Reyes-Soffer, G. | Search bioRxiv

bioRxiv2026

Proteomic and Kinetic Analyses Reveal Discordant Apolipoprotein Turnover and Support a Revised Model of Human Lipoprotein(a) Metabolism

Objective: Lipoprotein(a) [Lp(a)] is a causal risk factor for atherosclerotic cardiovascular disease composed of apolipoprotein(a) [APO(a)] covalently linked to apolipoprotein B100 (APOB). Although plasma Lp(a) concentrations are largely genetically determined, the mechanisms governing Lp(a) metabolism after particle assembly remain poorly understood. We sought to define the Lp(a) proteome and determine the metabolic behavior of APO(a) and APOB within circulating Lp(a) particles using integrated proteomic, kinetic, and imaging approaches. Approach and Results: Sixteen healthy adults underwent stable isotope tracer studies with 2H3-L-leucine and 2H5-glycerol. Lp(a) particles were isolated by APO(a)-specific immunoprecipitation for high-resolution liquid chromatography-mass spectrometry and kinetic analyses, and extracellular vesicles (EVs) were characterized by imaging flow cytometry and super-resolution microscopy. Proteomic analysis identified 92 proteins associated with immuno-isolated Lp(a), enriched in pathways related to immunity, coagulation, and atherogenesis. Lp(a)-APO(a) exhibited a mean fractional clearance rate of 0.04 pools/day, whereas Lp(a)-APOB cleared approximately sevenfold faster (0.25 pools/day), independent of plasma Lp(a) concentration or APO(a) isoform size. Both APO(a) and APOB were detected on circulating EVs, suggesting that EVs may contribute to post-secretory Lp(a) particle remodeling. Conclusion: These integrated human studies demonstrate marked discordance between APO(a) and APOB turnover within circulating Lp(a) particles, challenging the prevailing assumption that both apolipoproteins behave as a single metabolic unit after Lp(a) assembly and supporting a revised model of human Lp(a) metabolism.

physiology↗

bioRxiv2026

Associations Between Plasma Lipoprotein(a) Levels and Circulating Monocyte Subsets Differ across Populations

BackgroundLipoprotein(a) [Lp(a)] is a causal risk factor for cardiovascular disease (CVD), with plasma concentrations higher in Black individuals than in White individuals. Published findings support a model in which high Lp(a), in part through oxidized phospholipid (oxPL)-mediated signaling, promotes a pro-inflammatory monocyte phenotype that may contribute to arterial wall inflammation and the development of CVD. Here, we examined the relationship between Lp(a) concentrations and isoform size and the distribution of circulating monocyte populations in Black and White individuals using single-cell RNA sequencing (scRNA-seq) data. MethodsUsing standardized assays, we measured plasma Lp(a) levels, isoform size, inflammatory markers, and oxidized phospholipids in stored plasma samples from our previously published cohort of 128 participants. After excluding smokers and individuals with type II diabetes, a total of 34 participants (20 Black participants, 14 White participants) were included in analyses. Participants were further stratified by plasma Lp(a) levels into normal Lp(a) [median 12.6 nmol/L, with 15 individuals (8 Black participants) and high Lp(a) (median 159 nmol/L, with 19 individuals (12 Black partcipants)]. Multivariable linear regression was used to assess the association between plasma Lp(a) levels, Lp(a)-oxPL, and the proportion of monocyte subsets. Across all participants, scRNA-seq data identified six classical monocyte subsets, one non-classical monocyte subset, one MHCIIhi monocyte subset, and one interferon (IFN)-responsive monocyte subset. ResultsThe distribution of monocyte subsets was similar in individuals with normal versus high Lp(a) levels. Despite the small study cohort, self resported race modified the assocation between plasma Lp(a) levels and the proportion of non-classical monocytes (P = 0.032), which was inversely associated in White participants (P = 0.028), but not in Black partcipatns (P = 0.470). OxPL bound to APO(a) showed a positive correlation with plasma Lp(a) levels (R2 = 0.84; P = 3.3x10-14), and non-classical monocytes (PWhites = 0.027; PBlacks = 0.275; PInteraction = 0.014). Race also modified the association between plasma Lp(a) levels and the proportion of classical 2 monocytes (P = 0.027). ConclusionsThese results underscore the importance of self reported race when analysing studies on Lp(a), monocytes and, cardiovascular related monocyte immune functions.

immunology↗