靶向肝脏改善轻度认知障碍的作用机制与治疗策略

李金玉; 姜恒; 冯对平; 聂继盛

doi:10.12449/JCH260838

靶向肝脏改善轻度认知障碍的作用机制与治疗策略

DOI: 10.12449/JCH260838

李金玉^{1, 2},
姜恒³,
冯对平²,
聂继盛^3, , ,

1.
山西医科大学法医学院，太原 030001
2.
山西医科大学第一医院肿瘤与血管介入科，太原 030001
3.
山西医科大学公共卫生学院，煤炭环境致病与防治教育部重点实验室，太原 030001

基金项目:

国家自然科学基金 (82200650);

山西省自然科学基金 (202203021212046)

利益冲突声明：本文不存在任何利益冲突。

作者贡献声明：李金玉负责设计论文框架，起草论文；姜恒参与论文修改，绘制图表；冯对平参与查阅相关文献，修改论文；聂继盛负责拟定写作思路，指导撰写文章并最后定稿。

详细信息

通信作者:
聂继盛， niejisheng@sxmu.edu.cn （ORCID： 0000-0003-4351-2017）

计量
- 文章访问数: 4
- HTML全文浏览量: 2
- PDF下载量: 0
- 被引次数: 0
出版历程
- 收稿日期: 2025-12-26
- 录用日期: 2026-03-05
- 出版日期: 2026-08-25

Liver-targeted therapies for improving mild cognitive impairment: Mechanism of action and treatment strategies

Jinyu Li^{1, 2},
Heng Jiang³,
Duiping Feng²,
Jisheng Nie^{3
, ,
,}

1.
School of Forensic Medicine，Shanxi Medical University，Taiyuan 030001，China
2.
Department of Oncology and Vascular Intervention，The First Hospital of Shanxi Medical University，Taiyuan 030001，China
3.
School of Public Health，MOE Key Laboratory of Coal Environmental Pathogenicity and Prevention，Shanxi Medical University，Taiyuan 030001，China

Research funding:

National Natural Science Foundation of China (82200650);

Natural Science Foundation of Shanxi Province (202203021212046)

More Information

Corresponding author: Nie Jisheng， niejisheng@sxmu.edu.cn （ORCID： 0000-0003-4351-2017）

摘要

摘要: 轻度认知障碍（MCI）是阿尔茨海默病的重要前驱阶段，其发生与肝脏功能密切相关。肝脏作为代谢器官，通过肝-脑轴调控认知功能。流行病学提示肝功能指标与MCI存在关联。肝脏通过过氧化物酶体增殖物激活受体α-低密度脂蛋白受体相关蛋白质1通路清除外周β-淀粉样蛋白；分泌成纤维细胞生长因子21、可溶性环氧化物水解酶等肝因子调节神经元能量代谢；介导氧化应激与系统性炎症反应等途径影响认知功能。抗炎/抗氧化、饮食模式调整、有氧运动是调节肝脏降低MCI发生的有效措施。本综述系统阐述肝-脑轴在MCI中的作用和机制，为开发基于肝脏靶点的认知障碍治疗提供新视角。
- 认知功能障碍 /
- 肝-脑轴 /
- 治疗学
Abstract: Mild cognitive impairment （MCI） is a critical precursor stage of Alzheimer’s disease， and the development of MCI is closely associated with liver function. As a core metabolic organ， the liver regulates cognitive function through the liver-brain axis. Epidemiological studies have shown the association between liver function parameters and MCI. The liver affects cognitive function by clearing peripheral β-amyloid （mainly via the PPARα-LRP-1 pathway）， secreting hepatic factors such as FGF21 and sEH to modulate neuronal energy metabolism， and mediating oxidative stress and systemic inflammatory responses. Anti-inflammatory/antioxidant measures， dietary pattern adjustments， and aerobic exercise are currently effective strategies for regulating liver function and mitigating mild cognitive impairment. This article systematically reviews the role and mechanism of the liver-brain axis in MCI， in order to provide new perspectives for developing liver-targeted therapies for cognitive impairment.
- Cognitive Dysfunction /
- Liver-Brain Axis /
- Therapeutics

HTML全文

注： Aβ，β-淀粉样蛋白；PPARα，过氧化物酶体增殖物激活受体α；FGF21，成纤维细胞生长因子21；sEH，可溶性环氧化物水解酶；SELENOP，硒蛋白P；MANF，中脑星形胶质细胞源性神经营养因子；LRP-1，低密度脂蛋白受体相关蛋白质1；IL-6，白细胞介素6；TNF-α，肿瘤坏死因子α；CRP，C反应蛋白；ROS，活性氧；LPS，脂多糖。

图 1 肝损伤致认知障碍机制示意图

Figure 1. Schematic illustration of the mechanism underlying liver injury-induced cognitive impairment

下载: 全尺寸图片幻灯片

参考文献(29)

[1]	Zhao Y, Zhang H X, Cheng J, et al. Association between dyslipidaemia and cognitive impairment: A meta-analysis of cohort and case-control studies[J]. J Integr Neurosci, 2024, 23( 2): 40. DOI: 10.31083/j.jin2302040.
[2]	Mikkelsen A C D, Kjærgaard K, Schapira A H V, et al. The liver-brain axis in metabolic dysfunction-associated steatotic liver disease[J]. Lancet Gastroenterol Hepatol, 2025, 10( 3): 248- 258. DOI: 10.1016/S2468-1253(24)00320-0.
[3]	Mian M, Tahiri J, Eldin R, et al. Overlooked cases of mild cognitive impairment: Implications to early Alzheimer’s disease[J]. Ageing Res Rev, 2024, 98: 102335. DOI: 10.1016/j.arr.2024.102335.
[4]	Cong L, Ren Y F, Wang Y X, et al. Mild cognitive impairment among rural-dwelling older adults in China: A community-based study[J]. Alzheimers Dement, 2023, 19( 1): 56- 66. DOI: 10.1002/alz.12629.
[5]	Qin Y, Han HJ, Li Y, et al. Estimating bidirectional transitions and identifying predictors of mild cognitive impairment[J]. Neurology, 2023, 100( 3): e297- e307. DOI: 10.1212/WNL.0000000000201386.
[6]	Chen Zeqi, Chen Guolin, Jin Yiqiang, et al. Studies on the pathophysiological basis of the liver Qi stagnation syndrome[J]. China J Mod Med, 2000, 10( 10): 21- 23, 26. DOI: 10.3969/j.issn.1005-8982.2000.10.008. 陈泽奇, 陈国林, 金益强, 等. 肝气郁结证病理生理学基础研究[J]. 中国现代医学杂志, 2000, 10( 10): 21- 23, 26. DOI: 10.3969/j.issn.1005-8982.2000.10.008.
[7]	Deng Mingjie, Cai Jiarong, Shi Peimei, et al. Pathogenesis and treatment of hepatic encephalopathy: Research progress[J]. Acad J Nav Med Univ, 2025, 46( 6): 784- 789. DOI: 10.16781/j.CN31-2187/R.20240719. 邓明杰, 蔡加荣, 时培美, 等. 肝性脑病发病机制及治疗研究进展[J]. 海军军医大学学报, 2025, 46( 6): 784- 789. DOI: 10.16781/j.CN31-2187/R.20240719.
[8]	Weinstein G, O’Donnell A, Davis-Plourde K, et al. Non-alcoholic fatty liver disease, liver fibrosis, and regional amyloid-β and tau pathology in middle-aged adults: The Framingham study[J]. J Alzheimers Dis, 2022, 86( 3): 1371- 1383. DOI: 10.3233/JAD-215409.
[9]	Sharma A, Shrivastava S, Shukla S. Oxidative damage in the liver and brain of the rats exposed to frequency-dependent radiofrequency electromagnetic exposure: Biochemical and histopathological evidence[J]. Free Radic Res, 2021, 55( 5): 535- 546. DOI: 10.1080/10715762.2021.1966001.
[10]	Nho K, Kueider-Paisley A, Ahmad S, et al. Association of altered liver enzymes with Alzheimer disease diagnosis, cognition, neuroimaging measures, and cerebrospinal fluid biomarkers[J]. JAMA Netw Open, 2019, 2( 7): e197978. DOI: 10.1001/jamanetworkopen.2019.7978.
[11]	Tang Z Y, Chen X Y, Zhang W R, et al. Association between gamma-glutamyl transferase and mild cognitive impairment in Chinese women[J]. Front Aging Neurosci, 2021, 13: 630409. DOI: 10.3389/fnagi.2021.630409.
[12]	Nabizadeh F, Valizadeh P, Fallahi M S. Bile acid profile associated with CSF and PET biomarkers in Alzheimer’s disease[J]. Aging Clin Exp Res, 2024, 36( 1): 62. DOI: 10.1007/s40520-024-02729-3.
[13]	Chen T L, Pan F F, Huang Q, et al. Metabolic phenotyping reveals an emerging role of ammonia abnormality in Alzheimer’s disease[J]. Nat Commun, 2024, 15( 1): 3796. DOI: 10.1038/s41467-024-47897-y.
[14]	Markan K R, Naber M C, Ameka M K, et al. Circulating FGF21 is liver derived and enhances glucose uptake during refeeding and overfeeding[J]. Diabetes, 2014, 63( 12): 4057- 4063. DOI: 10.2337/db14-0595.
[15]	Peng X, Zhang X, Xu Z, et al. Peripheral amyloid-β clearance mediates cognitive impairment in non-alcoholic fatty liver disease[J]. EBioMedicine, 2024, 102: 105079. DOI: 10.1016/j.ebiom.2024.105079.
[16]	Cheng Y, He C Y, Tian D Y, et al. Physiological β-amyloid clearance by the liver and its therapeutic potential for Alzheimer’s disease[J]. Acta Neuropathol, 2023, 145( 6): 717- 731. DOI: 10.1007/s00401-023-02559-z.
[17]	Huang Z H, Lin H W K, Zhang Q G, et al. Targeting Alzheimer’s disease: The critical crosstalk between the liver and brain[J]. Nutrients, 2022, 14( 20): 4298. DOI: 10.3390/nu14204298.
[18]	Wu Y, Dong J H, Dai Y F, et al. Hepatic soluble epoxide hydrolase activity regulates cerebral Aβ metabolism and the pathogenesis of Alzheimer’s disease in mice[J]. Neuron, 2023, 111( 18): 2847- 2862. DOI: 10.1016/j.neuron.2023.06.002.
[19]	Zheng X, Toyama T, Siu S, et al. Selenoprotein P expression in glioblastoma as a regulator of ferroptosis sensitivity: Preservation of GPX4 via the cycling-selenium storage[J]. Sci Rep, 2024, 14( 1): 682. DOI: 10.1038/s41598-024-51259-5.
[20]	Mclean Diaz P, Vannier A, Joshi A D, et al. Serum fibroblast growth factor-21 discriminates between decompensated alcohol-associated cirrhosis and severe alcohol-associated hepatitis[J]. Clin Transl Gastroenterol, 2023, 14( 6): e00585. DOI: 10.14309/ctg.0000000000000585.
[21]	Gallego J J, Ballester M P, Fiorillo A, et al. Ammonia and beyond-biomarkers of hepatic encephalopathy[J]. Metab Brain Dis, 2025, 40( 1): 100. DOI: 10.1007/s11011-024-01512-7.
[22]	Lu J Y, Zuo H T, Feng R, et al. Parishin A reduces hepatic encephalopathy via gut microbiota increasing the activity of intestinal EAAT3 to reduce blood ammonia[J]. Pharmacol Res, 2025, 222: 108030. DOI: 10.1016/j.phrs.2025.108030.
[23]	Lu B J, Wu C, Azami N L B, et al. Babao Dan improves neurocognitive function by inhibiting inflammation in clinical minimal hepatic encephalopathy[J]. Biomed Pharmacother, 2021, 135: 111084. DOI: 10.1016/j.biopha.2020.111084.
[24]	Song D, Li Y, Yang L L, et al. Bridging systemic metabolic dysfunction and Alzheimer’s disease: The liver interface[J]. Mol Neurodegener, 2025, 20( 1): 61. DOI: 10.1186/s13024-025-00849-6.
[25]	Wang J, Li L, Li L, et al. Lycopene alleviates age-related cognitive deficit via activating liver-brain fibroblast growth factor-21 signalling[J]. Redox Biol, 2024, 77: 103363. DOI: 10.1016/j.redox.2024.103363.
[26]	Ahuja H, Sharma B C, Sachdeva S, et al. A double blind randomized controlled trial to assess efficacy of nutritional therapy for prevention of recurrence of hepatic encephalopathy in patients with cirrhosis[J]. J Gastroenterol Hepatol, 2023, 38( 3): 433- 440. DOI: 10.1111/jgh.16096.
[27]	Kim M, Liotta E M, Maas M B, et al. Rest-activity rhythm disturbance in liver cirrhosis and association with cognitive impairment[J]. Sleep, 2021, 44( 6): zsaa288. DOI: 10.1093/sleep/zsaa288.
[28]	Xiong Xin, Long Fuli. A review of traditional Chinese medicine exercise prescriptions for the prevention and treatment of metabolism related(non-alcoholic) fatty liver disease[J]. Tradit Chin Med, 2025, 14( 1): 367- 374. DOI: 10.12677/tcm.2025.141057. 熊欣, 龙富立. 中医运动处方防治代谢相关(非酒精性)脂肪性肝病的综述[J]. 中医学, 2025, 14( 1): 367- 374. DOI: 10.12677/tcm.2025.141057.
[29]	Wang Guibao, Wang Yuangang, Xu Kangmin, et al. The effect of Wuqinxi exercise on reactive inhibition ability of elderly people with mild cognitive impairment[J]. J Mudanjiang Norm Univ Nat Sci Ed, 2025( 4): 51- 56. DOI: 10.3969/j.issn.1003-6180.2025.04.010. 王桂宝, 王元刚, 许康敏, 等. 五禽戏锻炼对轻度认知障碍老年人反应性抑制能力的影响[J]. 牡丹江师范学院学报(自然科学版), 2025( 4): 51- 56. DOI: 10.3969/j.issn.1003-6180.2025.04.010.