Casillas-Ramírez Araní, Zaouali Amine, Padrissa-Altés Susagna, Ben Mosbah Ismail, Pertosa Anna, Alfany-Fernández Izabel, Bintanel-Morcillo Maria, Xaus Carme, Rimola Antoni, Rodés Juan, Roselló-Catafau Joan, Peralta Carmen
Unitat de Transplantament de Fetge i Viabilitat de l'Empelt, Institut d' Investigaciones Biomèdiques August Pi i Sunyer, Barcelona, Spain.
Endocrinology. 2009 Jul;150(7):3153-61. doi: 10.1210/en.2008-1458. Epub 2009 Mar 12.
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 microg/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 microg/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 gamma 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.
肝脂肪变性是缺血再灌注（I/R）的主要危险因素。胰岛素样生长因子结合蛋白（IGFBPs）通过将循环中的胰岛素样生长因子-I（IGF-I）转运至其作用部位来调节IGF-I的作用。表皮生长因子（EGF）在体外刺激IGF-I的合成。我们分别或联合检测了IGF-I和EGF治疗对脂肪变性肝脏I/R易损性的影响。我们的结果表明，I/R仅在脂肪变性肝脏中损害IGF-I的合成。仅当给肥胖动物给予高剂量的IGF-I（400μg/kg）时，它们才表现出高循环IGF-I:IGFBP水平、肝脏IGF-I水平升高以及对损伤的保护作用。在瘦动物中，100μg/kg的IGF-I剂量可保护非脂肪变性肝脏。我们的结果表明，IGF-I和EGF联合给药导致两种肝脏类型的肝损伤参数与单独给予IGF-I和EGF时相似。IGF-I在两种肝脏类型中均增加了EGF的表达。EGF对肝脏I/R损伤的有益作用可能归因于非脂肪变性肝脏中p38的抑制以及脂肪变性肝脏中过氧化物酶体增殖物激活受体γ（PPARγ）的过表达。总之，IGF-I和EGF可能构成降低脂肪变性肝脏对I/R损伤固有易感性的新的药理学策略。
