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The Role Of Histone Deacetylases During Hepatic Stellate Cell Activation And Fibrogenesis

Thursday, 6 October, 2011 - 17:00
Campus: Brussels Health Campus
Faculty: Medicine and Pharmacy
auditorium R. Vanden Driessche
Inge Mannaerts
phd defence

Liver fibrosis is caused by prolonged exposure to
viruses, toxins, and environmental factors among
others. Upon liver injury, hepatic stellate cells
transdifferentiate into contractile myofibroblastlike
cells that produce matrix proteins eventually
leading to scar formation and liver fibrosis.
Inhibition of this process is thus an important
target for therapeutic intervention in liver
fibrogenesis. An important step in developing an
efficient anti-fibrotic therapy would be to unravel
the underlying molecular mechanism. In this
thesis we focused on the transcriptional
regulation of the hepatic stellate cell activation
process. By using Histone deacetylase inhibitors,
valproic acid and MC1568, respectively inhibiting
the class I and class II histone deacetylases, we
demonstrate that members of both classes play a
role in the activation of hepatic stellate cells.
During a second part of the study, the effect of
valproic acid treatment on gene and microRNA
expression was studied. Identification of valproic
acid sensitive microRNAs can provide us
information about the underlying effect of
valproic acid treatment on stellate cell activation.
Our data suggest that valproic acid exerts its
effect on stellate cells partly by influencing
microRNA expression. In a last part, the role of
two transcriptional repressors during stellate
activation was studied, namely Zfhx1a and
Zfhx1b. We showed that over expression of miR-
200c mediated a down regulation of Zfhx1a and
Zfhx1b, combined with an up regulation of Ecadherin
expression levels. Over expression of
miR-200c was sufficient to inhibit stellate cell
migration and could have potential anti-fibrotic
properties. In conclusion, we have shown that
HDACs and their associated repressor complexes
represent targets to modulate fibrotic disorders.