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This version published online on July 8, 2004
Endocrinology, doi:10.1210/en.2004-0655
A more recent version of this article appeared on October 1, 2004
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Submitted on May 24, 2004
Accepted on June 29, 2004

ROLE OF GROWTH HORMONE (GH) IN LIVER REGENERATION

Patricia A. Pennisi, John Kopchick, Snorri Thorgeirsson, Derek LeRoith, and Shoshana Yakar*

Diabetes Branch, NIDDK, National Institutes of Health, Bethesda, MD 20892-1758; Edison Biotechnology Institute, Ohio University College of Osteopathic Medicine, Ohio University, Athens, OH 45701, USA; Laboratory of Experimental Carcinogenesis. CCR. National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-1758

* To whom correspondence should be addressed. E-mail: shoshanay{at}intra.niddk.nih.gov.

Liver regeneration is a fundamental mechanism by which the liver responds to injury. This process is regulated by endogenous growth factors and cytokines and it involves proliferation of all mature cells that exist within the intact organ. To understand the role of the growth hormone (GH)/insulin-like growth factor I (IGF-I) axis in liver regeneration, we performed partial hepatectomies in three groups of mice: GH antagonist (GHa) transgenic mice, in which the action of GH is blocked; liver IGF-I- deficient mice that lack IGF-I specifically in the liver and also lack the acid labile subunit (ALS) (LID+ALSKO mice), in which IGF-I levels are very low and GH secretion is increased; and control mice. Interestingly, the survival rate of GHa transgenic mice was dramatically reduced after partial hepatectomy (57%), compared with the survival rate of controls (100%) or LID+ALSKO mice (88%). In control mice, the liver was completely regenerated after 4 days, whereas liver regeneration required 7 days in LID+ALSKO mice. In contrast, in GHa mice liver regeneration reached only 70% of the original liver mass after 4 days and did not improve thereafter. Strikingly, at 36 and 48 h after hepatectomy, the livers of control and LID+ALSKO mice, respectively, exhibited intense BrdU-staining, whereas BrdU-staining was dramatically decreased in the livers of GHa mice. These results suggest that GH plays a critical role in liver regeneration, although whether it acts directly or indirectly remains to be determined.
Key words: GH • partial hepatectomy • liver regeneration • proliferation • GH antagonist • cell cycle • GHR • IGF-1




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