{"title":"Genetic evidence for the liver-brain axis: lipid metabolism and neurodegenerative disease risk.","authors":"Zeyu Wang, Zixiao Yin, Guangyong Sun, Dong Zhang, Jianguo Zhang","doi":"10.1186/s12944-025-02455-3","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>The liver‒brain axis is critical in neurodegenerative diseases (NDs), with lipid metabolism influencing neuroinflammation and microglial function. A systematic investigation of the genetic relationship between lipid metabolism abnormalities and ND, namely, Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS), is lacking. To assess potential causal links between ND and six lipid parameters, two-sample Mendelian randomization (MR) was used.</p><p><strong>Methods: </strong>Large-scale European ancestry GWAS data for lipid parameters and ND (AD, ALS, PD, and MS) were used. Genetic variants demonstrating significant correlations (P < 5 × 10<sup>-8</sup>) with lipid metabolism parameters were identified and employed as instrumental variables (IVs) after proper validation. The research incorporated UK Biobank genomic data to examine associations between genetic variants and lipid metabolism parameters. The analysis included primary MR, sensitivity analyses, and multivariable MR, which considered potential mediators.</p><p><strong>Results: </strong>MR via the inverse-variance weighted method revealed causal effects of cholesterol (CHOL, OR = 1.10, 95% CI: 1.03-1.18, P = 4.23 × 10⁻<sup>3</sup>) and low-density lipoprotein cholesterol (LDLC, OR = 1.10, 95% CI: 1.03-1.17, P = 3.28 × 10⁻<sup>3</sup>) on the risk of ALS, which were validated across multiple methods. Potential correlations were observed between ApoB and ALS and inversely correlated with AD, whereas no significant associations were found for PD or MS. CHOL and LDLC associations with ALS demonstrated no significant heterogeneity or pleiotropy, supporting their reliability.</p><p><strong>Conclusions: </strong>Higher CHOL and LDLC levels were associated with increased ALS risk, suggesting a potential causal link, and supporting the liver‒brain axis hypothesis in ND. Current genetic evidence does not support a significant role for lipid metabolism in PD and MS etiology, suggesting the relationship between lipid metabolism and other NDs may be more complex and warrants further investigation.</p>","PeriodicalId":18073,"journal":{"name":"Lipids in Health and Disease","volume":"24 1","pages":"41"},"PeriodicalIF":3.9000,"publicationDate":"2025-02-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11806572/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Lipids in Health and Disease","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1186/s12944-025-02455-3","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Background: The liver‒brain axis is critical in neurodegenerative diseases (NDs), with lipid metabolism influencing neuroinflammation and microglial function. A systematic investigation of the genetic relationship between lipid metabolism abnormalities and ND, namely, Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS), is lacking. To assess potential causal links between ND and six lipid parameters, two-sample Mendelian randomization (MR) was used.
Methods: Large-scale European ancestry GWAS data for lipid parameters and ND (AD, ALS, PD, and MS) were used. Genetic variants demonstrating significant correlations (P < 5 × 10-8) with lipid metabolism parameters were identified and employed as instrumental variables (IVs) after proper validation. The research incorporated UK Biobank genomic data to examine associations between genetic variants and lipid metabolism parameters. The analysis included primary MR, sensitivity analyses, and multivariable MR, which considered potential mediators.
Results: MR via the inverse-variance weighted method revealed causal effects of cholesterol (CHOL, OR = 1.10, 95% CI: 1.03-1.18, P = 4.23 × 10⁻3) and low-density lipoprotein cholesterol (LDLC, OR = 1.10, 95% CI: 1.03-1.17, P = 3.28 × 10⁻3) on the risk of ALS, which were validated across multiple methods. Potential correlations were observed between ApoB and ALS and inversely correlated with AD, whereas no significant associations were found for PD or MS. CHOL and LDLC associations with ALS demonstrated no significant heterogeneity or pleiotropy, supporting their reliability.
Conclusions: Higher CHOL and LDLC levels were associated with increased ALS risk, suggesting a potential causal link, and supporting the liver‒brain axis hypothesis in ND. Current genetic evidence does not support a significant role for lipid metabolism in PD and MS etiology, suggesting the relationship between lipid metabolism and other NDs may be more complex and warrants further investigation.
期刊介绍:
Lipids in Health and Disease is an open access, peer-reviewed, journal that publishes articles on all aspects of lipids: their biochemistry, pharmacology, toxicology, role in health and disease, and the synthesis of new lipid compounds.
Lipids in Health and Disease is aimed at all scientists, health professionals and physicians interested in the area of lipids. Lipids are defined here in their broadest sense, to include: cholesterol, essential fatty acids, saturated fatty acids, phospholipids, inositol lipids, second messenger lipids, enzymes and synthetic machinery that is involved in the metabolism of various lipids in the cells and tissues, and also various aspects of lipid transport, etc. In addition, the journal also publishes research that investigates and defines the role of lipids in various physiological processes, pathology and disease. In particular, the journal aims to bridge the gap between the bench and the clinic by publishing articles that are particularly relevant to human diseases and the role of lipids in the management of various diseases.