 3, 4 The identities of many of these factors have been established over the past decades, but the complexity of this response likely involves additional players. Here we provide several lines of evidence supporting AR, a ligand of the EGF-R, as a new factor involved in

References (36)

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This work was supported by the agreement between Fundación Investigación Médica Aplicada (FIMA) and the “Unión Temporal de Empresas (UTE) project CIMA,” Grants C03/02 and G03/015 from Instituto de Salud Carlos III (C.B., E.R.G.-T., J.P., M.A.A.), Grant SAF-2004-03538 (M.A.A.), National Institutes of Health Grants CA49793 and CA43793 (D.C.L.), and Grant FISPI040819 from Ministerio de Sanidad (to C. B.). E.E. is supported by a fellowship from Gobierno de Navarra, Spain.

1

Address correspondence to: Matias A. Avila, PhD, Division of Hepatology and Gene Therapy, CIMA, Universidad de Navarra, 31008 Pamplona, Spain. e-mail: [email protected]; fax: (34) 948-194717.

2

J.P. and M.A.A. share senior authorship.

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