The Lipid Paradox in Chronic Liver Disease: Integrative Evidence From Intrahepatic Transcriptomics and Population-based Cohorts

Chronic liver disease (CLD) is associated with major metabolic disturbances. Although an elevated atherogenic index of plasma (AIP) reflects cardiometabolic risk, progressive liver dysfunction may instead be accompanied by lipid depletion, suggesting a "lipid paradox." We aimed to investigate its intrahepatic transcriptomic basis, systemic manifestations, and clinical implications using an integrative molecular-to-population approach.

Intrahepatic transcriptomic data from the Gene Expression Omnibus were analyzed to identify differentially expressed genes associated with chronic hepatitis B progression, and hub genes were screened by machine learning. National Health and Nutrition Examination Survey (NHANES) 2015-2018 data were used to examine the association between the Fibrosis-4 (FIB-4) and AIP using survey-weighted models and mediation analyses. Data from the China Health and Retirement Longitudinal Study (CHARLS) were used to model 4-yr AIP trajectories and explore associations with cardiometabolic outcomes and all-cause mortality.

Transcriptomics identified nine immune-fibrotic hub genes; functional enrichment showed immune activation and matrix remodeling with suppressed lipid metabolism. In NHANES, higher fibrosis risk was independently associated with lower AIP, with mediation more consistent with metabolic depletion than inflammation and independent of the age term in FIB-4. In CHARLS, individuals with liver disease showed an attenuated AIP trajectory; within this subgroup, lower AIP was associated with a higher prevalence of cardiovascular disease and metabolic syndrome, with an exploratory adverse survival signal.

Across transcriptomic, cross-sectional, and longitudinal analyses, reduced AIP in CLD may reflect metabolic and nutritional vulnerability rather than cardiometabolic protection, warranting further evaluation as an indicator for risk stratification.