Axcella Health, Inc., Cambridge, MA, United States.
Department of Internal Medicine and Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University, Richmond, VA, United States.
Front Endocrinol (Lausanne). 2020 Dec 23;11:592373. doi: 10.3389/fendo.2020.592373. eCollection 2020.
Non-alcoholic fatty liver disease (NAFLD) has reached epidemic proportions, affecting an estimated one-quarter of the world's adult population. Multiple organ systems have been implicated in the pathophysiology of NAFLD; however, the role of skeletal muscle has until recently been largely overlooked. A growing body of evidence places skeletal muscle-via its impact on insulin resistance and systemic inflammation-and the muscle-liver axis at the center of the NAFLD pathogenic cascade. Population-based studies suggest that sarcopenia is an effect-modifier across the NAFLD spectrum in that it is tightly linked to an increased risk of non-alcoholic fatty liver, non-alcoholic steatohepatitis (NASH), and advanced liver fibrosis, all independent of obesity and insulin resistance. Longitudinal studies suggest that increases in skeletal muscle mass over time may both reduce the incidence of NAFLD and improve preexisting NAFLD. Adverse muscle composition, comprising both low muscle volume and high muscle fat infiltration (myosteatosis), is highly prevalent in patients with NAFLD. The risk of functional disability conferred by low muscle volume in NAFLD is further exacerbated by the presence of myosteatosis, which is twice as common in NAFLD as in other chronic liver diseases. Crosstalk between muscle and liver is influenced by several factors, including obesity, physical inactivity, ectopic fat deposition, oxidative stress, and proinflammatory mediators. In this perspective review, we discuss key pathophysiological processes driving sarcopenia in NAFLD: anabolic resistance, insulin resistance, metabolic inflexibility and systemic inflammation. Interventions that modify muscle quantity (mass), muscle quality (fat), and physical function by simultaneously engaging multiple targets and pathways implicated in muscle-liver crosstalk may be required to address the multifactorial pathogenesis of NAFLD/NASH and provide effective and durable therapies.
非酒精性脂肪性肝病 (NAFLD) 已达到流行程度，估计影响了世界上四分之一的成年人口。多个器官系统都与 NAFLD 的病理生理学有关；然而，直到最近，骨骼肌的作用在很大程度上仍被忽视。越来越多的证据将骨骼肌——通过其对胰岛素抵抗和全身炎症的影响——以及肌肉-肝脏轴置于 NAFLD 发病机制级联的中心。基于人群的研究表明，肌肉减少症是 NAFLD 谱中的一种效应调节剂，因为它与非酒精性脂肪肝、非酒精性脂肪性肝炎 (NASH) 和进展性肝纤维化的风险增加密切相关，而这些风险独立于肥胖和胰岛素抵抗。纵向研究表明，随着时间的推移，骨骼肌量的增加既可以降低 NAFLD 的发生率，又可以改善现有的 NAFLD。在患有 NAFLD 的患者中，骨骼肌组成不良，包括肌肉体积低和肌肉脂肪浸润（肌脂肪病）高，非常普遍。在 NAFLD 中，肌肉体积低带来的功能障碍风险因肌脂肪病的存在而进一步加剧，而肌脂肪病在 NAFLD 中的发生率是其他慢性肝病的两倍。肌肉和肝脏之间的串扰受多种因素影响，包括肥胖、身体活动不足、异位脂肪沉积、氧化应激和促炎介质。在这篇观点综述中，我们讨论了推动 NAFLD 肌肉减少症的关键病理生理过程：合成代谢抵抗、胰岛素抵抗、代谢灵活性和全身炎症。需要通过同时参与多个与肌肉-肝脏串扰有关的靶点和途径来改变肌肉数量（质量）、肌肉质量（脂肪）和身体功能的干预措施，以解决 NAFLD/NASH 的多因素发病机制，并提供有效和持久的治疗方法。
