Sane Rajas, Wirth Eva K, Köhrle Josef
Institut für Experimentelle Endokrinologie, Charité-Universitätsmedizin Berlin, Freie Universität Berlin and Humboldt-Universität zu Berlin, D-10115 Berlin, Germany.
Department of Endocrinology and Metabolism, Charité-Universitätsmedizin Berlin, Freie Universität Berlin and Humboldt-Universität zu Berlin, D-10115 Berlin, Germany.
Metabolites. 2022 Jun 23;12(7):582. doi: 10.3390/metabo12070582.
Thyroid hormones, their metabolites, and synthetic analogues are potential anti-steatotic drug candidates considering that subclinical and manifest hypothyroidism is associated with hepatic lipid accumulation, non-alcoholic fatty liver disease, and its pandemic sequelae. Thyromimetically active compounds stimulate hepatic lipogenesis, fatty acid beta-oxidation, cholesterol metabolism, and metabolic pathways of glucose homeostasis. Many of these effects are mediated by T3 receptor β1-dependent modulation of transcription. However, rapid non-canonical mitochondrial effects have also been reported, especially for the metabolite 3,5-diiodothyronine (3,5-T2), which does not elicit the full spectrum of "thyromimetic" actions inherent to T3. Most preclinical studies in rodent models of obesity and first human clinical trials are promising with respect to the antisteatotic hepatic effects, but potent agents exhibit unwanted thyromimetic effects on the heart and/or suppress feedback regulation of the hypothalamus-pituitary-thyroid-periphery axis and the fine-tuned thyroid hormone system. This narrative review focuses on 3,5-T2 effects on hepatic lipid and glucose metabolism and (non-)canonical mechanisms of action including its mitochondrial targets. Various high fat diet animal models with distinct thyroid hormone status indicate species- and dose-dependent efficiency of 3,5-T2 and its synthetic analogue TRC150094. No convincing evidence has been presented for their clinical use in the prevention or treatment of obesity and related metabolic conditions.
鉴于亚临床和显性甲状腺功能减退与肝脏脂质蓄积、非酒精性脂肪性肝病及其流行后遗症相关，甲状腺激素、其代谢产物和合成类似物是潜在的抗脂肪变性药物候选物。具有甲状腺激素模拟活性的化合物可刺激肝脏脂肪生成、脂肪酸β氧化、胆固醇代谢以及葡萄糖稳态的代谢途径。其中许多作用是由T3受体β1依赖性转录调节介导的。然而，也有报道称其具有快速的非经典线粒体效应，特别是对于代谢产物3,5-二碘甲腺原氨酸（3,5-T2）而言，它不会引发T3固有的全部“甲状腺激素模拟”作用。在肥胖啮齿动物模型中的大多数临床前研究以及首次人体临床试验在抗脂肪变性肝脏效应方面都很有前景，但强效药物对心脏表现出不良的甲状腺激素模拟效应和/或抑制下丘脑-垂体-甲状腺-外周轴的反馈调节以及精细调节的甲状腺激素系统。这篇叙述性综述重点关注3,5-T2对肝脏脂质和葡萄糖代谢的影响以及（非）经典作用机制，包括其线粒体靶点。各种具有不同甲状腺激素状态的高脂饮食动物模型表明3,5-T2及其合成类似物TRC150094具有物种和剂量依赖性效率。尚无令人信服的证据表明它们可用于预防或治疗肥胖症及相关代谢疾病。
