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

Abstract

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.

Growth Hormone Mediates Its Protective Effect in Hepatic Apoptosis through Hnf6

“…Hepatic Igf1 during BDL injury is unimpaired in KO mice. KO mice thus may have compensated for Hnf6 loss through, as previously described, Igf-1 pro-survival effects on cell proliferation [37,38] and anti-apoptotic activity [39–41]. The loss of Hnf6 function in KO mice may be further counterbalanced by preserved expression of Oc2 and Oc3 paralogs, Foxa2 , and notably by compensatory increases in Hnf1b .…”

Comparison of the effects of the n-3 polyunsaturated fatty acid eicosapentaenoic and fenofibrate on the inhibitory effect of arthritis on IGF1

“…In this sense, EPA is able to prevent LPS-induced increase in TNF expression in both liver cells alone or in liver cells cocultured with macrophages (Hao et al 2010), and LPS directly inhibits Igf1 expression in hepatocyte cultures and in cocultures with Kuppfer cells (Priego et al 2006, Granado et al 2008. Furthermore, EPA induces cell proliferation in primary hepatocyte cultures (Liu et al 2011), and IGF1 has been reported to be an important factor in proliferation and in the response to damage in liver cell (Gatto et al 2008).…”

Insulin-like growth factor 1 enhances bile-duct proliferation and fibrosis in Abcb4−/− mice

“…Since the biliary epithelium expresses IGF1R [12], and IGF1 protects cholangiocytes against cholestatic injury in vitro [13], overexpression of IGF1 could be beneficial in these diseases. Therefore the aim of this study was to investigate if a prolonged increase of hepatic IGF1 expression in a model for chronic cholangiopathy, the Abcb4 −/− mouse, was beneficial.…”