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3,5‐diiodo‐L‐thyronine increases de novo lipogenesis in liver from hypothyroid rats by SREBP‐1 and ChREBP‐mediated transcriptional mechanisms
Author(s) -
Gi Antonio,
Siculella Luisa,
Paglialonga Giuseppina,
Damiano Fabrizio,
Giudetti Anna Maria
Publication year - 2019
Publication title -
iubmb life
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.132
H-Index - 113
eISSN - 1521-6551
pISSN - 1521-6543
DOI - 10.1002/iub.2014
Subject(s) - lipogenesis , medicine , endocrinology , fatty acid synthesis , fatty acid synthase , acetyl coa carboxylase , thyronine , atp citrate lyase , euthyroid , pyruvate carboxylase , lipid metabolism , chemistry , triiodothyronine , carbohydrate responsive element binding protein , cytosol , sterol regulatory element binding protein , hormone , fatty acid , transcription factor , biology , enzyme , biochemistry , citrate synthase , gene , sterol , cholesterol
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