Chronotype, serum metabolome, and nonalcoholic fatty liver disease in middle-aged and older adults: Association and potential mediation analyses

OBJECTIVE: Chronotype represents individual's circadian preference in behavioral and circadian rhythm. This study aimed to investigate association between chronotype and nonalcoholic fatty liver disease (NAFLD) and underlying metabolic mechanisms in middle-aged and older adults. METHODS: This cross-sectional study included 744 general middle-aged and older adults. Chronotype was assessed using the Morningness-Eveningness Questionnaire. Untargeted metabolomic profiling was identified using liquid chromatography with high-resolution mass spectrometry. Logistic regression model was used to evaluate association between chronotype and NAFLD. A metabolome-wide association study coupled with mediation analysis was conducted to assess metabolic dysregulation related with chronotype and NAFLD. RESULTS: Chronotype was categorized as morning in 33.1 % of participants, intermediate in 46.8 %, and evening in 20.1 %. After adjustment for covariates, evening chronotype was significantly associated with higher NAFLD risk (OR = 1.70, 95 % CI: 1.03, 2.81) compared to morning chronotype. We identified 81 metabolite features that were significantly associated with chronotype. The comparison between NAFLD and non-NAFLD revealed 251 metabolic differences, implicating 5 metabolic pathways: Arginine biosynthesis, Histidine metabolism, Alanine, aspartate and glutamate metabolism, Arginine and proline metabolism, and beta-Alanine metabolism. Mediation analyses suggested that 7 metabolites (such as Asparaginyl-Proline and DG(11D3/11D5/0:0)) might be potential mediators in association of chronotype with NAFLD, with mediated proportions ranging from 12.1 % to 20.6 %. CONCLUSION: Evening chronotype was associated with increased risk of NAFLD in middle-aged and older adults. Chronotype-related metabolomic alterations, including Asparaginyl-Proline and some lipid metabolites, might represent an associative pathway between chronotype and NAFLD. This highlighted the importance of maintaining circadian rhythms for metabolic health.