Abstract
3,3′,5-triiodo-L-thyronine (T3) improves hepatic lipid accumulation by increasing lipid catabolism but it also increases lipogenesis, which at first glance appears contradictory. Recent studies have shown that 3,5-diiodothyronine (T2), a natural thyroid hormone derivative, also has the capacity to stimulate hepatic lipid catabolism, however, little is known about its possible effects on lipogenic gene expression. Because genes classically involved in hepatic lipogenesis such as SPOT14, acetyl-CoA-carboxylase (ACC), and fatty acid synthase (FAS) contain thyroid hormone response elements (TREs), we studied their transcriptional regulation, focusing on TRE-mediated effects of T3 compared to T2 in rats receiving high-fat diet (HFD) for 1 week. HFD rats showed a marked lipid accumulation in the liver, which was significantly reduced upon simultaneous administration of either T3 or T2 with the diet. When administered to HFD rats, T2, in contrast with T3, markedly downregulated the expression of the above-mentioned genes. T2 downregulated expression of the transcription factors carbohydrate-response element-binding protein (ChREBP) and sterol regulatory element binding protein-1c (SREBP-1c) involved in activation of transcription of these genes, which explains the suppressed expression of their target genes involved in lipogenesis. T3, however, did not repress expression of the TRE-containing ChREBP gene but repressed SREBP-1c expression. Despite suppression of SREBP-1c expression by T3 (which can be explained by the presence of nTRE in its promoter), the target genes were not suppressed, but normalized to HFD reference levels or even upregulated (ACC), partly due to the presence of TREs on the promoters of these genes and partly to the lack of suppression of ChREBP. Thus, T2 and T3 probably act by different molecular mechanisms to achieve inhibition of hepatic lipid accumulation.
Highlights
Lipogenesis, lipolysis, and carbohydrate metabolism are the principal pathways that modulate metabolism
To verify whether administration of iodothyronines to high-fat diet (HFD) animals might alter organ weight and induce a thyrotoxic-like state, we measured the weights of organs such as liver, heart, skeletal muscle, and adipose tissue that are most sensitive to thyroid status
Serum total T4 (TT4) and total T3 (TT3) levels did not change between HFD and HFD+T2 animals, whereas levels of TT3 significantly increased in the HFD+T3 compared to HFD and HFD+T2 groups (Table 1)
Summary
Lipogenesis, lipolysis, and carbohydrate metabolism are the principal pathways that modulate metabolism. T3 has long been recognized as an important inducer of hepatic lipogenic enzyme gene transcription (Roncari and Murthy, 1975; Llobera et al, 1979; Oppenheimer et al, 1987, 1991; Freake et al, 1989; Cable et al, 2009; Zhu and Cheng, 2010; Yao et al, 2014; Chen et al, 2015) by binding to specific nuclear receptors, thyroid hormone receptors (TRs) that are present in the liver and widely distributed throughout the body (Yen, 2001; Brent, 2012; Sinha and Yen, 2014). Research has focused on identifying and developing thyroid hormone (TH) analogs that are both tissueand TRβ- (the isoform predominantly involved in TH-induced hepatic metabolism) (Moreno et al, 2008) selective in order to stimulate hepatic metabolism without causing side effects on the heart (Raparti et al, 2013)
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