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.