(1) Changes in cellular cholesterol homeostasis may also underlie the anti-inflammatory and antioxidative effects of HDL, as well as increases in endothelial nitric oxide synthase activity that induce production of the antiatherogenic molecule nitric oxide (NO). It is mostly known for mediating reverse cholesterol transport from peripheral tissues and arterial walls back to the liver, either specifically via the interaction with scavenger receptor class B member 1 (SCARB1) and ATP binding cassette (ABC) transporters or non-specifically by aqueous diffusion. (1) HDLs exert a multiplicity of functions potentially beneficial for human health. The most abundant apolipoproteins in the particle are APOA-I and APOA-II, which account for about 65 and 15%, respectively, of the protein mass in HDL particles. It contains the highest proportion of proteins relative to lipids of characterized lipoprotein particles. High-density lipoprotein (HDL) is the smallest and densest of all lipoprotein particles in the human body. Together, DIA-based HDL proteotyping enables the robust digitization of HDL proteotypes as a basis for the analysis of larger clinical cohorts. From a technical point of view, data analysis further shows that protein and peptide quantities are currently more discriminative between different HDL proteotypes than peptidoforms without further enrichment. HDL peptidoform analysis enabled by using spectral libraries allowed for the identification of post-translational modifications, such as in APOA1, which could affect HDL functionality. Bioinformatic interrogation of the data using the generated spectral libraries showed that the DIA approach enabled robust HDL proteotype determination. HDL proteome spectral libraries consisting of 296 protein groups and more than 786 peptidoforms were established, and the performance of the DIA strategy was benchmarked for the detection of HDL proteotype differences between healthy individuals and a cohort of patients suffering from diabetes mellitus type 2 and/or coronary heart disease. In order to create the required spectral libraries enabling these data-independent acquisition (DIA) strategies, HDL was isolated from the plasma of more than 300 patients with a multiplicity of physiological HDL states. Recent advancements in mass spectrometry-based proteotype analysis show promise for the analysis of proteoforms across large patient cohorts. High-density lipoprotein (HDL) is a heterogeneous mixture of blood-circulating multimolecular particles containing many different proteins, lipids, and RNAs.
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