Gene expression during chemically induced liver fibrosis: effect of halofuginone on TGF-β signaling

Abstract

Hepatic fibrosis is associated with the activation of stellate cells (HSCs), the major source of extracellular matrix (ECM) proteins. Transforming growth factor-beta (TGF-beta), signaling via Smad3, is the most profibrogenic cytokine and the major promoter of ECM synthesis. Halofuginone, an inhibitor of liver fibrosis, inhibits TGF-beta-dependent Smad3 phosphorylation in human HSCs in culture. We have used transcriptional profiling to evaluate the effect of halofuginone on gene expression during the progression of thioacetamide (TAA)-induced liver fibrosis in the rat and have focused on genes that are associated with TGF-beta. TAA treatment causes alterations in the expression of 7% of liver genes. Halofuginone treatment prevents the changes in the expression of 41% of these genes and results in the inhibition of HSC activation and collagen synthesis. During the early stages of the disease, halofuginone affects genes involved in alcohol, lipid, protein, and phosphate metabolism and cell adhesion and, at later stages, in the cell cycle (cell development, differentiation, cell proliferation, and apoptosis). The activation of TGF-beta-dependent genes, such as tartrate-resistant acid phosphatase, its putative substrate osteopontin, stellate cell activation-association protein, and fibrillin-1, during chemically induced fibrosis is prevented by halofuginone. This study thus highlights the role of TGF-beta signaling in liver fibrosis and especially its potential for pharmacological intervention. Halofuginone, which has demonstrated efficacy and tolerance in animals and humans, could become an effective and novel therapy for liver fibrosis.

Halofuginone upregulates the expression of heparanase in thioacetamide-induced liver fibrosis in rats

“…In later stages, HF affects genes involved in cell development, proliferation, differentiation and apoptosis. 18 We cannot exclude that a component of fibrogenesis in this model is contributed by portal-tract myofibroblasts. 45 However, the primary site of TAA cytotoxicity and fibrogenesis is centrilobular.…”

“…As a specific inhibitor of collagen type I synthesis, HF has extensively been studied in the setting of experimental fibrosis. [16][17][18][19] In the past we have demonstrated the beneficial effect of HF on fibrotic rat liver regeneration following PHx. 20 In the present study, we investigated whether the beneficial effects of HF on thioacetamide (TAA)-induced liver fibrosis stem from its already known antifibrogenic effects and its capacity to enhance regeneration via production of heparanase.…”

Transforming growth factor-β and fibrosis

“…In this context, halofuginone a low molecular weight plant alkaloid used as a coccidiostat for poultry, was effective in inhibiting dermal fibrosis in the tight skin mouse of scleroderma, and radiation-induced fibrosis [63][64][65] . Thus, halofuginone, which has demonstrated efficacy and tolerance in humans, could become an effective and novel therapy for example for liver fibrosis [66] . Secondly, activation of the MAP kinase JNK, whether by cytokines such as TNF-α or by pharmacologic molecules such as 5-fluoro-uracyl, blocks the transcriptional outcome of the TGF-β/Smad3 signaling pathway by induction of c-Jun phosphorylation which, directly interferes with Smad3-de pendent transcription (Figure 4) [67][68][69][70][71][72] .…”

Análise dos efeitos antiangiogênicos e antiproliferativos da halofuginona na leucemia promielocítica aguda

“…Nos estágios iniciais da doença, a halofuginona foi responsável por afetar a expressão de genes envolvidos no metabolismo lipídico, protéico, alcoólico e do fosfato, além de moléculas de adesão. Por outro lado, no momento mais tardio da progressão da doença, os genes afetados relacionam-se basicamente com ciclo celular (desenvolvimento celular, diferenciação, proliferação e apoptose) (GNAINSKY et al, 2007).…”

“…Esses resultados estão em acordo com diferentes estudos que demonstraram a inibição da via do TGF-β pela HF (GNAINSKY et al, 2007;LEIBA et al, 2006;XAVIER et al, 2004 …”