Amphiregulin: an early trigger of liver regeneration in mice.
OBJECTIVE
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 1beta and prostaglandin E(2), but not by hepatocyte growth factor, interleukin 6, or tumor necrosis factor alpha. 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.
Berasain
Carmen
C
Division of Hepatology and Gene Therapy, Cntro de Investigción Médica Aplicada, Facultad e Medicina,Universidad de Navarra, Pamplona, Spain.
García-Trevijano
Elena R
ER
Castillo
Josefa
J
Erroba
Elena
E
Lee
David C
DC
Prieto
Jesús
J
Avila
Matías A
MA
D000328:Adult; D000368:Aged; D066258:Amphiregulin; D000818:Animals; D001706:Biopsy; D004261:DNA Replication; D004195:Disease Models, Animal; D066255:EGF Family of Proteins; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology*; D006023:Glycoproteins / Q000235:genetics*; D022781:Hepatocytes / Q000502:physiology; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics*; D008099:Liver / Q000473:pathology; D008115:Liver Regeneration / Q000235:genetics*; D008297:Male; D051379:Mice; D008875:Middle Aged; D051381:Rats; D017208:Rats, Wistar
C587848:AREG protein, human; D066258:Amphiregulin; C587849:Areg protein, mouse; C587850:Areg protein, rat; D066255:EGF Family of Proteins; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins