High cholesterol absorption efficiency enhances proatherogenic properties of low‐density lipoprotein particles

Background and Aims High cholesterol absorption efficiency is determined by genetic variation in small intestinal sterol transporters and affects one‐third of individuals. Their risk for atherosclerotic cardiovascular disease (ASCVD) is increased compared with low cholesterol absorbers, despite similar serum lipid concentrations. We investigated the association of cholesterol absorption efficiency with proatherogenic properties of low‐density lipoproteins (LDLs). Methods The study cohort consisted of 90 middle‐aged participants, 56 females and 34 males, without lipid‐lowering therapy or ASCVD. They were divided into low ( n = 45) and high ( n = 45) cholesterol absorbers by the median value of serum cholestanol to cholesterol ratio. LDL aggregation susceptibility and binding of lipoproteins to proteoglycans were determined as biomarkers of lipoprotein atherogenicity. Nuclear magnetic resonance spectroscopy, mass spectrometry, and gas–liquid chromatography were used to determine lipoprotein subclass profile, LDL lipidome, and serum concentrations of cholesterol and noncholesterol sterols, respectively. Results Age, dietary cholesterol, and serum total cholesterol or lipoprotein cholesterol levels did not differ between the groups. In the high absorbers, LDL particles were larger, and LDL aggregation susceptibility and the binding of lipoproteins to proteoglycans were increased in the low absorbers. Of LDL surface lipids, sphingomyelin 42:3;O2, and phosphatidylcholine (PC) 32:0 correlated positively, whereas PC 32:1 correlated negatively with serum cholestanol levels. These LDL surface lipids were also associated with increased LDL aggregation susceptibility and proteoglycan‐binding. Conclusions The present findings suggest that increased proatherogenic properties in high cholesterol absorbers may contribute to increased ASCVD risk. Registration https://clinicaltrials.gov/study/NCT01315964 .