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Excessive hepatomegaly of mice with hepatocyte-targeted elimination of integrin linked kinase following treatment with 1,4-bis [2-(3,5-dichaloropyridyloxy)] benzene
Hepatology
  • Shashikiran Donthamsetty
  • Vishakha Bhave, Philadelphia College of Osteopathic Medicine
  • Corrine S. Kliment
  • William C. Bowen
  • Wendy M. Mars
  • Aaron W. Bell
  • Rachel E. Stewart
  • Anne Orr
  • Chuanyue Wu
  • George K. Michalopoulos
Document Type
Article
Publication Date
1-1-2011
Disciplines
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. Conclusion: 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. © 2010 American Association for the Study of Liver Diseases.
Comments

This article was published in Hepatology, Volume 53, Issue 2, Pages 587-595.

The published version is available at http://dx.doi.org/10.1002/hep.24040.

Copyright © 2011 Scopus.

Citation Information
Shashikiran Donthamsetty, Vishakha Bhave, Corrine S. Kliment, William C. Bowen, et al.. "Excessive hepatomegaly of mice with hepatocyte-targeted elimination of integrin linked kinase following treatment with 1,4-bis [2-(3,5-dichaloropyridyloxy)] benzene" Hepatology Vol. 53 Iss. 2 (2011) p. 587 - 595
Available at: http://works.bepress.com/vishakha_bhave/2/