Differential regulation of activin A for hepatocyte growth and fibronectin synthesis in rat liver injury.
OBJECTIVE
Both hepatocyte growth and production of extracellular matrix such as fibronectin are essential for liver regeneration. Although activin A is reported to inhibit DNA replication in rat hepatocytes, the role of activin A for liver regeneration after acute injury has not been fully assessed. This study investigated the mechanism by which hepatocyte growth is regulated by activin A during liver regeneration and the effects of activin A on extracellular matrix production.


METHODS
The mRNA for betaA subunit of activin A and activin receptors in hepatocytes and hepatic stellate cells after CCl4 administration were studied by Northern blotting. Binding of 125I-activin A was tested in these cells. Effects of activin A were examined by DNA, collagen and fibronectin synthesis.


RESULTS
betaA mRNA was expressed in quiescent hepatocytes, and this expression peaked 12 h after CCl4 administration. Activin receptor mRNAs and cross-linked ligand/receptor complexes were expressed in hepatocytes and hepatic stellate cells However, these levels decreased specifically in hepatocytes at 24 h and had normalized by 72 h. The down-regulation of activin receptor was also observed after partial hepatectomy. Antiproliferative response to activin A decreased in hepatocytes at 24 h. Activin A stimulated production of fibronectin by hepatic stellate cells, but the synthesis of collagen was only slightly elevated in hepatic stellate cells following activin stimulation.


CONCLUSIONS
The down-regulation of activin receptors in hepatocytes may be partly responsible for these cells becoming responsive to mitogenic stimuli. The increase of activin A at the early stage of liver injury has the potential to contribute to the regulation of fibronectin production in hepatic stellate cells.
Date
M
M
Third Department of Internal Medicine, Kansai Medical University, Osaka, Japan.
Matsuzaki
K
K
Matsushita
M
M
Tahashi
Y
Y
Sakitani
K
K
Inoue
K
K
D029404:Activin Receptors; D028341:Activins; D000818:Animals; D002251:Carbon Tetrachloride / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D056486:Chemical and Drug Induced Liver Injury; D005109:Extracellular Matrix / Q000378:metabolism; D005353:Fibronectins / Q000096:biosynthesis*; D006498:Hepatectomy / Q000379:methods; D007265:Inhibins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*; D008099:Liver / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D008107:Liver Diseases / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D008115:Liver Regeneration / Q000502:physiology*; D008297:Male; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D017978:Receptors, Growth Factor / Q000235:genetics / Q000378:metabolism
D005353:Fibronectins; D012333:RNA, Messenger; D017978:Receptors, Growth Factor; D028341:Activins; D007265:Inhibins; D002251:Carbon Tetrachloride; D029404:Activin Receptors