• V Drudi Metalli, M G Mancino, A Mancino, A Torrice, M Gatto, A F Attili, G Alpini, and D Alvaro.
• Division of Gastroenterology, Department of Clinical Medicine, University of Rome, La Sapienza, Rome, Italy.
• Dig Liver Dis. 2007 Jul 1;39(7):654-62.

BackgroundIn different cell types, the insulin-like growth factor 1 and its receptor modulate growth, apoptosis and damage repair in cooperation with estrogen receptors.AimTo evaluate the involvement of the insulin-like growth factor 1 system and estrogen receptors in bile salts modulation of apoptosis/proliferation of hepatocytes and cholangiocytes. Primary cultures of rat hepatocytes and cholangiocytes were exposed to glycochenodeoxycholate or tauro-CDC in the presence or absence of insulin-like growth factor 1 receptor blocking antibody (alphaIR3), small interfering RNA for insulin-like growth factor 1, 17beta-estradiol or estrogen receptor antagonist (ICI 182,780). Proliferation was evaluated by proliferating cell nuclear antigen Western blot and apoptosis by measuring caspase-3 activity or annexin-V.ResultsIn hepatocytes, the insulin-like growth factor 1 receptor blocker enhanced glycochenodeoxycholate-induced apoptosis and caused tauro-CDC to promote apoptosis. 17Beta-estradiol or the estrogen receptor antagonist (ICI 182,780) did not influence the apoptotic effect of glycochenodeoxycholate. In cholangiocytes, both glycochenodeoxycholate and tauro-CDC induced proliferation at 100microM, while they induced apoptosis at 1mM with a more pronounced effect of glycochenodeoxycholate. Apoptosis induced by 1mM glycochenodeoxycholate or tauro-CDC in cholangiocytes was enhanced by blocking insulin-like growth factor 1 receptor or by silencing insulin-like growth factor 1. 17Beta-estradiol counteracts glycochenodeoxycholate-induced cholangiocyte apoptosis by enhancing insulin-like growth factor 1 secretion and activating the insulin-like growth factor 1 system.ConclusionsModulation of the IGF1 system could represent a potential strategy for the management of bile salts-induced liver injury.

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