Halofuginone, an inhibitor of collagen synthesis by rat stellate cells, stimulates insulin-like growth factor binding protein-1 synthesis by hepatocytes.
OBJECTIVE
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.
Gnainsky
Yulia
Y
Institute of Animal Sciences, Agricultural Research Organization, the Volcani Center, PO Box 6, Bet Dagan 50250, Israel.
Spira
Gadi
G
Paizi
Melia
M
Bruck
Rafael
R
Nagler
Arnon
A
Abu-Amara
Suha Naffar
SN
Geiger
Benjamin
B
Genina
Olga
O
Monsonego-Ornan
Efrat
E
Pines
Mark
M
D000818:Animals; D002465:Cell Movement / Q000187:drug effects; D024042:Collagen Type I / Q000235:genetics*; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D018970:Insulin-Like Growth Factor Binding Protein 1 / Q000235:genetics*; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000235:genetics; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D010880:Piperidines; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology*; D052999:Quinazolinones; D051381:Rats; D017208:Rats, Wistar; D013853:Thioacetamide; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000235:genetics
D024042:Collagen Type I; D018970:Insulin-Like Growth Factor Binding Protein 1; D018972:Insulin-Like Growth Factor Binding Protein 3; D010880:Piperidines; D011500:Protein Synthesis Inhibitors; D011799:Quinazolines; D052999:Quinazolinones; D013853:Thioacetamide; D019716:Tissue Inhibitor of Metalloproteinase-2; C010176:halofuginone