Impaired Phorbol Ester-Induced Hepatocyte Proliferation in Cirrhosis

Hiroaki Imanishi, Piyush C. Kothary, Faizullah Y. Bhora, Frederic Eckhauser, Steven E. Raper

Research output: Contribution to journalArticle

Abstract

Cirrhotic livers are considered to regenerate less actively than normal livers after hepatic resection. Little is known about the mechanisms responsible for impaired capacity of regeneration in cirrhotic liver. In the present study, we investigated the effect of phorbol ester on hepatocyte proliferation in healthy and cirrhotic hepatocytes, using one of the phorbol esters, 12-O-tetradecanoyl-phorbol-13-acetate (TPA), which has a direct effect on activation of protein kinase C (PKC). Cirrhosis was established by the administration of carbon tetrachloride and phenobarbital to rats. Healthy and cirrhotic hepatocytes were isolated from Wistar male rats by a two-step collagenase perfusion technique. DNA synthesis was estimated by [3H]thymidine incorporation into DNA and by autoradiographic nuclear labeling index. [3H]Thymidine incorporation was measured 24 hr after hepatocytes were stimulated by appropriate reagents. TPA (50 nM) stimulated [3H]thymidine incorporation in healthy hepatocytes (control vs TPA, 991 ± 247 vs 2569 ± 766 mean ± SEM cpm/μg DNA; P <0.05), whereas TPA (50 nM) failed to stimulate in cirrhotic hepatocytes (control vs TPA, 1144 ± 184 vs 1304 ± 187 cpm/μg DNA; NS). Staurosporine, a specific PKC inhibitor, suppressed [3H]thymidine incorporation in TPA-stimulated healthy hepatocytes (806 ± 263 cpm/μg DNA; P ± 0.05); however, it had no effect on cirrhotic hepatocytes (1295 ± 180 cpm/μg DNA; NS). An autoradiographic nuclear labeling index exhibited the same results with [3H]thymidine incorporation. We conclude that TPA stimulates hepatocyte proliferation in healthy rat hepatocytes but has no effect on cirrhotic hepatocytes.

Original languageEnglish (US)
Pages (from-to)435-440
Number of pages6
JournalJournal of Surgical Research
Volume58
Issue number4
DOIs
StatePublished - Apr 1995
Externally publishedYes

Fingerprint

Phorbol Esters
Hepatocytes
Fibrosis
Acetates
Thymidine
DNA
Liver
Protein Kinase C
Staurosporine
Protein C Inhibitor
Carbon Tetrachloride
Tetradecanoylphorbol Acetate
Collagenases
Protein Kinase Inhibitors
Phenobarbital
phorbol
Wistar Rats
Regeneration
Perfusion

ASJC Scopus subject areas

  • Surgery

Cite this

Impaired Phorbol Ester-Induced Hepatocyte Proliferation in Cirrhosis. / Imanishi, Hiroaki; Kothary, Piyush C.; Bhora, Faizullah Y.; Eckhauser, Frederic; Raper, Steven E.

In: Journal of Surgical Research, Vol. 58, No. 4, 04.1995, p. 435-440.

Research output: Contribution to journalArticle

Imanishi, Hiroaki ; Kothary, Piyush C. ; Bhora, Faizullah Y. ; Eckhauser, Frederic ; Raper, Steven E. / Impaired Phorbol Ester-Induced Hepatocyte Proliferation in Cirrhosis. In: Journal of Surgical Research. 1995 ; Vol. 58, No. 4. pp. 435-440.
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