甲状腺激素类似物与代谢相关脂肪性肝病：探索超越雷司美托的新型分子。

Thyromimetics and MASLD: Unveiling the Novel Molecules Beyond Resmetirom.

作者信息

Ezhilarasan Devaraj

机构信息

Department of Pharmacology, Hepatology and Molecular Medicine Lab, Saveetha Dental College and Hospitals, Saveetha Institute of Medical and Technical Sciences (SIMATS), Chennai, Tamil Nadu, India.

出版信息

J Gastroenterol Hepatol. 2025 Feb;40(2):367-378. doi: 10.1111/jgh.16874. Epub 2025 Jan 16.

DOI:10.1111/jgh.16874

PMID:39817461

Abstract

BACKGROUND

Resmetirom, the first FDA-approved drug for nonalcoholic steatohepatitis (NASH) with fibrosis in obese patients, when combined with lifestyle modifications, improves NASH resolution and reduces fibrosis by at least one stage. Low thyroid hormone (T) levels are linked to a higher risk of developing metabolic dysfunction-associated steatotic liver disease (MASLD). Epidemiological studies have confirmed the positive correlation between hypothyroidism and MASLD. Unraveling the molecular mechanisms of T signaling pathways in MASLD will enhance the prospects of identifying effective and specific targets. Therefore, this review discusses the significant role of thyroid hormones in the homeostasis of fat metabolism and describes the possible molecular mechanisms of thyromimetics in the treatment of MASLD.

METHODS

A comprehensive search in PubMed and EMBASE was conducted using the keywords "thyromimetics and liver diseases," "thyroid hormone and liver diseases," "hypothyroidism and liver diseases," "T, T and liver disease," and "resmetirom and liver disease." Relevant papers published before October 2024 were included.

RESULTS

T treatment enhances mitochondrial respiration, biogenesis, β-oxidation, and mitophagy, reducing liver lipid accumulation. However, T treatment causes cardiotoxicity through thyroid hormone receptor (THR)α agonistic activity. To address this, molecules with high THRβ agonistic but lower THRα activity have been developed. Besides resmetirom, other THRβ agonists like TG68, CS27109, MB07811, and KB-141 show promising results in experimental studies. These molecules upregulate THRβ target genes, activate genes for fatty acid β-oxidation in mitochondria and fatty acid breakdown in peroxisomes, downregulate the genes involved in de novo lipogenesis, reduce inflammation by downregulating NF-κB/JNK/STAT3 signaling pathways, and accelerate fibrosis resolution by downregulating the expressions of fibrosis marker genes in NASH liver tissue.

CONCLUSION

Future clinical studies should thoroughly investigate THRβ agonists, including TG68, CS27109, MB07811, and KB-141.

摘要

背景

瑞美替隆是美国食品药品监督管理局（FDA）批准的首个用于治疗肥胖患者非酒精性脂肪性肝炎（NASH）伴纤维化的药物，与生活方式改变相结合时，可改善NASH的消退并使纤维化至少减轻一个阶段。低甲状腺激素（T）水平与发生代谢功能障碍相关脂肪性肝病（MASLD）的较高风险相关。流行病学研究已证实甲状腺功能减退与MASLD之间存在正相关。阐明MASLD中T信号通路的分子机制将提高识别有效和特异性靶点的前景。因此，本综述讨论了甲状腺激素在脂肪代谢稳态中的重要作用，并描述了甲状腺模拟物治疗MASLD的可能分子机制。

方法

在PubMed和EMBASE中使用关键词“甲状腺模拟物与肝脏疾病”、“甲状腺激素与肝脏疾病”、“甲状腺功能减退与肝脏疾病”、“T、T与肝脏疾病”以及“瑞美替隆与肝脏疾病”进行全面检索。纳入2024年10月之前发表的相关论文。

结果

T治疗可增强线粒体呼吸、生物发生、β-氧化和线粒体自噬，减少肝脏脂质蓄积。然而，T治疗通过甲状腺激素受体（THR）α激动活性导致心脏毒性。为解决这一问题，已开发出具有高THRβ激动活性但较低THRα活性的分子。除瑞美替隆外，其他THRβ激动剂如TG68、CS27109、MB07811和KB-141在实验研究中显示出有前景的结果。这些分子上调THRβ靶基因，激活线粒体中脂肪酸β-氧化和过氧化物酶体中脂肪酸分解的基因，下调参与从头脂肪生成的基因，通过下调NF-κB/JNK/STAT3信号通路减轻炎症，并通过下调NASH肝组织中纤维化标志物基因的表达加速纤维化消退。