Laboratory of Hormonal Regulation, Cardiovascular and Metabolic Disorders, Duke-NUS Medical School, 8 College Road, Singapore 169857, Singapore; Department of Endocrinology & Metabolism, Amsterdam Gastroenterology, Endocrinology & Metabolism, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands.
Laboratory of Hormonal Regulation, Cardiovascular and Metabolic Disorders, Duke-NUS Medical School, 8 College Road, Singapore 169857, Singapore.
Mol Metab. 2021 Nov;53:101266. doi: 10.1016/j.molmet.2021.101266. Epub 2021 Jun 5.
Nonalcoholic fatty liver disease (NAFLD) comprises a spectrum ranging from hepatosteatosis to progressive nonalcoholic steatohepatitis that can lead to cirrhosis. Humans with low levels of prohormone thyroxine (T) have a higher incidence of NAFLD, and thyroid hormone treatment is very promising in all patients with NAFLD. Deiodinase type 1 (Dio1) is a hepatic enzyme that converts T to the bioactive T and therefore regulates thyroid hormone availability within hepatocytes. We investigated the role of this intrahepatic regulation during the progression of NAFLD.
We investigated hepatic thyroid hormone metabolism in two NAFLD models: wild-type mice fed a Western diet with fructose and Lepr mice fed a methionine- and choline-deficient diet. AAV8-mediated liver-specific Dio1 knockdown was employed to investigate the role of Dio1 during the progression of NAFLD. Intrahepatic thyroid hormone levels, deiodinase activity, and metabolic parameters were measured.
Dio1 expression and activity were increased in the early stages of NAFLD and were associated with an increased T/T ratio. Prevention of this increase by AAV8-mediated liver-specific Dio1 knockdown increased hepatic triglycerides and cholesterol and decreased the pACC/ACC ratio and acylcarnitine levels, suggesting there was lower β-oxidation. Dio1 siRNA KD in hepatic cells treated with fatty acids showed increased lipid accumulation and decreased oxidative phosphorylation.
Hepatic Dio1 gene expression was modulated by dietary conditions, was increased during hepatosteatosis and early NASH, and regulated hepatic triglyceride content. These early adaptations likely represent compensatory mechanisms that reduce hepatosteatosis and prevent NASH progression.
非酒精性脂肪性肝病（NAFLD）是一个谱，从肝脂肪变性到进展性非酒精性脂肪性肝炎，可导致肝硬化。甲状腺素前体（T）水平低的人患 NAFLD 的发病率更高，甲状腺激素治疗对所有 NAFLD 患者都非常有希望。脱碘酶 1 型（Dio1）是一种肝脏酶，可将 T 转化为生物活性 T，从而调节肝细胞内甲状腺激素的可用性。我们研究了这种肝内调节在 NAFLD 进展过程中的作用。
我们研究了两种 NAFLD 模型中的肝甲状腺激素代谢：用果糖喂养的野生型小鼠的西方饮食和用蛋氨酸和胆碱缺乏饮食喂养的 Lepr 小鼠。AAV8 介导的肝特异性 Dio1 敲低用于研究 Dio1 在 NAFLD 进展过程中的作用。测量了肝内甲状腺激素水平、脱碘酶活性和代谢参数。
Dio1 的表达和活性在 NAFLD 的早期阶段增加，并与 T/T 比值增加相关。AAV8 介导的肝特异性 Dio1 敲低可预防这种增加，增加肝甘油三酯和胆固醇，并降低 pACC/ACC 比值和酰基辅酶 A 水平，表明β-氧化减少。用脂肪酸处理的肝细胞中的 Dio1 siRNA KD 显示出脂质积累增加和氧化磷酸化减少。
肝 Dio1 基因表达受饮食条件调节，在肝脂肪变性和早期 NASH 期间增加，并调节肝甘油三酯含量。这些早期适应可能代表了减少肝脂肪变性和防止 NASH 进展的代偿机制。
