Chen, Yun; Zheng, Yinan; Zhao, Longgang; Gao, Tao; Qu, Yishu; Carr, John Jeffrey; Terry, James G.; Ning, Hongyan; Kim, Kyeezu; Long, Michelle T.; Zhang, Xinyuan; Wilkins, John T.; Chen, Aimin; Zhang, Kai; Allen, Norrina Bai; Lloyd-Jones, Donald M.; Hou, Lifang; & Zhang, Xuehong. (2026). Cumulative lipid exposure in young adulthood and risk of midlife MASLD. JHEP Reports, 8(3), 101679. https://doi.org/10.1016/j.jhepr.2025.101679
Metabolic dysfunction-associated steatotic liver disease, or MASLD, is a condition in which excess fat builds up in the liver and can lead to serious health problems. While abnormal lipid levels, also known as dyslipidemia, are known risk factors for MASLD, most research has focused on cholesterol and triglyceride levels measured in midlife. It is less clear whether long-term exposure to unhealthy lipid levels during young adulthood increases the risk of developing MASLD later in life.
In this study, researchers followed 2,577 participants in the Coronary Artery Risk Development in Young Adults study for 25 years. They calculated time-weighted average (TWA) lipid levels from ages 18 to 39 using up to seven repeated measurements, providing a measure of cumulative exposure over time rather than relying on a single test. At midlife, around age 50, participants underwent non-contrast abdominal CT scans to measure liver fat. The researchers also analyzed blood DNA methylation (DNAm), an epigenetic modification that can influence gene activity, at more than 840,000 sites across the genome. A total of 492 participants developed MASLD.
The results showed that higher long-term levels of triglycerides, low high-density lipoprotein (HDL) cholesterol, high non-HDL cholesterol, elevated apolipoprotein B, high low-density lipoprotein (LDL) cholesterol, and higher total cholesterol during young adulthood were all associated with a significantly increased risk of MASLD in midlife. These associations were consistent across sex, race, alcohol intake, and genetic risk groups. In addition, DNA methylation changes in the CPT1A, ABCG1, and DHCR24 genes explained between about 3 percent and 15 percent of these associations, suggesting that epigenetic mechanisms may partly link long-term lipid exposure to liver disease.
Overall, the findings show that cumulative exposure to abnormal lipid levels in young adulthood strongly predicts MASLD risk decades later, more effectively than single measurements. They also suggest that lipid-related DNA methylation changes may partially mediate this relationship, highlighting potential biological pathways and prevention targets.
Fig. 1
Flow chart for selecting the Coronary Artery Risk Development in Young Adults study participants for analysis.