Regulation of Thyroid Function by Retinol Saturase

甲状腺激素是生长、细胞分化和能量平衡的主要调节因子。这些激素在甲状腺的滤泡上皮细胞中合成并分泌到血液中。在进入组织后，局部表达的去碘酶然后以细胞类型特异性的方式微调甲状腺激素的作用。我们发现视黄醇饱和酶（RetSat），一种依赖于NAD(P)H或fadh的氧化还原酶，最初被证明可以将视黄醇还原为13,14-二氢视黄醇，也可能催化其他反应，在小鼠和人甲状腺中强烈表达。此外，RetSat在小鼠甲状腺中的表达被碘喂养改变，碘是一种已知的甲状腺功能调节剂。为了解剖RetSat在甲状腺中的功能，我们建立了一个新的遗传小鼠模型，该模型特异性地删除了甲状腺细胞中的RetSat。从这些小鼠中获得的初步数据表明RetSat参与甲状腺激素的合成。因此，本研究旨在研究其潜在机制，描述其表型后果，并阐明RetSat在甲状腺功能低下和甲状腺功能亢进状态中的作用。解决这些问题将破译RetSat在甲状腺中的功能，并可能找到治疗甲状腺功能障碍和相关代谢病理的新药理学靶点。

Thyroid hormones are major regulators of growth, cell differentiation, and energy homeostasis. These hormones are synthesized in follicular epithelial cells of the thyroid gland and secreted into the blood. Upon the uptake into tissues, locally expressed deiodinases then fine-tune thyroid hormone action in a cell type-specific manner. We found that the enzyme Retinol Saturase (RetSat), a NAD(P)H or FADH-dependent oxidoreductase initially shown to reduce retinol to 13,14-dihydroretinol that may also catalyze other reactions, is strongly expressed in murine and human thyroid gland. Moreover, RetSat expression in the murine thyroid was altered by iodide feeding, a known modulator of thyroid function. To dissect the function of RetSat in the thyroid, we generated a new genetic mouse model that deletes RetSat specifically in thyrocytes. Preliminary data gained from these mice implicate RetSat in the synthesis of thyroid hormones. Hence, this proposal aims at investigating the underlying mechanisms, characterize the phenotypical consequences, and elucidate RetSat’s role in hypo-and hyperthyroid states. Addressing these question will decipher the function of RetSat in the thyroid gland and may identify a novel pharmacologic target to treat thyroid dysfunction and related metabolic pathologies.