Cumulative lipid exposure in young adulthood and risk of midlife MASLD.

BACKGROUND & AIMS: The importance of maintaining optimal lipid levels across young adulthood in preventing metabolic dysfunction-associated steatotic liver disease (MASLD) is unclear. This study aimed to evaluate associations of lipid profiles through young adulthood with midlife MASLD risk and assess the mediating effect of epigenomic biomarkers.

METHODS

This study included 2,577 participants from the Coronary Artery Risk Development in Young Adults study using data from baseline (Year 0 [Y0], 1985-1986) to Y25 (2010-2011). Time-weighted average (TWA) lipid exposures during young adulthood (ages 18-39 years) were estimated using up to seven measurements (Y0-Y20). Non-contrast abdominal CT scans were performed to measure steatosis at Y25 (mean age, 50 years). Blood DNA methylation (DNAm) was measured at >840,000 methylation sites at Y20. A total of 492 MASLD cases were identified.

RESULTS

Compared with optimal TWA lipid levels, multivariable-adjusted odds ratios of developing MASLD were 3.26 (95% CI 2.51-4.25) for abnormal triglycerides (≥100 vs. <75 mg/dl), 2.39 (95% CI 1.73-3.31) for high-density lipoprotein cholesterol (<40 [men]/50 [women] vs. ≥60 mg/dl), 1.77 (95% CI 1.37-2.30) for non-high-density lipoprotein cholesterol (≥150 vs. <130 mg/dl), 1.74 (95% CI 1.19-2.51) for apolipoprotein B (≥110 vs. <90 mg/dl), 1.43 (95% CI 1.08-1.90) for low-density lipoprotein cholesterol (≥130 vs. <100 mg/dl), and 1.39 (95% CI 1.07-1.81) for total cholesterol (≥200 vs. <180 mg/dl). These associations were consistent across sex, race, alcohol intake, and genetic susceptibility. DNAm markers located in CPT1A, ABCG1, and DHCR24 genes mediated 2.9%-15.4% of observed associations.

CONCLUSIONS

Cumulative exposure to abnormal lipids through young adulthood contributes to MASLD development in midlife, with these associations partially mediated by lipid-associated DNAm.

IMPACT AND IMPLICATIONS: Dyslipidemia is a major modifiable risk factor for metabolic dysfunction-associated steatotic liver disease (MASLD). Evidence largely focuses on mid-to-late-life lipid levels, while the impact of cumulative lipid exposure through young adulthood on midlife MASLD risk remains unclear. Using seven repeated lipid measures in a longitudinal observational study, we found that cumulative abnormal lipid exposure during young adulthood (ages 18-39 years) strongly predicted MASLD risk over a 25-year follow-up, outperforming single-visit measures. DNA methylation markers in CPT1A, ABCG1, and DHCR24 mediated 2.9%-15.4% of observed associations. Our findings underscore the value of assessing cumulative lipid exposure for midlife MASLD risk stratification and highlight epigenomic mediators as potential targets to strengthen MASLD prevention strategies.