Thyroid hormone regulation of Sirtuin 1 expression and implications to integrated responses in fasted mice

Abstract

Sirtuin 1 (SIRT1), a NAD C -dependent deacetylase, has been connected to beneficial effects elicited by calorie restriction. Physiological adaptation to starvation requires higher activity of SIRT1 and also the suppression of thyroid hormone (TH) action to achieve energy conservation. Here, we tested the hypothesis that those two events are correlated and that TH may be a regulator of SIRT1 expression. Forty-eight-hour fasting mice exhibited reduced serum TH and increased SIRT1 protein content in liver and brown adipose tissue (BAT), and physiological thyroxine replacement prevented or attenuated the increment of SIRT1 in liver and BAT of fasted mice. Hypothyroid mice exhibited increased liver SIRT1 protein, while hyperthyroid ones showed decreased SIRT1 in liver and BAT. In the liver, decreased protein is accompanied by reduced SIRT1 activity and no alteration in its mRNA. Hyperthyroid and hypothyroid mice exhibited increases and decreases in food intake and body weight gain respectively. Food-restricted hyperthyroid animals (pair-fed to euthyroid group) exhibited liver and BAT SIRT1 protein levels intermediary between euthyroid and hyperthyroid mice fed ad libitum. Mice with TH resistance at the liver presented increased hepatic SIRT1 protein and activity, with no alteration in Sirt1 mRNA. These results suggest that TH decreases SIRT1 protein, directly and indirectly, via food ingestion control and, in the liver, this reduction involves TRb. The SIRT1 reduction induced by TH has important implication to integrated metabolic responses to fasting, as the increase in SIRT1 protein requires the fasting-associated suppression of TH serum levels.

(Healthy) Ageing: Focus on Iodothyronines

“…Nuclear TRβ protein levels decrease in both of those organs with age, whereas nuclear TRα1 levels are unaltered. Notably, the same authors showed that total cellular TRβ protein levels increase during ageing in both liver and kidney (in the latter, TRα protein also increases), which might suggest that certain extra-nuclear non-genomic actions, several of which being reported to depend on TRs [13,14,22,24] are more pronounced during ageing. However, to our knowledge no information exists in the literature on this subject.…”

“…A recent study addressed the effect of T3 on SIRT1 activity in vivo [22]. Transgenic mice harboring a dominant-negative mutation in TRβ, created to serve as a model of thyroid hormone resistance [119], have higher hepatic SIRT1 activity, and so do hypothyroid wild-type mice, compared to their respective wild-type littermates [22]. Conversely, in hypothyroid mice, T4 supplementation reduces liver SIRT activity [22].…”

“…Transgenic mice harboring a dominant-negative mutation in TRβ, created to serve as a model of thyroid hormone resistance [119], have higher hepatic SIRT1 activity, and so do hypothyroid wild-type mice, compared to their respective wild-type littermates [22]. Conversely, in hypothyroid mice, T4 supplementation reduces liver SIRT activity [22]. In addition, fasted mice (having undetectable serum T4 levels and a 26% lower T3 level) display increased SIRT1 activity, which becomes normalized to control levels after T4 supplementation [22].…”

“…The recognition of the tissue-specific expression of the TR isoforms (TRβ is expressed predominantly in liver, TRα in heart [10,11]) has had a potentially important outcome: namely, the development of TRβ-specific thyroid hormone analogs aimed at a lowering of serum cholesterol with minimal cardiac side-effects (which are known to be induced by T3) [12]. In recent years, thyroid hormone and its metabolites have been shown to have non-genomic effects too, via actions at the level of the cell membrane [13], the cytosol [14–17], the mitochondrion [18–20], or the nucleus [21,22]. Many aspects of the genomic and non-genomic actions of thyroid hormones have been reviewed elsewhere [1,12,13,23,24].…”

Sirtuin 1 suppresses mitochondrial dysfunction of ischemic mouse livers in a mitofusin 2-dependent manner

“…This view is supported by previous studies that SIRT1 protein levels, but not its mRNA, decrease by various stresses. 31,32 We have shown that activation of calpains causes impaired autophagy, mitochondrial dysfunction, and hepatocyte death after I/R. [4][5][6] As calpain inhibition suppressed both SIRT1 loss and cell death after I/R, calpains are, at least in part, an integral contributor to SIRT1 loss.…”