Insulin-like Growth Factor-I Reduces Collagen Production by Hepatic Stellate Cells Through Stimulation of Collagen Degradation System via mTOR-Dependent Signaling Pathway.

Aim: The liver is the major source of circulating insulin-like growth factor (IGF)-I. Serum IGF-I levels are decreased in cirrhotic patients depending on severity. IGF-I administration was shown to improve liver function in patients and animal models of liver cirrhosis. However, controversy exists as to whether IGF-I stimulates or reduces fibrosis in the liver. The effects of IGF-I on collagen accumulation by hepatic stellate cells (HSCs) and its mechanisms were studied.

Methods: A moderately activated HSC clone was used to determine the effect of IGF-I administration on the collagen production system, including its degradation. The intracellular signaling system was also studied in the cells stimulated by IGF-I.

Results: IGF-I treatment reduced total amounts of collagen deposition in a dose-related manner, while DNA synthesis was stimulated by IGF-I. IGF-I treatment did not affect transforming growth factor-beta levels and type I procollagen mRNA expression. Expression of matrix metalloproteinase (MMP)-2 and -9 was upregulated, and tissue inhibitor of metalloproteinase (TIMP)-1 expression was downregulated by IGF-I treatment. Rapamycin, an inhibitor of mammalian target of rapamycin (mTOR), suppressed phosphorylation of 70 kDa ribosomal protein S6 kinase and eukaryotic initiation factor 4E-binding protein 1, and abrogated IGF-I-induced increase in MMP-2 and -9 expression and decrease in TIMP-1 expression.

Conclusions: IGF-I has the ability to stimulate the collagen degradation system by HSCs through an mTOR-dependent pathway independent of modulation of the activation state of HSCs.