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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
Author(s) -
Donthamsetty Shashikiran,
Bhave Vishakha S.,
Kliment Corrine S.,
Bowen William C.,
Mars Wendy M.,
Bell Aaron W.,
Stewart Rachel E.,
Orr Anne,
Wu Chuanyue,
Michalopoulos George K.
Publication year - 2011
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.24040
Subject(s) - integrin linked kinase , hepatocyte , medicine , endocrinology , chemistry , proliferating cell nuclear antigen , hyperplasia , integrin , kinase , pharmacology , receptor , protein kinase a , biochemistry , immunohistochemistry , in vitro , cyclin dependent kinase 2
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. (H EPATOLOGY 2011;53:587‐595)