title: Epidermal growth factor receptor ligands in murine models for erythropoietic protoporphyria: potential novel players in the progression of liver injury.
abstract: Activation of the epidermal growth factor receptor (EGFR) plays an important role in liver regeneration and resistance to acute injury. However its chronic activation participates in the progression of liver disease, including fibrogenesis and malignant transformation. Hepatobiliary disease represents a constant feature in the clinically relevant Fechm1pas/Fechm1pas genetic model of erythropoietic protoporphyria (EPP). Similarly, chronic administration of griseofulvin to mice induces pathological changes similar to those found in patients with EPP-associated liver injury. We investigated the hepatic expression of the EGFR and its seven most relevant ligands in Fechm1pas/Fechm1pas mice bred in three different backgrounds, and in griseofulvin-induced protoporphyria. We observed that the expression of amphiregulin, betacellulin and epiregulin was significantly increased in young EPP mice when compared to aged-matched controls in all genetic backgrounds. The expression of these ligands was also tested in older (11 months) BALB/cJ EPP mice, and it was found to remain induced, while that of the EGFR was downregulated. Griseofulvin feeding also increased the expression of amphiregulin, betacellulin and epiregulin. Interestingly, protoporphyrin accumulation in cultured hepatic AML-12 cells readily elicited the expression of these three EGFR ligands. Our findings suggest that protoporphyrin could directly induce the hepatic expression of EGFR ligands, and that their chronic upregulation might participate in the pathogenesis of EPP-associated liver disease.
authors.affiliation: Gene Therapy and Hepatology, CIMA, Pamplona, Navarra, Spain.
authors.forename: C
authors.initials: C
authors.lastname: Berasain
authors.forename: A
authors.initials: A
authors.lastname: Sampedro
authors.forename: I
authors.initials: I
authors.lastname: Mauleón
authors.forename: S
authors.initials: S
authors.lastname: Goñi
authors.forename: M U
authors.initials: MU
authors.lastname: Latasa
authors.forename: N
authors.initials: N
authors.lastname: Matscheko
authors.forename: M
authors.initials: M
authors.lastname: García-Bravo
authors.forename: C
authors.initials: C
authors.lastname: Unzu
authors.forename: F J
authors.initials: FJ
authors.lastname: Corrales
authors.forename: R
authors.initials: R
authors.lastname: Enríquez de Salamanca
authors.forename: J
authors.initials: J
authors.lastname: Prieto
authors.forename: M A
authors.initials: MA
authors.lastname: Avila
authors.forename: A
authors.initials: A
authors.lastname: Fontanellas
mesh_terms: D066258:Amphiregulin; D000818:Animals; D066259:Betacellulin; D002460:Cell Line; D066255:EGF Family of Proteins; D004815:Epidermal Growth Factor / Q000235:genetics; D066261:Epigen; D066260:Epiregulin; D066246:ErbB Receptors / Q000819:agonists* / Q000378:metabolism*; D006023:Glycoproteins / Q000235:genetics; D006118:Griseofulvin / Q000494:pharmacology; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics; D008099:Liver / Q000187:drug effects* / Q000378:metabolism*; D008107:Liver Diseases / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D046351:Protoporphyria, Erythropoietic / Q000235:genetics / Q000378:metabolism*; D011524:Protoporphyrins / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016211:Transforming Growth Factor alpha / Q000235:genetics
chemical_list: D066258:Amphiregulin; C587849:Areg protein, mouse; D066259:Betacellulin; C587852:Btc protein, mouse; D066255:EGF Family of Proteins; C587855:Epgn protein, mouse; D066261:Epigen; D066260:Epiregulin; C587881:Ereg protein, mouse; D006023:Glycoproteins; C587884:Hbegf protein, mouse; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D011524:Protoporphyrins; D016211:Transforming Growth Factor alpha; D006118:Griseofulvin; D004815:Epidermal Growth Factor; D066246:ErbB Receptors