title: Excessive hepatomegaly of mice with hepatocyte-targeted elimination of integrin linked kinase following treatment with 1,4-bis [2-(3,5-dichaloropyridyloxy)] benzene.
abstract: TCBOPOP (1,4-bis [2-(3,5-dichaloropyridyloxy)] benzene) an agonist of the constitutive androstane receptor (CAR), produces rapid hepatocyte hyperplasia and hepatomegaly in the absence of hepatic injury. In this study we demonstrate that integrin-linked kinase (ILK), which is involved in transmission of the extracellular matrix (ECM) signaling by way of integrin receptors, plays an important role in regulating TCPOBOP-induced proliferation of hepatocytes and hepatomegaly. Hepatocyte-specific ILK knockout mice (ILK/liver-/- mice) and wildtype mice (WT) were given a single dose of TCPOBOP (3 mg/kg) by oral gavage. Mice were sacrificed at days 1, 2, 5, and 7 after TCPOBOP administration. WT mice showed maximum proliferation on days 1 and 2, which came back to baseline levels by days 5 and 7 after TCPOBOP administration. The ILK/liver-/- mice, on the other hand, showed a prolonged and a sustained proliferative response as evident by an increased number of proliferative cell nuclear antigen assay (PCNA)-positive cells even at days 5 and 7 after TCPOBOP administration. At day 7 the WT mice showed close to a 2.5-fold increase in liver weight, whereas the ILK/liver-/- mice showed a 3.7-fold increase in liver weight. The prolonged proliferative response in the ILK/liver-/- mice seems to be due to sustained induction of CAR leading to sustained induction of c-Myc, which is known to be a key mediator of TCPOPOP-CAR induced direct liver hyperplasia.
  
  
  CONCLUSIONS
  The data indicate that ECM-mediated signaling by way of ILK is essential for adjustment of final liver size and proper termination of TCPOBOP-induced proliferation of hepatocytes.
authors.affiliation: Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
authors.forename: Shashikiran
authors.initials: S
authors.lastname: Donthamsetty
authors.forename: Vishakha S
authors.initials: VS
authors.lastname: Bhave
authors.forename: Corrine S
authors.initials: CS
authors.lastname: Kliment
authors.forename: William C
authors.initials: WC
authors.lastname: Bowen
authors.forename: Wendy M
authors.initials: WM
authors.lastname: Mars
authors.forename: Aaron W
authors.initials: AW
authors.lastname: Bell
authors.forename: Rachel E
authors.initials: RE
authors.lastname: Stewart
authors.forename: Anne
authors.initials: A
authors.lastname: Orr
authors.forename: Chuanyue
authors.initials: C
authors.lastname: Wu
authors.forename: George K
authors.initials: GK
authors.lastname: Michalopoulos
mesh_terms: D000818:Animals; D001835:Body Weight / Q000502:physiology; D002453:Cell Cycle / Q000502:physiology; D049109:Cell Proliferation; D004195:Disease Models, Animal; D005109:Extracellular Matrix / Q000502:physiology; D022781:Hepatocytes / Q000378:metabolism* / Q000473:pathology*; D006529:Hepatomegaly / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D009929:Organ Size / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D011725:Pyridines / Q000009:adverse effects*; D015398:Signal Transduction / Q000502:physiology; D000099200:Scaffold Protein ILK
chemical_list: D017346:Protein Serine-Threonine Kinases; D016271:Proto-Oncogene Proteins c-myc; D011725:Pyridines; D000099200:Scaffold Protein ILK; C028474:1,4-bis(2-(3,5-dichloropyridyloxy))benzene