Journal
ARCHIVES OF TOXICOLOGY
Volume 90, Issue 2, Pages 347-357Publisher
SPRINGER HEIDELBERG
DOI: 10.1007/s00204-014-1436-y
Keywords
Acute hepatotoxicity; CCl4; Regeneration; ALK5; LY364947; TGF beta; Smad
Categories
Funding
- Netherlands Organization for Scientific Research (NWO-MW)
- Netherlands Institute for Regenerative Medicine (NIRM)
- Marie Curie Initial Training Network (ITN) IT-Liver grant
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Liver exhibits a remarkable maintenance of functional homeostasis in the presence of a variety of damaging toxic factors. Tissue regeneration involves cell replenishment and extracellular matrix remodeling. Key regulator of homeostasis is the transforming growth factor-beta (TGF beta) cytokine. To understand the role of TGF beta during liver regeneration, we used the single-dose carbon tetrachloride (CCl4) treatment in mice as a model of acute liver damage. We combined this with in vivo inhibition of the TGF beta pathway by a small molecule inhibitor, LY364947, which targets the TGF beta type I receptor kinase [activin receptor-like kinase 5 (ALK5)] in hepatocytes but not in activated stellate cells. Co-administration of LY364947 inhibitor and CCl4 toxic agent resulted in enhanced liver regeneration; cell proliferation (measured by PCNA, phosphorylated histone 3, p21) levels were increased in CCl4 + LY364947 versus CCl4-treated mice. Recovery of CCl4-metabolizing enzyme CYP2E1 expression in hepatocytes is enhanced 7 days after CCl4 intoxication in the mice that received also the TGF beta inhibitor. In summary, a small molecule inhibitor that blocks ALK5 downstream signaling and halts the cytostatic role of TGF beta pathway results in increased cell regeneration and improved liver function during acute liver damage. Thus, in vivo ALK5 modulation offers insight into the role of TGF beta, not only in matrix remodeling and fibrosis, but also in cell regeneration.
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