Linking cellular lipid metabolism profiles to the outcomes of cholesterol-lowering therapy in a general population cohort study

Background and Aims : Alterations in cellular lipid metabolism are linked to differential treatment outcomes in familial hypercholesterolemia patients. However, whether similar effects exist in the general population is not known.Methods: Methods: Previously, we established a multiparametric analysis platform to quantify lipid uptake and storage in leukocytes from human subjects (BioRxiv, doi:10.1101/2021.04.19.440471). Here we use this pipeline to analyse 400 subject samples from the FINRISK 2012 cohort study, including 200 recipients of cholesterol-lowering medication. For each subject we have access to drug reimbursement, NMR-metabolomics and clinical follow-up data.Results: We observe large inter-individual variation of LDL uptake and lipid mobilization, the velocity with which cells deplete their lipid reservoirs, varying up to 8-fold. In subjects on a high potency statin, LDL uptake shows a negative correlation with LDL-cholesterol as well as cholesterol and cholesterol esters in VLDL and LDL particles. In the same subject group LDL uptake displays a positive correlation with triglycerides in VLDL particles. These correlation profiles are reduced in subjects on less potent statins and absent in control individuals. Likewise, lipid mobilization shows a differential correlation profile with certain lipid types and lipoprotein subclasses, which is dependent on whether the subjects are on cholesterol-lowering therapy.Conclusions: Our study highlights that each individual has a defined cellular lipid uptake and storage potential, providing deeper insight into differential treatment outcomes of cholesterol-lowering therapy in the general population. Background and Aims : Alterations in cellular lipid metabolism are linked to differential treatment outcomes in familial hypercholesterolemia patients. However, whether similar effects exist in the general population is not known. Methods: Methods: Previously, we established a multiparametric analysis platform to quantify lipid uptake and storage in leukocytes from human subjects (BioRxiv, doi:10.1101/2021.04.19.440471). Here we use this pipeline to analyse 400 subject samples from the FINRISK 2012 cohort study, including 200 recipients of cholesterol-lowering medication. For each subject we have access to drug reimbursement, NMR-metabolomics and clinical follow-up data. Results: We observe large inter-individual variation of LDL uptake and lipid mobilization, the velocity with which cells deplete their lipid reservoirs, varying up to 8-fold. In subjects on a high potency statin, LDL uptake shows a negative correlation with LDL-cholesterol as well as cholesterol and cholesterol esters in VLDL and LDL particles. In the same subject group LDL uptake displays a positive correlation with triglycerides in VLDL particles. These correlation profiles are reduced in subjects on less potent statins and absent in control individuals. Likewise, lipid mobilization shows a differential correlation profile with certain lipid types and lipoprotein subclasses, which is dependent on whether the subjects are on cholesterol-lowering therapy. Conclusions: Our study highlights that each individual has a defined cellular lipid uptake and storage potential, providing deeper insight into differential treatment outcomes of cholesterol-lowering therapy in the general population.