Thyroid Status Affects Rat Liver Regeneration After Partial Hepatectomy by Regulating Cell Cycle and Apoptosis

Abstract

In rats, various growth factors and hormones, as well as partial hepatectomy (PH) are able to trigger the proliferative response of hepatocytes. Although recent evidence highlights the important role of thyroid hormones and thyroid status in regulating the growth of liver cells in vitro and in vivo models, the mechanism involved in the pro-proliferative effects of thyroid hormones is still unclear. Here we have investigated how in rats made hypo- and hyperthyroid after prolonged treatment respectively with propylthiouracil (PTU) and triiodothyronine (T3), the thyroid status affects liver regeneration after PH by regulating cell cycle and apoptosis proteins. Our results show that both in control and partially hepatectomized animals hyperthyroidism increases the cyclin D1, E and A levels and the activity of cyclin-cdk complexes, and decreases the levels of cdk inhibitors such as p16 and p27. On the contrary hypothyroidism induces a down-regulation of the activity of cyclin cdk complexes decreasing cyclin levels. Thyroid hormones control also p53 and p73, two proteins involved in apoptosis and growth arrest which are induced by PH. In particular, hypothyroidism increases and T3 treatment decreases p73 levels. The analysis of the phosphorylated forms of p42/44 and p38 MAPK revealed that they are induced during hepatic regeneration in euthyroid and hyperthyroid rats whereas they are negatively regulated in hypothyroid rats. In conclusion our data demonstrate that thyroid status can affects liver regeneration, altering the expression and the activity of the proteins involved in the control of cell cycle and growth arrest.

Thyroid status modulates T lymphoma growth via cell cycle regulatory proteins and angiogenesis

“…Alisi et al (2005) demonstrated that hyperthyroidism increased the expression of cyclins D1, E, and A and decreased the expression of p16/INK4A and p27/KIP1 in a rat model of liver regeneration; this study also showed that hypothyroidism resulted in the reduced expression of these cyclins, as well as the increased expression of p16/INK4A, p27/KIP1, and p53.…”

“…TH-mediated regulation of cyclin-CDK complexes leading to cell arrest (Toms et al 1998) or cell differentiation (Ballock et al 2000) has also been demonstrated. Alisi et al (2005) showed in vivo that hyperthyroidism increases the levels of cyclins D1, E, and A and the activity of cyclin-CDK complexes, and decreases the levels of CDKIs, such as p16/INK4A (CDKN2A) and p27/KIP1 (CDKN1B). They also demonstrated that hypothyroidism induces contrary effects and that THs modulate the expression of the tumor suppressor genes p53 (Trp53) and p73 (Trp73), both involved in apoptosis and growth arrest.…”

The Nuclear Receptor Constitutively Active/Androstane Receptor Regulates Type 1 Deiodinase and Thyroid Hormone Activity in the Regenerating Mouse Liver

“…It is also well established that thyroid hormone can increase the growth of the liver after PH because injection of T3 into mice after PH increases the rate of liver regeneration (Moro et al, 2004;Alisi et al, 2005). It does not appear that CAR directly regulates the levels of T3, although ability of CAR to regulate the levels of rT3 may be akin to regulation of T3 itself.…”

Morphological and biochemical changes in the Harderian gland of hypothyroid rats

“…Recently, a possible involvement of pronerve growth factor-p75 neurotrophin receptor pathway in hypothyroidism-enhanced apoptosis has been demonstrated during rat cortical development (Kumar et al, 2006). In addition, it has been demonstrated that hypothyroidism increases the level of p73, a protein involved in apoptosis, during rat liver regeneration (Alisi et al, 2005).…”