Department of Cellular and Molecular Physiology, Yale School of Medicine, New Haven, CT 06510.
Department of Comparative Medicine, Yale School of Medicine, New Haven, CT 06510.
Proc Natl Acad Sci U S A. 2017 Oct 24;114(43):E9172-E9180. doi: 10.1073/pnas.1707797114. Epub 2017 Oct 10.
Hypothyroidism, a metabolic disease characterized by low thyroid hormone (TH) and high thyroid-stimulating hormone (TSH) levels in the serum, is strongly associated with nonalcoholic fatty liver disease (NAFLD). Hypothyroidism-induced NAFLD has generally been attributed to reduced TH signaling in the liver with a consequent decrease in lipid utilization. Here, we found that mildly hypothyroid mice develop NAFLD without down-regulation of hepatic TH signaling or decreased hepatic lipid utilization. NAFLD was induced by impaired suppression of adipose tissue lipolysis due to decreased insulin secretion and to a reduced response of adipose tissue itself to insulin. This condition leads to increased shuttling of fatty acids (FAs) to the liver, where they are esterified and accumulated as triglycerides. Lipid accumulation in the liver induces hepatic insulin resistance, which leads to impaired suppression of endogenous glucose production after feeding. Hepatic insulin resistance, synergistically with lowered insulin secretion, increases serum glucose levels, which stimulates de novo lipogenesis (DNL) in the liver. Up-regulation of DNL also contributes to NAFLD. In contrast, severely hypothyroid mice show down-regulation of TH signaling in their livers and profound suppression of adipose tissue lipolysis, which decreases delivery of FAs to the liver. The resulting lack of substrates for triglyceride esterification protects severely hypothyroid mice against NAFLD. Our findings demonstrate that NAFLD occurs when TH levels are mildly reduced, but, paradoxically, not when they are severely reduced. Our results show that the pathogenesis of hypothyroidism-induced NAFLD is both intra- and extrahepatic; they also reveal key metabolic differences between mild and severe hypothyroidism.
甲状腺功能减退症是一种代谢疾病，其特征是血清中甲状腺激素（TH）水平低，促甲状腺激素（TSH）水平高，与非酒精性脂肪性肝病（NAFLD）密切相关。甲状腺功能减退症引起的 NAFLD 一般归因于肝脏中 TH 信号的减少，导致脂质利用减少。在这里，我们发现轻度甲状腺功能减退症小鼠会发展为 NAFLD，而肝脏中 TH 信号没有下调或肝内脂质利用没有减少。NAFLD 是由于胰岛素分泌减少和脂肪组织对胰岛素反应减弱，导致脂肪组织脂解抑制受损引起的。这种情况导致脂肪酸（FAs）向肝脏转移增加，在肝脏中它们被酯化并积累为甘油三酯。肝脏内的脂质积累会导致肝胰岛素抵抗，从而导致进食后内源性葡萄糖产生的抑制受损。肝胰岛素抵抗与降低的胰岛素分泌协同作用，会增加血清葡萄糖水平，从而刺激肝脏中的从头合成（DNL）。DNL 的上调也有助于 NAFLD 的发生。相比之下，严重甲状腺功能减退症小鼠的肝脏中 TH 信号下调，脂肪组织脂解受到深刻抑制，导致 FAs 向肝脏的输送减少。甘油三酯酯化缺乏底物导致严重甲状腺功能减退症小鼠免受 NAFLD 的影响。我们的研究结果表明，当 TH 水平轻度降低时会发生 NAFLD，但当 TH 水平严重降低时则不会发生。我们的结果表明，甲状腺功能减退症引起的 NAFLD 的发病机制既有肝内的，也有肝外的；它们还揭示了轻度和重度甲状腺功能减退症之间的关键代谢差异。
