Department of Endocrinology and Metabolism, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.
DZHK (German Centre for Cardiovascular Research), Partner Site Berlin, Berlin, Germany.
Expert Rev Endocrinol Metab. 2022 Sep;17(5):425-434. doi: 10.1080/17446651.2022.2110864. Epub 2022 Aug 11.
Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease worldwide and closely interconnected to the metabolic syndrome. Liver-specific and systemic signaling pathways orchestrating glucose and fatty acid metabolism contribute to intrahepatic accumulation of lipids and inflammatory processes eventually causing disease progression to nonalcoholic steatohepatitis (NASH), liver fibrosis, and cirrhosis. Since a high number of key regulatory genes regarding liver homeostasis are directly mediated via thyroid hormone (TH) signaling, targeting TH receptors (TRs) represent a promising therapeutic potential for the treatment of NAFLD.
In this review, we elucidate the effects of TH on metabolic regulations in the liver via local availability and actions. We discuss recent advances and the potential impact of thyromimetics in basic research and clinical trials including liver-targeted and TRβ-specific agents for the treatment of NAFLD.
Unselective TR targeting can be accompanied by negative side effects due to high TRβ expression in other organs and TRα-mediated effects. Recent advances in drug development and the introduction of liver-targeted thyromimetics selectively activating TRβ such as Resmetirom (MGL-3196) and VK2809 bring new hope of translating the knowledge on local TH effects into effective hepatic lipid-clearing therapies against NASH.
非酒精性脂肪性肝病（NAFLD）是全球最常见的慢性肝病病因，与代谢综合征密切相关。调节葡萄糖和脂肪酸代谢的肝脏特异性和系统性信号通路有助于肝脏内脂质的积累和炎症过程，最终导致疾病进展为非酒精性脂肪性肝炎（NASH）、肝纤维化和肝硬化。由于许多与肝脏稳态相关的关键调节基因直接受甲状腺激素（TH）信号转导调控，因此靶向 TH 受体（TR）代表了治疗 NAFLD 的一种很有前途的治疗潜力。
在这篇综述中，我们通过局部可用性和作用阐明了 TH 对肝脏代谢调节的影响。我们讨论了最近的进展以及新型甲状腺激素激动剂在基础研究和临床试验中的潜在影响，包括用于治疗 NAFLD 的肝靶向和 TRβ 特异性药物。
由于其他器官中 TRβ 的高表达和 TRα 介导的作用，非选择性 TR 靶向可能伴随着负面的副作用。药物开发的最新进展和肝靶向甲状腺激素激动剂（如 Resmetirom（MGL-3196）和 VK2809）的引入为将局部 TH 作用的知识转化为针对 NASH 的有效肝脏脂质清除治疗方法带来了新的希望。
