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

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

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 and estrogen receptors

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Determinants for the Occurrence of Acute Exacerbation after HBeAg Seroclearance in Chinese Patients

This free journal suppl. entitled: AASLD AbstractsMultiple episodes of acute exacerbation in HBeAg-negative patients would accelerate the progression of liver disease. AIM: This study was performed to determine the factors for predicting the occurrence of acute exacerbation in HBeAg-negative patients. METHODS: Two hundred and one patients were recruited at the time of HBeAg seroclearance and prospectively followed up. HBV DNA levels were determined by the Digene Hybrid Capture I1 assay (lower limit of detection 1.4X105 copies/ml). Precore and core promoter mutations were detected by the line probe assay (Innogenetics). RESULTS: The male to female ratio was 13467 with a median age of 34.5(range: 15.2-80.5) years at the time of HBeAg seroclearance. The prevalence of precore and core promoter mutations at the time of HBeAg seroclearance were 95/201(47.3%) and 1411 201(70.2%) respectively. The median follow-up was 26.3(range: 3.0-113.6) months after HBeAg seroclearance. Fifty-six patients had acute exacerbation during this period. Compared with patients without acute exacerbation, patients with acute exacerbations were more likely to be male (P=0.0054), had higher frequency of core promoter mutations at the time of HBeAg seroclearance (P=0.003), were older (P=0.019), had comparable HBV DNA level (P=0.16) and higher serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), bilirubin and alpha-fetoprotein (AFP) levels (P=0.002, < 0.001, 0.003 and 0.003 respectively). Patients with and without precore mutations had comparable chance of acute exacerbation. Using Cox regression with a proportional-hazards model, the male gender, increasing age and presence of core promoter mutations at the time of HBeAg seroclearance were determined to be independent factors associated with the development of acute exacerbation after HBeAg seroclearance (P=0.025,0.018 and 0.001, respectively). CONCLUSION: The male patients with core promoter mutations and delayed HBeAg seroclearance had higher risk of acute exacerbations in the HBeAg-negative phase.link_to_OA_fulltex