3,5‐diiodo‐L‐thyronine increases de novo lipogenesis in liver from hypothyroid rats by SREBP‐1 and ChREBP‐mediated transcriptional mechanisms

Abstract

Hepatic de novo lipogenesis (DNL), the process by which carbohydrates are converted into lipids, is strictly controlled by nutritional and hormonal status. 3,5‐Diiodo‐L‐thyronine (T2), a product of the 3,5,3′‐triiodo‐L‐thyronine (T3) peripheral metabolism, has been shown to mimic some T3 effects on lipid metabolism by a short‐term mechanism independent of protein synthesis. Here, we report that T2, administered for 1 week to hypothyroid rats, increases total fatty acid synthesis from acetate in isolated hepatocytes. Studies carried out on liver subcellular fractions demonstrated that T2 not only increases the activity and the expression of acetyl‐CoA carboxylase and fatty acid synthase but also of other proteins linked to DNL such as the mitochondrial citrate carrier and the cytosolic ATP citrate lyase. Parallelly, T2 stimulates the activities of enzymes supplying cytosolic NADPH needed for the reductive steps of DNL. With respect to both euthyroid and hypothyroid rats, T2 administration decreases the hepatic mRNA level of SREBP‐1, a transcription factor which represents a master regulator of DNL. However, when compared to hypothyroid rats T2 significantly increases, without bringing to the euthyroid value, the content of both mature (nSREBP‐1), and precursor (pSREBP‐1) forms of the SREBP‐1 protein as well as their ratio. Moreover, T2 administration strongly augmented the nuclear content of ChREBP, another crucial transcription factor involved in the regulation of lipogenic genes. Based on these results, we can conclude that in the liver of hypothyroid rats the transcriptional activation by T2 of DNL genes could depend, at least in part, on SREBP‐1‐ and ChREBP‐dependent mechanisms. © 2019 IUBMB Life, 2019

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“…SREBP1c is also a key regulator of hepatic DNL [93,94,95,96,97,98]. It has been demonstrated that, in the liver, SREBP1c and ChREBP are both necessary for the expression of lipogenic and glycolytic genes [88,99] In adipose tissue, the role of SREPB1c is more controversial. In adipose tissue, the mRNA levels of lipogenic genes did not change in animals using a Srebp1c loss of function or gain of function approach, thus indicating that in this tissues Srebp1c is not essential for DNL activation [58].…”

Genomic and Non-Genomic Mechanisms of Action of Thyroid Hormones and Their Catabolite 3,5-Diiodo-L-Thyronine in Mammals

“…The effect of 3,5-T2 seems to be the opposite in the liver of hypothyroid rats, in which the hormone, after a long-term treatment (15 µg/100 g of body weight, for 1 week) was found to activate genes involved in de novo lipogenesis, by increasing the amount of the nuclear forms of SREBP and ChREBP [231]. Although further studies are necessary to better understand the mechanisms underlying these effects, it may be hypothesized that the 3,5-T2 nuclear effects observed in hypothyroid rats are due to SREBP and ChREBP, while 3,5-T2 should have an indirect effect, due to its ability to activate a still-unknown pathway leading to SREBP/ChREBP activation.…”

“…Thus, it is possible that 3,5-T2 is also involved in some of the non-genomic T4/T3 effects described in Section 3.3. On the other hand, long-term effects of 3,5-T2 on de novo lipogenesis (see Section 4.3) have been also reported [231]. Interestingly, 3,5-T2, at a concentration of 0.1-1.0 µm, can also modulate energy metabolism in cardiomyoblasts, in both ex vivo and in vitro models; in particular, this effect was found to be based on an increase of glucose consumption [232], as also shown in skeletal muscle [233].…”

3,5-Diiodo-L-Thyronine (T2) Administration Affects Visceral Adipose Tissue Inflammatory State in Rats Receiving Long-Lasting High-Fat Diet

“…In the last decades many laboratories have demonstrated that T2 exhibits interesting favorable effects in different metabolically active tissues such as liver (34)(35)(36)(37)(38)(39), skeletal muscle (40,41), heart (42), and adipose tissues (43,44). In male wistar rats housed at thermoneutrality and fed on a high fat diet, simultaneous T2 administration reduces hepatic fat accumulation and hyperlipidemia (34), and induces a protein profile favoring a shift toward type 2 skeletal muscle fibers (40).…”