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Insulin-Like Growth Factor and Epidermal Growth Factor Treatment: New Approaches to Protecting Steatotic Livers against Ischemia-Reperfusion Injury

Unitat de Transplantament de Fetge i Viabilitat de l’Empelt (A.C.-R., I.A.-F., M.B.-M., J.R.-C., C.P.), Institut d' Investigaciones Biomèdiques August Pi i Sunyer; Experimental Hepatic Ischemia-Reperfusion Unit (A.Z., S.P.-A., I.B.M., A.P., C.X., J.R.-C.), Consejo Superior de Investigaciones Científicas; Centro de Investigaciones Biomédicas Esther Koplowitz (A.R., J.R., J.R.-C., C.P.), Centro de Investigación Biomédica en Red en el Área temática de Enfermedades Hepáticas y Digestivas, Instituto de Salud Carlos III; and Liver Unit (A.R., J.R.), Hospital Clinic Universitari, E-08036 Barcelona, Spain

Address all correspondence and requests for reprints to: Dr. J. Roselló-Catafau, Experimental Hepatic Ischemia-Reperfusion Unit, Instituto de Investigaciones Biomédicas de Barcelona-Consejo Superior de Investigaciones Cientificas, C/ Rosellón 161, Seventh floor, E-08036 Barcelona, Spain. E-mail: jrcbam{at}iibb.csic.es; or Dra. C. Peralta, Unitat de Transplantament de Fetge i Viabilitat de l’Empelt, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Consejo Superior de Investigaciones Científicas, E-08036 Barcelona, Spain. E-mail: cpubam{at}iibb.csic.es.

Hepatic steatosis is a major risk factor in ischemia-reperfusion (I/R). IGF-binding proteins (IGFBPs) modulate IGF-I action by transporting circulating IGF-I to its sites of action. Epidermal growth factor (EGF) stimulates IGF-I synthesis in vitro. We examined the effect of IGF-I and EGF treatment, separately or in combination, on the vulnerability of steatotic livers to I/R. Our results indicated that I/R impaired IGF-I synthesis only in steatotic livers. Only when a high dose of IGF-I (400 µg/kg) was given to obese animals did they show high circulating IGF-I:IGFBP levels, increased hepatic IGF-I levels, and protection against damage. In lean animals, a dose of 100 µg/kg IGF-I protected nonsteatotic livers. Our results indicated that the combined administration of IGF-I and EGF resulted in hepatic injury parameters in both liver types similar to that obtained by IGF-I and EGF separately. IGF-I increased egf expression in both liver types. The beneficial role of EGF on hepatic I/R injury may be attributable to p38 inhibition in nonsteatotic livers and to PPAR overexpression in steatotic livers. In conclusion, IGF-I and EGF may constitute new pharmacological strategies to reduce the inherent susceptibility of steatotic livers to I/R injury.