Endocrinologia e Nutrição, Hospital Divino Espirito Santo de Ponta Delgada, EPE, Açores, Portugal.
Department of Endocrinology and Metabolism, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.
Thyroid. 2021 Jul;31(7):1127-1134. doi: 10.1089/thy.2020.0651. Epub 2021 Feb 19.
Thyroid hormone (TH) has important functions in controlling hepatic lipid metabolism. Individuals with resistance to thyroid hormone beta (RTHβ) who harbor mutations in the gene experience loss-of-function of thyroid hormone receptor beta (TRβ), which is the predominant TR isoform expressed in the liver. We hypothesized that individuals with RTHβ may have increased hepatic steatosis. Controlled attenuation parameter (CAP) was assessed in individuals harboring the R243Q mutation of the gene ( = 21) and in their wild-type (WT) first-degree relatives ( = 22) using the ultrasound-based transient elastography (TE) device (FibroScan). All participants belonged to the same family, lived on the same small island, and were therefore exposed to similar environmental conditions. CAP measurements and blood samples were obtained after an overnight fast. The observers were blinded to the status of the patients. The hepatic fat content was increased in RTHβ individuals compared with their WT relatives (CAP values of 263 ± 21 and 218.7 ± 43 dB/m, respectively, = 0.007). The CAP values correlated with age and body mass index (BMI) (age: = 0.55, = 0.011; BMI: = 0.51, = 0.022) in the WT first-degree relatives but not in RTHβ individuals, suggesting that the defect in TRβ signaling was predominant over the effects of age and obesity. Circulating free fatty acid levels were significantly higher in RTHβ individuals (0.29 ± 0.033 vs. 0.17 ± 0.025 mmol/L, = 0.02). There was no evidence of insulin resistance evaluated by the homeostatic model assessment of insulin resistance in both groups studied. Our findings provide evidence that impairments in intrahepatic TRβ signaling due to mutations of the gene can lead to hepatic steatosis, which emphasizes the influence of TH in the liver metabolism of lipids and provides a rationale for the development TRβ-selective thyromimetics. Consequently, new molecules with a very high TRβ affinity and hepatic selectivity have been developed for the treatment of lipid-associated hepatic disorders, particularly nonalcoholic fatty liver disease.
甲状腺激素 (TH) 在控制肝脏脂质代谢方面具有重要功能。β 型甲状腺激素抵抗症 (RTHβ) 患者携带甲状腺激素受体 β (TRβ) 基因突变，该基因突变导致 TRβ 失活，而 TRβ 是肝脏中表达的主要 TR 同工型。我们假设 RTHβ 患者可能存在肝脂肪变性增加。
使用基于超声的瞬时弹性成像 (TE) 设备 (FibroScan)，对携带 基因 R243Q 突变的个体 ( = 21) 及其野生型 (WT) 一级亲属 ( = 22) 进行受控衰减参数 (CAP) 评估。所有参与者均来自同一家庭，居住在同一小岛上，因此暴露于相似的环境条件下。在禁食过夜后获取 CAP 测量值和血样。观察者对患者的情况不知情。
与 WT 亲属相比，RTHβ 个体的肝脂肪含量增加（CAP 值分别为 263 ± 21 和 218.7 ± 43 dB/m， = 0.007）。WT 一级亲属的 CAP 值与年龄和体重指数 (BMI) 相关（年龄： = 0.55， = 0.011；BMI： = 0.51， = 0.022），但 RTHβ 个体的 CAP 值则不然，这表明 TRβ 信号传导缺陷超过了年龄和肥胖的影响。RTHβ 个体的循环游离脂肪酸水平明显升高（0.29 ± 0.033 对 0.17 ± 0.025 mmol/L， = 0.02）。在两组研究中，均未发现胰岛素抵抗的证据，采用稳态模型评估胰岛素抵抗进行评估。
我们的研究结果提供了证据，表明由于 基因的突变导致肝内 TRβ 信号转导受损可导致肝脂肪变性，这强调了 TH 对肝脏脂质代谢的影响，并为开发 TRβ 选择性甲状腺激素激动剂提供了依据。因此，已经开发出具有非常高的 TRβ 亲和力和肝脏选择性的新型分子，用于治疗与脂质相关的肝脏疾病，特别是非酒精性脂肪性肝病。
