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Role of Growth Hormone (GH) in Liver Regeneration

Diabetes Branch, National Institute of Diabetes and Digestive and Kidney Diseases (P.A.P., D.L., S.Y.), and Laboratory of Experimental Carcinogenesis, Center of Cancer Research, National Cancer Institute (S.T.), National Institutes of Health, Bethesda, Maryland 20892-1758; and Edison Biotechnology Institute, Ohio University College of Osteopathic Medicine, Ohio University (J.J.K.), Athens, Ohio 45701

Address all correspondence and requests for reprints to: Dr. Shoshana Yakar, Diabetes Branch, National Institute of Diabetes and Digestive and Kidney Diseases, Room 8D12, Building 10, National Institutes of Health, Bethesda, Maryland 20892-1758. 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 GH/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 d, whereas liver regeneration required 7 d in LID+ALSKO mice. In contrast, in GHa mice, liver regeneration reached only 70% of the original liver mass after 4 d and did not improve thereafter. Strikingly, 36 and 48 h after hepatectomy, the livers of control and LID+ALSKO mice, respectively, exhibited intense 5-bromo-2'-deoxyuridine (BrdU) staining, whereas BrdU staining was dramatically decreased in the livers of GHa-treated mice. These results suggest that GH plays a critical role in liver regeneration, although whether it acts directly or indirectly remains to be determined.

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