Insulin and insulin-like growth factor-1 stimulate proliferation and type I collagen accumulation by human hepatic stellate cells

Differential effects on signal transduction pathways

G. Svegliati-Baroni, F. Ridolfi, A. Di Sario, A. Casini, L. Marucci, G. Gaggiotti, P. Orlandoni, G. Macarri, L. Perego, A. Benedetti, F. Folli

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246 Citations (Scopus)

Abstract

Insulin and insulin-like growth factor (IGF-1) are mitogenic for fibroblasts and smooth muscle cells, IGF-1 increases in inflamed and fibrotic tissues and induces proliferation of rat hepatic stellate cells (HSC). This study evaluates the potential roles of these hormones in the development of liver fibrosis. Insulin and IGF-1 receptor expression was evaluated by immunohistochemistry in both cultured human HSC and human liver tissue. Phosphorylation of both 70-kd S6 kinase and extracellular-regulated kinase (ERK), cell proliferation, type I collagen gene expression, and accumulation in HSC culture media were evaluated by Western blot, immunohistochemistry for bromodeoxyuridine (BrdU), Northern blot, and enzyme-linked immunosorbent assay, respectively Insulin and IGF-1 receptors were detected in HSC in vitro and in liver sections from patients with chronic active hepatitis. Insulin and IGF-1 induced 70-kd S6 kinase phosphorylation in HSC, whereas IGF-1 only induced ERK phosphorylation. Insulin and IGF-1 stimulated HSC proliferation in a dose-dependent fashion, with IGF-1 being four to five times more potent than insulin. Cell exposure to specific inhibitors showed that both phosphatidylinositol 3-kinase (PI3-K) and ERK are involved in IGF-1-induced mitogenesis, whereas insulin stimulated mitogenesis through a PI3-K-dependent ERK-independent pathway IGF-1 increased type I collagen gene expression and accumulation in HSC culture media through a PI3-K- and ERK-dependent mechanism. In conclusion, insulin and IGF-I, which stimulate HSC mitogenesis and collagen synthesis, may act in concert to promote liver fibrosis in vivo by a differential activation of PI3-K- and ERK1-dependent pathways.

Original languageEnglish
Pages (from-to)1743-1751
Number of pages9
JournalHepatology
Volume29
Issue number6
DOIs
Publication statusPublished - 1999

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Hepatic Stellate Cells
Somatomedins
Collagen Type I
Insulin-Like Growth Factor I
Signal Transduction
Insulin
Phosphatidylinositol 3-Kinase
Phosphotransferases
Ribosomal Protein S6 Kinases
IGF Type 1 Receptor
Phosphorylation
Liver Cirrhosis
Culture Media
Cell Culture Techniques
Immunohistochemistry
Cell Proliferation
Gene Expression
Liver
Bromodeoxyuridine
Chronic Hepatitis

ASJC Scopus subject areas

  • Hepatology

Cite this

Insulin and insulin-like growth factor-1 stimulate proliferation and type I collagen accumulation by human hepatic stellate cells : Differential effects on signal transduction pathways. / Svegliati-Baroni, G.; Ridolfi, F.; Di Sario, A.; Casini, A.; Marucci, L.; Gaggiotti, G.; Orlandoni, P.; Macarri, G.; Perego, L.; Benedetti, A.; Folli, F.

In: Hepatology, Vol. 29, No. 6, 1999, p. 1743-1751.

Research output: Contribution to journalArticle

Svegliati-Baroni, G, Ridolfi, F, Di Sario, A, Casini, A, Marucci, L, Gaggiotti, G, Orlandoni, P, Macarri, G, Perego, L, Benedetti, A & Folli, F 1999, 'Insulin and insulin-like growth factor-1 stimulate proliferation and type I collagen accumulation by human hepatic stellate cells: Differential effects on signal transduction pathways', Hepatology, vol. 29, no. 6, pp. 1743-1751. https://doi.org/10.1002/hep.510290632
Svegliati-Baroni, G. ; Ridolfi, F. ; Di Sario, A. ; Casini, A. ; Marucci, L. ; Gaggiotti, G. ; Orlandoni, P. ; Macarri, G. ; Perego, L. ; Benedetti, A. ; Folli, F. / Insulin and insulin-like growth factor-1 stimulate proliferation and type I collagen accumulation by human hepatic stellate cells : Differential effects on signal transduction pathways. In: Hepatology. 1999 ; Vol. 29, No. 6. pp. 1743-1751.
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T1 - Insulin and insulin-like growth factor-1 stimulate proliferation and type I collagen accumulation by human hepatic stellate cells

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AU - Ridolfi, F.

AU - Di Sario, A.

AU - Casini, A.

AU - Marucci, L.

AU - Gaggiotti, G.

AU - Orlandoni, P.

AU - Macarri, G.

AU - Perego, L.

AU - Benedetti, A.

AU - Folli, F.

PY - 1999

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