Hepatocyte proliferation and gene expression induced by triiodothyronine in vivo and in vitro

Abstract

Subcutaneous injections of hormone triiodothyronine in rats resulted in peak blood levels at 24 hr with return to baseline by 96 hr. The injections stimulated a liver regeneration response that resembled in timing and in magnitude of DNA synthesis (peak, 24 hr) that induced by 40% hepatic resection. The principal proliferation was of hepatocytes. Although there were some temporal differences from the gene expression of transforming growth factor-a, transforming growth factor-~, and c-Ha-ras that are known to follow partial hepatectomy, the overall profile of these changes was similar to those after partial resection. The effect was liver specific and could be reproduced three times with no diminution in response in the same animal with injections at 10-day intervals. No response was detected in kidney or intestine. This effect in intact animals contrasted with the minimal ability of triiodothyronine to stimulate hepatocytes in culture. However, when the culture medium was enriched with epidermal growth factor, there was a dose-related response to triiodothyronine. The totality of these experiments provides a preliminary basis for the creation with pharmacological techniques of an in vivo hyperplastic hepatic condition permissive of transfection of new genes, as an alternative to partial hepatectomy. Although triiodothyronine was the test agent used, other hepatic growth factors singly or in combination could be candidates for this purpose.

Role of thyroid hormone in stimulating liver repopulation in the rat by transplanted hepatocytes

“…This agent is considered a ''weak'' mitogen in that it causes a much lower level of hepatocyte proliferation than two-thirds PH. 13,14 Our finding of a slower rate of liver repopulation in the first month following T 3 administration compared with two-thirds PH (see Laconi et al 11 ) is consistent with this interpretation. An alternative explanation is that in PH-treated animals, there is an acute loss of hepatocyte mass, whereas in T 3 -treated animals, hepatocyte loss occurs more slowly, and replacement by transplanted cells follows the kinetics of endogenous hepatocyte loss.…”

“…17 Numerous studies have shown also that T 3 , as well as 9-cis retinoic acid and some peroxisome proliferators, are specific inducers of hepatocyte proliferation in rats. 13,14,[18][19][20] To the best of our knowledge, however, no study published to date has evaluated the role of T 3 in stimulating liver repopulation by transplanted hepatocytes.…”

Hormetic responses of thyroid hormone calorigenesis in the liver: Association with oxidative stress

“…2A; 29, 39) secondary to T 3 administration involves the expansion of Kupffer cell precursors by means of circulating monocyte recruitment, the differentiation of pre-existing local Kupffer cell precursors into mature macrophages, or both, as result of the action of T 3 as a primary hepatic mitogen in vivo, triggering the process of direct hyperplasia (61,62). Consequently, an enhanced ROS generation at the Kupffer cell level is likely to occur in agreement with the significant 105% increase in the NADPH oxidase-dependent respiratory burst activity assessed in the perfused rat liver upon Figure 2.…”

Poly(cationic lipid)-mediated in vivo gene delivery to mouse liver

“…20 Therefore, for clinical applications of liposome-mediated gene delivery, a non-invasive approach that leads to marked hepatocyte proliferation is required. It has been reported recently that thyroid hormone, specifically T 3 , which is used for the treatment of hypothyroidism, and is well tolerated in a clinical setting, causes a repeatable surge of DNA synthesis in the intact livers of euthyroid rats 21 and can stimulate repopulation of transplanted hepatocytes in rats. 22 Pretreatment with thyroid hormone and keratinocyte growth factor significantly enhanced rat hepatocyte proliferation and enabled retroviral gene transfer through systemic administration.…”