Song Dan, Li Yang, Yang Ling-Ling, Luo Ya-Xi, Yao Xiu-Qing
Department of Rehabilitation, The Second Affiliated Hospital of Chongqing Medical University, No. 74 Linjiang Road, Yuzhong District, Chongqing, 400010, China.
Chongqing Municipality Clinical Research Center for Geriatric Medicine, No. 76 Linjiang Road, Yuzhong District, Chongqing, 400010, China.
Mol Neurodegener. 2025 May 28;20(1):61. doi: 10.1186/s13024-025-00849-6.
Alzheimer's disease (AD) is increasingly recognized as a systemic disorder with a substantial metabolic disorder component, where the liver significantly impacts the brain via the liver-brain axis. Key mechanisms include the liver's role in clearing peripheral β-amyloid (Aβ), the influence of hepatic enzymes and metabolites on cognitive decline, and the systemic effects of metabolic disorders on AD progression. Hepatokines, liver-secreted proteins including fibroblast growth factor (FGF)-21, selenoprotein P (SELENOP), Fetuin-A, Midbrain astrocyte-derived neurotrophic factor (MANF), apolipoprotein J (ApoJ), sex hormone-binding globulin (SHBG), Adropin and Angiopoietin-like protein 3 (ANGPTL3), could regulate insulin sensitivity, lipid metabolism, oxidative stress, immune responses, and neurotrophic support. These pathways are closely linked to core AD pathologies, including Aβ aggregation, tau hyperphosphorylation, neuroinflammation, oxidative stress and mitochondrial dysfunction. Lifestyle interventions, including exercise and dietary modifications, that regulate hepatokines expression may offer novel preventive and therapeutic strategies for AD. This review synthesizes current knowledge on the liver-brain crosstalk in AD, emphasizing the mechanistic role of liver in bridging metabolic dysfunction with neurodegeneration and underscores the diagnostic and therapeutic potential of hepatokines in addressing AD's complex pathology.
阿尔茨海默病（AD）日益被认为是一种具有大量代谢紊乱成分的全身性疾病，其中肝脏通过肝脑轴对大脑产生显著影响。关键机制包括肝脏在清除外周β-淀粉样蛋白（Aβ）中的作用、肝酶和代谢产物对认知衰退的影响，以及代谢紊乱对AD进展的全身影响。肝因子是肝脏分泌的蛋白质，包括成纤维细胞生长因子（FGF）-21、硒蛋白P（SELENOP）、胎球蛋白A、中脑星形胶质细胞衍生的神经营养因子（MANF）、载脂蛋白J（ApoJ）、性激素结合球蛋白（SHBG）、Adropin和血管生成素样蛋白3（ANGPTL3），它们可以调节胰岛素敏感性、脂质代谢、氧化应激、免疫反应和神经营养支持。这些途径与AD的核心病理密切相关，包括Aβ聚集、tau蛋白过度磷酸化、神经炎症、氧化应激和线粒体功能障碍。包括运动和饮食调整在内的生活方式干预可调节肝因子的表达，这可能为AD提供新的预防和治疗策略。这篇综述综合了目前关于AD中肝脑相互作用的知识，强调了肝脏在将代谢功能障碍与神经退行性变联系起来的机制作用，并强调了肝因子在解决AD复杂病理方面的诊断和治疗潜力。
