Halofuginone, an inhibitor of collagen synthesis by rat stellate cells, stimulates insulin-like growth factor binding protein-1 synthesis by hepatocytes

Yulia Gnainsky, Gadi Spira, Melia Paizi, Rafael Bruck, Arnon Nagler, Suha Naffar Abu-Amara, Benjamin Geiger, Olga Genina, Efrat Monsonego-Ornan, Mark Pines*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

25 Scopus citations

Abstract

Background/Aims: Halofuginone, an inhibitor of collagen synthesis, prevented and caused resolution of established hepatic fibrosis. A genomic approach in vivo was used to search for additional genes responsible for halofuginone mode of action. Methods: Fibrosis was induced in rats by thioacetamide (TAA) and evaluated by collagen type I gene expression and the levels of collagen, tissue inhibitors of metalloproteinases-2 and smooth-muscle actin. Halofuginone was given in the diet. cDNA from liver biopsies was hybridized on Atlas arrays comprising of 588 genes. The results were confirmed by Northern blots and in situ hybridization. Results: Insulin-like growth factor binding protein-1 (IGFBP-1) was one of the 13 genes differentially expressed in the fibrotic liver after halofuginone treatment. After 2 and 4 weeks, halofuginone prevented the TAA-induced down-regulation of IGFBP-1 gene expression. Halofuginone also prevented the TAA-dependent changes in IGFBP-3 gene expression. Halofuginone affected IGFBP-1 synthesis in rat hepatocytes and cells of hepatocyte origin and caused time- and dose-dependent increases in the IGFBP-1 gene expression and synthesis by HepG2 cells. The IGFBP-1 secreted by HepG2-inhibited stellate cell motility. Conclusions: Halofuginone is an anti-fibrotic drug that inhibits collagen synthesis by stellate cells and preventing alteration in the synthesis of IGFBPs by hepatic cells.

Original languageAmerican English
Pages (from-to)269-277
Number of pages9
JournalJournal of Hepatology
Volume40
Issue number2
DOIs
StatePublished - Feb 2004
Externally publishedYes

Bibliographical note

Funding Information:
Research supported by the NSF MRSEC division under grunt N DMR0080604.

Keywords

  • Atlas microarrays
  • IGFBP-3
  • Smooth muscle actin
  • TIMP-2

Fingerprint

Dive into the research topics of 'Halofuginone, an inhibitor of collagen synthesis by rat stellate cells, stimulates insulin-like growth factor binding protein-1 synthesis by hepatocytes'. Together they form a unique fingerprint.

Cite this