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


OBJECTIVE
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.
Drudi Metalli
V
V
Division of Gastroenterology, Department of Clinical Medicine, University of Rome, La Sapienza, Rome, Italy.
Mancino
M G
MG
Mancino
A
A
Torrice
A
A
Gatto
M
M
Attili
A F
AF
Alpini
G
G
Alvaro
D
D
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D001647:Bile Acids and Salts / Q000378:metabolism*; D001652:Bile Ducts / Q000166:cytology / Q000378:metabolism; D049109:Cell Proliferation; D022781:Hepatocytes / Q000378:metabolism / Q000502:physiology*; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism
D001647:Bile Acids and Salts; D011960:Receptors, Estrogen; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1