The Expression of a Metallothionein-Ovine Growth Hormone Fusion Gene in Transgenic Mice Does Not Impair Fertility but Results in Pathological Lesions in the Liver

Abstract

The physiological effects of high serum levels of ovine GH (oGH) were studied in three generations of transgenic mice carrying a metallothionein 1-(MT)oGH fusion gene. Livers of mice expressing oGH were enlarged, irrespective of the level of serum oGH detected. In mice expressing high levels of oGH, direct measurements of hepatocytes in liver sections revealed that cell and nuclear size were abnormally large. Hepatocytes of different transgenic mice varied from 1.4-2.2 times normal size and hepatocyte nuclei varied from 1.7-2.4 times normal size. In addition, intranuclear inclusions were observed in hepatocytes of transgenic mice and their presence was always associated with high serum levels of oGH. In contrast to female transgenic mice containing mouse MT-human, rat, or bovine GH fusion genes female mice containing the MT oGH fusion gene were fertile and their pituitary glands showed synthesis of GH.

Abrogation of growth hormone secretion rescues fatty liver in mice with hepatocyte-specific deletion of JAK2

“…However, there is contradictory evidence as to the role of GH in FL (31,32). FL has not been described in any of the mouse models of GH excess or deficiency (24,(33)(34)(35)(36)(37). Interestingly, neither global disruption of GHR nor the N-terminal truncation of STAT5A and -B leads to FL (24,25).…”

Effects of Growth Hormone (GH) Overexpression in Signaling Cascades Involved in Promotion of Cell Proliferation and Survival

“…The liver is one of the principal target organs of growth hormone, and GH overexpressing mice exhibit phenotypic characteristics that indicate GH is indeed acting in this tissue. For instance, absolute and relative liver weight is higher in GH-transgenic than in control mice, accompanied by pathological alterations in the liver (Orian et al, 1989;Quaife et al, 1989;Snibson, 2002;Bartke, 2003). Circulating levels of IGF1 and hepatic levels of IGF1 mRNA, which are primarily regulated by GH action in the liver, are increased in GH transgenic mice.…”

“…The preneoplasic liver pathology observed in the GHoverexpressing transgenic mice resembles that seen in human patients at high risk of developing liver cancer, which turns this animal model suitable for studies of hepatic cancer. The liver of GH-transgenic mice develops various degrees of necroinflammatory, cirrhotic, fibrotic and regenerative changes, all of which are factors known to predispose human individuals to hepatocarcinogenesis (Orian et al, 1989;Snibson et al, 1999;Snibson 2002;Bartke 2003). Moreover, high GH levels are observed in patients with liver conditions associated with increased risk of liver cancer (Hattori et al, 1992;Kratzsch et al, 1995).…”

Growth Hormone and Translational Research: From the 'Bench' to the 'Bedside'

“…Specific pathological organ changes in these mice have been noted as a result of high GH levels. These changes include severe glomerulosclerosis and lipid accumulation in the kidney as well as enlargement of most GH sensitive tissues, with liver and spleen experiencing the greatest disproportionate increase in size [35][36][37][38][39][40][41]. There is also evidence of impaired cardiac and vascular function [42][43][44][45], lipid abnormalities [46], kidney damage [47,48], and greater incidence and early onset of mammary tumors in at least hGH transgenic mice [49].…”