title: Inhibition of TGFβ type I receptor activity facilitates liver regeneration upon acute CCl4 intoxication in mice.
abstract: 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-β (TGFβ) cytokine. To understand the role of TGFβ 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 TGFβ pathway by a small molecule inhibitor, LY364947, which targets the TGFβ 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 TGFβ inhibitor. In summary, a small molecule inhibitor that blocks ALK5 downstream signaling and halts the cytostatic role of TGFβ 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 TGFβ, not only in matrix remodeling and fibrosis, but also in cell regeneration.
authors.affiliation: Department of Molecular and Cell Biology, Leiden University Medical Center, Einthovenweg 20, 2333ZC, Leiden, The Netherlands.
authors.forename: Sofia
authors.initials: S
authors.lastname: Karkampouna
authors.affiliation: Department of Molecular and Cell Biology, Leiden University Medical Center, Einthovenweg 20, 2333ZC, Leiden, The Netherlands.
authors.forename: Marie-José
authors.initials: MJ
authors.lastname: Goumans
authors.affiliation: Department of Molecular and Cell Biology, Leiden University Medical Center, Einthovenweg 20, 2333ZC, Leiden, The Netherlands.
authors.forename: Peter
authors.initials: P
authors.lastname: Ten Dijke
authors.affiliation: Molecular Hepatology - Alcohol Associated Diseases II Medical Clinic Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
authors.forename: Steven
authors.initials: S
authors.lastname: Dooley
authors.affiliation: Department of Molecular and Cell Biology, Leiden University Medical Center, Einthovenweg 20, 2333ZC, Leiden, The Netherlands. M.de_Julio@lumc.nl.|Department of Dermatology, Leiden University Medical Center, Einthovenweg 20, 2333ZC, Leiden, The Netherlands. M.de_Julio@lumc.nl.
authors.forename: Marianna
authors.initials: M
authors.lastname: Kruithof-de Julio
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002252:Carbon Tetrachloride Poisoning / Q000188:drug therapy / Q000503:physiopathology*; D055166:Hepatic Stellate Cells / Q000187:drug effects / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008115:Liver Regeneration / Q000187:drug effects*; D008297:Male; D008810:Mice, Inbred C57BL; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology*; D011758:Pyrroles / Q000494:pharmacology*; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000378:metabolism; D011804:Quinolines
chemical_list: D015415:Biomarkers; D017346:Protein Serine-Threonine Kinases; D011720:Pyrazoles; D011758:Pyrroles; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; C506615:HTS 466284; D011804:Quinolines; C000625842:Tgfbr1 protein, mouse
keywords: ALK5; Acute hepatotoxicity; CCl4; LY364947; Regeneration; Smad; TGFβ