Thyroid Hormone and Mitochondrial Dysfunction: Therapeutic Implications for Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD).
Thyroid Hormone and Mitochondrial Dysfunction: Therapeutic Implications for Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD).
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代谢功能障碍相关脂肪性肝病（MASLD），以前称为非酒精性脂肪性肝病（NAFLD），是一个普遍的全球健康问题，影响全球约25%的人口。它的影响正在扩大，预计它将超过酒精，成为全球肝功能衰竭和肝脏相关死亡的主要原因。不幸的是，没有批准的MASLD疗法;因此，国家和国际卫生监管机构采取了旨在加快开发治疗MASLD药物的战略和行动计划。久坐不动的生活方式和不健康的饮食摄入是重要的风险因素。西方国家的MASLD估计患病率较高，部分原因是生活习惯。线粒体功能障碍与MASLD的发展密切相关。此外，据推测，线粒体自噬，一种类型的线粒体质量控制，可能是受损的MASLD。甲状腺激素（TH）协调来自核和线粒体基因组的信号，以控制肝细胞中线粒体的生物发生和功能。线粒体是已知的TH靶点，临床前和临床研究表明TH、甲状腺受体β（TR-β）类似物和对肝脏特异性的合成类似物在治疗MASLD中可能具有治疗益处。在这篇综述中，我们强调了线粒体功能障碍如何有助于MASLD的发展，以及如何理解TH在改善线粒体功能中的作用，为基于TH的靶向MASLD治疗的创新药物开发计划铺平了道路。
Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly termed nonalcoholic fatty liver disease (NAFLD), is a widespread global health concern that affects around 25% of the global population. Its influence is expanding, and it is anticipated to overtake alcohol as the leading cause of liver failure and liver-related death worldwide. Unfortunately, there are no approved therapies for MASLD; as such, national and international regulatory health agencies undertook strategies and action plans designed to expedite the development of drugs for treatment of MASLD. A sedentary lifestyle and an unhealthy diet intake are important risk factors. Western countries have a greater estimated prevalence of MASLD partly due to lifestyle habits. Mitochondrial dysfunction is strongly linked to the development of MASLD. Further, it has been speculated that mitophagy, a type of mitochondrial quality control, may be impaired in MASLD. Thyroid hormone (TH) coordinates signals from the nuclear and mitochondrial genomes to control mitochondrial biogenesis and function in hepatocytes. Mitochondria are known TH targets, and preclinical and clinical studies suggest that TH, thyroid receptor β (TR-β) analogs, and synthetic analogs specific to the liver could be of therapeutic benefit in treating MASLD. In this review, we highlight how mitochondrial dysfunction contributes to development of MASLD, and how understanding the role of TH in improving mitochondrial function paved the way for innovative drug development programs of TH-based therapies targeting MASLD.
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