Differential effects of experimental and cold-induced hyperthyroidism on factors inducing rat liver oxidative damage

Abstract

SUMMARY Thyroid hormone-induced increase in metabolic rates is often associated with increased oxidative stress. The aim of the present study was to investigate the contribution of iodothyronines to liver oxidative stress in the functional hyperthyroidism elicited by cold, using as models cold-exposed and 3,5,3′-triiodothyronine (T3)- or thyroxine(T4)-treated rats. The hyperthyroid state was always associated with increases in both oxidative capacity and oxidative damage of the tissue. The most extensive damage to lipids and proteins was found in T3-treated and cold-exposed rats, respectively. Increase in oxygen reactive species released by mitochondria and microsomes was found to contribute to tissue oxidative damage, whereas the determination of single antioxidants did not provide information about the possible contribution of a reduced effectiveness of the antioxidant defence system. Indeed, liver oxidative damage in hyperthyroid rats was scarcely related to levels of the liposoluble antioxidants and activities of antioxidant enzymes. Conversely,other biochemical changes, such as the degree of fatty acid unsaturation and hemoprotein content, appeared to predispose hepatic tissue to oxidative damage associated with oxidative challenge elicited by hyperthyroid state. As a whole, our results confirm the idea that T3 plays a key role in metabolic changes and oxidative damage found in cold liver. However,only data concerning changes in glutathione peroxidase activity and mitochondrial protein content favour the idea that dissimilarities in effects of cold exposure and T3 treatment could depend on differences in serum levels of T4.

Involvement of PGC-1, NRF-1, and NRF-2 in metabolic response by rat liver to hormonal and environmental signals

“…Conversely, other factors, exhibiting different serum concentrations in functional and experimental hyperthyroidism, should be involved in mitochondrial proliferation associated to cold exposure. Unlike cold exposure, T 3 administration strongly decreases serum levels of T 4 , (Venditti et al, 2006a), which has been reported to have intrinsic biological activity in the cold (Cageao et al, 1992). Plasma levels of catecholamines, which are not modified in altered thyroid states (Stoffer et al, 1973), remarkably increase during cold exposure (Storm et al, 1981).…”

“…Thus, long-term effects of thyroid hormones or states modulating thyroid gland activity, such as cold exposure, are believed to be transduced through T 3 -induced changes in both nuclear and mitochondrial gene expression. In liver from both T 3 -treated (Fernández et al, 1985;Seitz et al, 1985;Venditti et al, 2006a) and cold-exposed animals (Guernsey and Stevens, 1977;Shiota et al, 1985;Venditti et al, 2004) such changes lead to enhanced tissue O 2 consumption. However, in experimental hyperthyroidism the increase in liver respiration involves increases in the amount of respiratory chain proteins and inner surface area (Jacovcic et al, 1978) of mitochondria without changes in their number (Goglia et al, 1989) and protein mass (Venditti, et al, 2006a).…”

“…Conversely, in cold-induced functional hyperthyroidism the increase in liver respiration involves proliferation of mitochondria (Goglia et al, 1983) associated with an enhancement in tissue content of mitochondrial proteins (Venditti et al, 2004;Venditti et al, 2006a).…”

“…In a previous work we used euthyroid rats to examine liver metabolic response to treatments, which differentially affect circulating T 4 levels (Venditti et al, 2006a). Despite some supporting results, the idea Page 4 of 29 A c c e p t e d M a n u s c r i p t 4 that thyroxine can play a role in liver response to cold remains still to demonstrate.…”

Severe cholestatic jaundice associated with Graves’ disease

“…Cases have been reported to occur with and without heart failure, although cholestasis is usually more severe in cases with concurrent heart failure 5. There is evidence of a mechanism involving mitochondrial‐induced apoptosis, another theory cites evidence that oxidative stress from a hyperthyroid state as a cause of hepatotoxicity and cholestasis 7. To date, there is no strong evidence to suggest that thyroid hormone is directly toxic to the liver 8.…”