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.
Keywords
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to Journal of HepatologyAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- In vivo inhibition of rat stellate cells activation by soluble transforming growth factor β type II receptor: a potential new therapy for hepatic fibrosis.Proc Natl Acad Sci USA. 1999; 96: 12719-12724
- Liver fibrosis.Springer Semin Immunopathol. 1999; 21: 475-490
- The cellular basis of hepatic fibrosis. Mechanism and treatment strategies.N Engl J Med. 1993; 328: 1828-1835
- Liver fibrogenesis and the role of hepatic stellate cells: new insights and prospects for therapy.J Gastroenterol Hepatol. 1999; 14: 618-633
- The hepatic stellate (Ito) cell: its role in human liver disease.Virchows Arch. 1997; 430: 195-207
- Activation of hepatic stellate cells—a key issue in liver fibrosis.Front Biosci. 2002; 7: d808-d826
- Transdifferentiation of hepatic stellate cells (Ito cells) to myofibroblasts: a key event in hepatic fibrogenesis.Kidney Int. 1996; 54: S39-S45
- Pathogenesis of liver fibrosis.Clin Sci. 1997; 92: 103-112
- Collagen of normal and cirrhotic human liver.Connect Tissue Res. 1989; 23: 19-31
- Structure of the extracellular matrix in normal and fibrotic liver: collagens and glycoproteins.Semin Liver Dis. 1990; 10: 1-10
- Type I collagen gene regulation and molecular pathogenesis of cirrhosis.Am J Physiol. 1993; 264: G589-G595
- Changes in albumin, α-fetoprotein and collagen gene transcription in CCl4-induced hepatic fibrosis.Hepatology. 1988; 8: 259-266
- Gene expression of type I, III, and IV collagens in hepatic fibrosis induced by dimethylnitrosamine in the rat.Biochem J. 1987; 244: 75-79
- Molecular characteristics of dimethylnitrosamine induced fibrotic liver collagen.Biochim Biophys Acta. 1996; 1292: 215-222
- Synthesis of cellular fibronectin by rat liver fat-storing (Ito) cells: regulation by cytokines.Gastroenterology. 1992; 103: 1313-1321
- Cellular and molecular aspects of hepatic fibrosis.J Pathol. 1993; 170: 105-114
- Tissue inhibitor of metalloproteinase-1 messenger RNA expression is enhanced relative to interstitial collagenase messenger RNA in experimental liver injury and fibrosis.Hepatology. 1996; 24: 176-184
- Tissue inhibitors of metalloproteinases, hepatic stellate cells and liver fibrosis.J Gastroenterol Hepatol. 1998; 13: S33-S38
- Mechanism of spontaneous resolution of rat liver fibrosis. Hepatic stellate cell apoptosis and reduced hepatic expression of metalloproteinase inhibitors.J Clin Invest. 1998; 102: 538-549
- Inhibition of apoptosis of activated hepatic stellate cells by tissue inhibitor of metalloproteinase-1 is mediated via effects on matrix matalloproteinase inhibition: implications for reversibility of liver fibrosis.J Biol Chem. 2002; 277: 11069-11076
- Hepatic stellate cell behavior during resolution of liver injury.Semin Liver Dis. 2001; 21: 427-436
- Cooperation of liver cells in health and disease.Adv Anat Embryol Cell Biol. 2001; 161: 1-151
- Halofuginone: a novel anti-fibrotic therapy.Gen Pharmacol. 1998; 30: 445-450
- Halofuginone: from veterinary use to human therapy.Drug Dev Res. 2000; 50: 371-378
- Halofuginone: an inhibitor of collagen type I synthesis.Biochim Biophys Acta. 1993; 1156: 107-112
- Halofuginone, a specific collagen type I inhibitor, reduces anastomotic intima hyperplasia.Arch Surg. 1995; 130: 257-261
- Inhibition of collagen type I synthesis by skin fibroblasts of graft versus host disease and scleroderma patients: effect of halofuginone.Biochem Pharmacol. 1996; 52: 1057-1063
- Inhibition of collagen synthesis and changes in skin morphology in murine graft versus host disease and tight skin mice: effect of halofuginone.J Invest Dermatol. 1996; 106: 84-88
- Reduction in dermal fibrosis in the tight-skin (Tsk) mouse after local application of halofuginone.Biochem Pharmacol. 2001; 62: 1221-1227
- Reduction in pulmonary fibrosis in vivo by halofuginone.Am J Respir Crit Care Med. 1996; 154: 1082-1086
- Topically applied halofuginone, an inhibitor of collagen type I transcription, reduces peritendinous fibrous adhesions following surgery.Connect Tissue Res. 1996; 34: 97-103
- Halofuginone—an inhibitor of collagen type I synthesis—prevents postoperation abdominal adhesions formation.Ann Surg. 1998; 227: 575-582
- Halofuginone, an inhibitor of collagen type I synthesis, prevents formation of postoperative adhesions formation in the rat uterine horn model.Am J Obstet Gynecol. 1999; 180: 558-563
- The effect of halofuginone, an inhibitor of collagen type I synthesis, on urethral stricture formation: in vivo and in vitro study in a rat model.J Urol. 2000; 164: 1776-1780
- Topical treatment of cutaneous chronic graft versus host disease (cGvHD) with halofuginone: a novel inhibitor of collagen type I synthesis.Transplantation. 1999; 68: 1806-1809
- Halofuginone, a specific inhibitor of collagen type I synthesis, prevents dimethylnitrosamine-induced liver cirrhosis.J Hepatol. 1997; 26: 391-398
- Halofuginone to prevent and treat thioacetamide-induced liver fibrosis in rats.Hepatology. 2001; 33: 379-386
- Halofuginone, a collagen type I inhibitor improves liver regeneration in cirrhotic rats.J Hepatol. 2002; 37: 331-339
- Halofuginone, an inhibitor of type-I collagen synthesis and skin sclerosis, blocks transforming-growth-factor-β-mediated Smad3 activation in fibroblasts.J Invest Dermatol. 2002; 118: 461-470
- Assessment of cisplatin-induced nephrotoxicity by microarray technology.Toxicol Sci. 2001; 63: 196-207
- Proteome analysis of rat hepatic stellate cells.Hepatology. 2000; 32: 268-277
- Circulating levels of insulin-like growth factors and their binding proteins in patients with chronic liver disease: lack of correlation with bone mineral density.Liver. 2001; 21: 123-128
- Prognostic value of insulin-like growth factor I and its binding protein in patients with alcohol-induced liver disease. EMALD group.Hepatology. 1996; 23: 1703-1708
- Diet and diabetic state modify glycogen synthase activity and expression in rat hepatocytes.J Nutr Biochem. 2001; 12: 458-464
- Histological grading and staging of chronic hepatitis.J Hepatol. 1995; 22: 696-699
- Insulin and glucocorticoids regulate IGFBP-1 expression via a common promoter region.Biochem Biophys Res Commun. 1994; 200: 226-232
- Activation of hepatic stellate cells by TGF α and collagen type I is mediated by oxidative stress through c-myb expression.J Clin Invest. 1995; 96: 2461-2468
- Maintenance of differentiated phenotype of cultured rat hepatic lipocytes by basement membrane matrix.J Biol Chem. 1989; 264: 10756-10762
- Altered balance between matrix metalloproteinases and their inhibitors in experimental biliary fibrosis.Am J Pathol. 1998; 153: 1895-1902
- Regulation of growth hormone receptor/binding protein, insulin-like growth factor ternary complex system in human cirrhosis.J Hepatol. 2002; 36: 751-758
- Growth hormone, insulin-like growth factor 1 and insulin-like growth factor binding proteins 1 and 3 in chronic liver disease.Hepatology. 1995; 21: 680-688
- Differential cellular synthesis of insulin-like growth factor binding protein-1 (IGFBP-1) and IGFBP-3 within human liver.J Clin Endocrinol Metab. 1994; 79: 1871-1876
- Cell-specific localization of insulin-like growth factor binding protein mRNAs in rat liver.Am J Physiol Gastrointest Liver Physiol. 2000; 278: G447-G457
- Differential effects of malnutrition, bile duct ligation and galactose-amine injection in young rats on serum levels and gene expression of IGF-binding proteins.J Endocrinol. 1996; 149: 465-472
- Concentrations, release and disposal of insulin-like growth factor (IGF)-binding proteins (IGFBP), IGF-I, and growth hormone in different vascular beds in patients with cirrhosis.J Clin Endocrinol Metab. 1995; 80: 1148-1157
- Expression of IGF-I and IGF-binding protein genes in cirrhotic liver.J Endocrinol. 1996; 149: 209-216
- Interleukin-6-induced STAT3 and AP-1 amplify hepatocyte nuclear factor 1-mediated transactivation of hepatic genes, an adaptive response to liver injury.Mol Cell Biol. 2001; 21: 414-424
- Mitogenic up-regulation of PRL-1 protein-tyrosine phosphatase gene by Egr-1. EGR-1 activation is an early event in liver regeneration.J Biol Chem. 1999; 274: 4513-4520
- Halofuginone inhibition of COL1A2 promoter activity via a c-Jun-dependent mechanism.Arthritis Rheum. 2002; 46: 2748-2761
- Protein kinase B/Akt mediates effects of insulin on hepatic insulin-like growth factor binding protein-1 gene expression through a conserved insulin response sequence.J Biol Chem. 1998; 273: 6482-6487
- Insulin and insulin-growth factor 1 stimulate proliferation and type I collagen accumulation by human hepatic stellate cells: differential effects on signal transduction pathways.Hepatology. 1999; 29: 1743-1751
- The cytokine hepatocyte growth factor/scatter factor inhibits apoptosis and enhances DNA repair by a common mechanism involving signaling through phosphatidyl inositol 3′ kinase.Oncogene. 2000; 19: 2212-2223
- Rapid induction of mRNAs for liver regeneration factor and insulin-like growth factor binding protein-1 in primary cultures of rat hepatocytes by hepatocyte growth factor and epidermal growth factor.Hepatology. 1994; 20: 955-960
- The decrease in total collagen fibers in the liver by hepatocyte growth factor after formation of cirrhosis induced by thioacetamide.Biochem Pharmacol. 2000; 59: 681-690
- Evidence for an in vivo role of insulin-like growth factor binding protein 1 and 2 as inhibitors of collagen gene expression in vitamin C-deficient and fasted guinea pigs.Endocrinology. 1994; 134: 1329-1339
- Impaired hepatocyte DNA synthetic response posthepatectomy in insulin-like growth factor binding protein 1-deficient mice with defects in C/EBPβ and mitogen-activated protein kinase/extracellular signal-regulated kinase regulation.Mol Cell Biol. 2003; 23: 1251-1259
- Massive hepatic apoptosis associated with TGF-β1 activation after Fas ligand treatment of IGF binding protein1-deficient mice.J Clin Invest. 2003; 111: 129-139
- Insulin-like growth factor-binding protein 1 stimulates human trophoblast migration by signaling through α5β1 integrin via mitogen-activated protein kinase pathway.J Clin Endocrinol Metab. 2001; 86: 2484-2493
- Insulin-like growth factor (IGF)-binding proteins inhibit the smooth muscle cell migration responses to IGF-I and IGF-II.Endocrinology. 1995; 136: 4173-4186
- Insulin-like growth factor binding protein-1 (IGFBP-1) inhibits breast cancer cell motility.Cancer Res. 2002; 62: 4369-4375
- Liver fibrosis: insight into migration of hepatic stellate cells in response to extracellular matrix and growth factors.Gastroenterology. 2003; 124: 147-159
Article info
Publication history
Accepted:
October 12,
2003
Received in revised form:
October 10,
2003
Received:
April 30,
2003
xIdentification
Copyright
© 2003 European Association for the Study of the Liver. Published by Elsevier Inc. All rights reserved.
