Interazioni tra IGF-1 ed Estrogeni nella regolazione della proliferazione dei colangiociti

Interazioni tra IGF-1 ed Estrogeni nella regolazione della proliferazione dei colangiocit

Bile salts regulate proliferation and apoptosis of liver cells by modulating the IGF1 system and estrogen receptors

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Insulin-like growth factor-1 isoforms in rat hepatocytes and cholangiocytes and their involvement in protection against cholestatic injury

A 'locally acting' IGF1 ( insulin- like growth factor 1) isoform has been recently identified in the skeletal muscle and neural tissues where it accelerates injury repair. No information exist on the expression and function of IGF1 isoforms in the liver. We investigated IGF1 isoforms in rat hepatocytes and cholangiocytes and evaluated their involvement in cell proliferation or damage induced by experimental cholestasis ( bile duct ligation, BDL) or hydrophobic bile salts. IGF1 isoforms were analyzed by real- time PCR by using b- actin as internal reference. In both hepatocytes and cholangiocytes, the ` locally acting' IGF1 isoform ( XO6108) and ` circulating' IGF1 isoform ( NM_ 178866) represented respectively 44 and 52% of the total IGF1. Basal mRNAs for both ` locally acting' and ` circulating' IGF1 isoforms were higher ( Po0.05) in hepatocytes than cholangiocytes. After BDL for 3 h, the ` locally acting' IGF1 isoform decreased threefold ( Po0.05) in hepatocytes but remained stable in cholangiocytes with respect to sham- controls. After 1 week of BDL, hepatocytes displayed a further fivefold decrease of ` locally acting' IGF1 mRNA. In contrast, cholangiocytes showed an eightfold increase of the ` locally acting' IGF1 mRNA. The effect of 3 h of BDL on IGF1 isoforms was reproduced in vitro by incubation with glycochenodeoxycholate ( GCDC). The cytotoxic effects ( inhibition of proliferation and induction of apoptosis) of GCDC on isolated cholangiocytes were more pronounced after selective silencing ( SiRNA) of ` locally acting' than ` circulating' IGF1 isoform. Rat hepatocytes and cholangiocytes express the ` locally acting' IGF1 isoform, which decreased during cell damage and increased during cell proliferation. The ` locally acting' IGF1 was more active than the ` circulating' isoform in protecting cholangiocytes from GCDC- induced cytotoxicity. These findings indicate that, besides muscle and neural tissues, also in liver cells the ` locally acting' IGF1 isoform is important in modulating response to damage

Bile salts regulate proliferation and apoptosis of liver cells by modulating the IGF1 system

Abstract BACKGROUND: In different cell types, the insulin-like growth factor 1 and its receptor modulate growth, apoptosis and damage repair in cooperation with estrogen receptors. AIM: To 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. RESULTS: In 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. CONCLUSIONS: Modulation of the IGF1 system could represent a potential strategy for the management of bile salts-induced liver injury