Plasma lipoprotein(a) [Lp(a)] concentrations are primarily genetically determined, but whether disruption of triglyceride-rich lipoprotein metabolism modifies Lp(a) expression is unknown. Familial chylomicronemia syndrome (FCS) provides a human model to investigate this relationship. In the phase 3 Balance trial, 66 participants with genetically confirmed FCS (triglycerides ≥880 mg/dL) underwent Lp(a) measurement, apo(a) isoform phenotyping, and measurement of OxPL-apo(a) and OxPL-apoB. Results were compared with 66 age- and sex-matched participants with moderate hypertriglyceridemia from Essence-TIMI 73b. Median Lp(a) concentrations were similar (9.77[4.64-33.6] vs 11.8[5.23-90.4] nmol/L; P=0.148), but the Lp(a) distribution in FCS was shifted downward, driven by fewer individuals with high Lp(a) concentrations despite similar apo(a) isoform distributions. The inverse relationship between apo(a) isoform size and Lp(a) was preserved (P for trend <0.001), with lower Lp(a) in FCS after stratification by apo(a) isoform size (P=0.006). Median [IQR] Lp(a) was lower in FCS with <17 KIV repeats (67.4 [49.2-93.7] vs 175 [145-324] nmol/L; P=0.018) and 17-20 KIV repeats (23.9 [9.37-55.3] vs 138 [17.1-192] nmol/L; P=0.012). OxPL-apo(a) and OxPL-apoB were lower in FCS (P=0.026 and P<0.0001, respectively). The OxPL-apo(a)/OxPL-apoB ratio was approximately 70% lower (0.60 [0.27-1.69] vs 2.05 [1.49-2.79]; P<0.0001) and showed a pronounced inverse trend across apo(a) isoform size in FCS (P<0.001), consistent with altered relative OxPL carriage among apoB-containing lipoproteins. Olezarsen had no consistent effects on Lp(a) or OxPL biomarkers. These findings demonstrate that functional deficiency of the LPL pathway modifies the phenotypic expression of genetically determined Lp(a) and alters OxPL distribution among apoB-containing lipoproteins.

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 performed a cross sectional, observational study 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. 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. 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.

Although the association of lipoprotein(a) (Lp(a)) with coronary heart disease was reported over 60 years ago, and subsequent studies have identified a causal and independent role for Lp(a) in disease, many fundamental unanswered questions persist surrounding the biology of this enigmatic lipoprotein. There remain critical questions surrounding the structure and metabolism of Lp(a) and the unique biochemical properties of Lp(a) that drive its pathogenic properties in the vasculature. These questions are critical to address as we rapidly approach the availability of drugs that can specifically lower Lp(a).

Metabolic syndrome (MetS), characterized by a cluster of interrelated metabolic abnormalities including central obesity, elevated blood pressure, dysglycemia, hypertriglyceridemia, and reduced high-density lipoprotein cholesterol (HDL-C), substantially increases type 2 diabetes and cardiovascular disease risk. Conventional genome-wide association studies (GWASs) analyze individual traits or a dichotomized MetS status, only partially capturing its heritability and potentially overlooking variants with shared (pleiotropic) effects across correlated traits. Here, we performed a multiple-trait GWAS using data from the Korean Genome and Epidemiology Study. Using the Korea Biobank Array (K-Chip), we analyzed a discovery cohort from the Ansan and Ansung studies (1490 cases and 3856 controls) and validated the findings in CAVAS (3620 cases and 4461 controls) and HEXA (15,257 cases and 41,807 controls) cohorts. We jointly modeled six MetS-related traits using the complementary multivariate frameworks Multiple Phenotype Association Tests and Genome-wide Efficient Mixed Model Association, alongside a baseline logistic regression. Whereas logistic regression detected 2 APOA5 variants (rs662799 and rs2075291), the multivariate analyses identified 79 significant single-nucleotide polymorphisms; all were replicated in the HEXA cohort. Functional annotation prioritized 27 high-risk variants mapping to 12 genes, whereas pathway analysis (DAVID) implicated eight Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathways related to lipid metabolism. Our findings demonstrate that multivariate analysis substantially improves the identification of pleiotropic susceptibility loci for MetS in the Korean population and indicates candidate genes for early detection and management.

High-density lipoproteins (HDL) are essential to alleviate the progression of atherosclerosis by mediating reverse-cholesterol transport, antioxidant and anti-inflammatory effects. We aimed to enhance the expression of endogenous HDL components, apolipoprotein A1 (APOA1) and antioxidant enzyme paraoxonase 1 (PON1), and to investigate their athero-protective effects. The CRISPR/dCas9 technology was used to activate the transcription of endogenous APOA1/PON1 in human hepatocytes (Huh7 line) and Apoa1/Pon1 in apoE-/- mice. The expression of APOA1/PON1 genes was successfully upregulated in hepatocytes, and their proteins were secreted in the culture medium in the presence/absence of tumor necrosis factor-α (TNFα). APOA1-rich Huh7-derived conditioned medium exerted antioxidant and anti-inflammatory effects in TNFα-activated EA.hy926 endothelial cells. A single dose of the CRISPR/dCas9 plasmids i.v. injected in apoE-/- mice increased the expression of hepatic Apoa1/Pon1 and their serum levels up to four weeks. FPLC analysis showed that increased serum APOA1 was distributed between HDL, LDL, and in lipid-free form. These mice also exhibited high levels of hepatic, gallbladder and feces cholesterol, in part due to the upregulation of hepatic scavenger receptor class-B1, cholesterol 7-alpha-hydroxylase, and ATP-binding cassette sub-family-G-member-8 transporter. In apoE-/- mice with upregulated Apoa1/Pon1, no increased inflammatory stress or innate immune activation were detected, while lipid peroxides were decreased in PON1 mice. Of major interest, the area of aortic lipid deposits was halved in the treated mice. Our findings demonstrate the successful upregulation of endogenous Apoa1/Pon1 in apoE-/- mice by using the CRISPR/dCas9 system, and highlight new mechanisms for APO1/PON1 anti-atherosclerotic action, explaining the reduction of aortic lipid deposits.

The APOA1 rs670 (-75 G>A) polymorphism has been implicated in lipid metabolism and susceptibility to metabolic syndrome (MetS). However, individual studies have reported inconsistent associations with circulating apolipoprotein A1 (Apo A1) and lipid parameters, and no meta-analysis has comprehensively evaluated these associations stratified by metabolic disorder status. We therefore quantified the associations between APOA1 rs670 and serum Apo A1 and lipid parameters, and determined whether these associations are modified by metabolic disorder status. PubMed, Embase, Web of Science, Cochrane Library, and ClinicalTrials.gov were searched from inception to March 2026. Eligible studies reported APOA1 rs670 genotype data with quantitative lipid measurements. Forty studies involving 22,175 participants met the inclusion criteria. Pooled effect sizes were estimated as standardized mean differences (SMDs) with 95% confidence intervals (CIs) using random-effects models. This review was registered in PROSPERO (CRD420261333145). A allele carriers had significantly higher serum Apo A1 (SMD, 0.20; p < 0.001) and HDL-C levels (SMD, 0.14; p < 0.001) than GG homozygotes. Subgroup analyses stratified by metabolic disorder status revealed that the associations with Apo A1 (SMD, 0.53 vs. 0.11) and HDL-C (SMD, 0.23 vs. 0.08) were substantially stronger among individuals with metabolic disorders than among metabolically healthy individuals. No significant associations were observed for LDL-C or triglyceride levels. The APOA1 rs670 polymorphism is associated with higher circulating Apo A1 and HDL-C levels, with stronger associations in individuals with metabolic disorders. These findings suggest that metabolic status modifies the phenotypic effects of rs670 on the Apo A1-HDL pathway.

The limited benefits of high-density lipoprotein (HDL)-targeted therapies have shifted the research focus to HDL quality; some HDL subtypes may be pro-atherogenic and may counteract the potential benefits of HDL therapies. This study investigated the pathological mechanism of H5, a highly electronegative and compositionally abnormal HDL subfraction characterized by impaired cholesterol efflux. We used anion-exchange chromatography to separate HDL into five subfractions (H1-H5) from blood from 131 asymptomatic individuals (95 with metabolic syndrome and 36 without [controls]). Plasma H5 levels were significantly elevated in individuals with cardiovascular disease risk compared to controls (4.0 ± 3.5% vs. 2.7 ± 1.0%, p = 0.024). Clinically, elevated H5 levels were independently associated with structural markers of subclinical carotid atherosclerosis, including increased intima-media thickness (IMT) and plaque burden, in an imaging cohort of 118 participants. Mechanistically, the triglyceride-rich H5 showed a distinct lipoproteome, enriched with apolipoproteins including Apo(a), ApoB, and ApoC3. H5 induced endothelial dysfunction through pathways associated with reactive oxygen species (ROS) accumulation, DNA damage, and cellular senescence in vitro and in vivo. The p53-p21 signaling axis was the central mediator of this H5-induced dysfunction. In mice, H5-induced dysfunction promoted a pro-atherogenic phenotype, mediated centrally by the p53-p21 signaling axis. Our study suggests that elevated Apo(a)-rich H5 levels are associated with atherosclerotic cardiovascular disease (ASCVD) risk and validates targeting HDL quality-specifically the H5 subfraction-as a novel therapeutic strategy.

Blood levels of high-density lipoprotein (HDL) are significantly inversely correlated with the risk of numerous malignancies and overall mortality in most tumor types. This review focuses on the antitumor role of HDL and its main protein component, apolipoprotein A-I (apoA-I). The association of HDL/apoA-I with various cancer types and the probable mechanisms of their antitumor action, including cholesterol removal from tumor cells, modulation of the tumor microenvironment, and involvement in the regulation of oncogenic signaling pathways, are discussed. The identified high expression of the SR-B1 receptor in tumor cells supports the use of HDL and its synthetic analogs (apoA-I mimetics) as a platform for the targeted delivery of antitumor agents. Using various tumor models, it has been demonstrated that the use of these plasma components for targeted drug delivery enhanced their antitumor effect and reduced side effects.

Background: To evaluate the effects of three lifestyle modification strategies-dietary supplementation with phenolic acid-rich Brussels chicory (Cho), Brussels chicory supplementation combined with supervised concurrent resistance exercise and high-intensity interval training (Cho-CT) or mindfulness-enhanced concurrent resistance exercise and high-intensity interval training (Cho-MeCT)-on high-density lipoprotein cholesterol efflux capacity (HDL-CEC) from macrophages and HDL subclass profiles (pre-β-HDL, HDL3, HDL2) in overweight adults. Methods: This study is an 8-week randomized controlled trial in which 97 overweight college students were randomized to Cho, Cho-CT, Cho-MeCT or control group. HDL-CEC from macrophages, the primary outcome, HDL subclass profiles, plasma activities of lecithin, such as cholesterol acyltransferase (LCAT) and cholesteryl ester transfer protein (CETP) involved in remodeling HDL subclass profiles and plasma lipid profiles, and apolipoprotein AI were assessed at baseline and post-intervention. Results: Compared with the control treatment, all three lifestyle interventions comparably elicited a 1.18% to 1.78% elevations in HDL-CEC from macrophages (p < 0.001). Their improvements were accompanied by reductions in pre-β-HDL and HDL3 concentrations and increased HDL2 concentrations. However, there were no significant differences in plasma lipid profiles, apolipoprotein A-I, and plasma LCAT and CETP activities among the tested groups. Within the Cho, Cho-CT, and Cho-MeCT groups, changes in HDL-CEC from macrophages were positively correlated with changes in HDL2 levels, whereas weak negative correlations were observed for pre-β-HDL and HDL3, though these associations did not reach statistical significance. No comparable significant correlations were found in the control group. Conclusions: In overweight adults, sustained Brussels chicory supplementation, either alone or combined with concurrent exercise training, may yield comparable favorable changes in HDL-CEC from macrophages and HDL subclass profiles, though effect magnitudes appear modest in this pilot trial.

Objective: This study aims to explore the association of lipid indicators, including LDL-C, HDL-C, TC, lipoprotein a (Lpa), apolipoprotein A1 (ApoA1), apolipoprotein B (ApoB), and the composite lipid indicator triglyceride-glucose index (TyG), with the risk of osteoporotic fracture. Methods: A retrospective analysis was performed based on clinical data from 3 987 patients hospitalized in the Department of Osteoporosis at West China Fourth Hospital, Sichuan University, between December 2017 and October 2024. Based on the presence or absence of osteoporotic fracture, the patients were divided into cases and controls. Logistic regression models, mediation effect models, and stratified analysis were applied to explore the association. The area under the curve (AUC) was used to evaluate the model's prediction performance. Maximum likelihood estimation and targeted maximum likelihood estimation were used under the causal contrast weighting framework for causal inference analysis. Results: The level of HDL-C in the case group was higher than that in the control group, while the opposite was true for the levels of ApoA1 and ApoB (all P<0.05). Logistic regression analysis revealed a positive correlation between HDL-C and osteoporotic fracture risk (OR=1.36, 95%CI: 1.12-1.66, P=0.002), while ApoA1 (OR=0.76, 95%CI: 0.64-0.90, P=0.002) and ApoB (OR=0.83, 95%CI: 0.70-0.98, P=0.031) showed a negative correlation with osteoporotic fracture risk. Stratified analysis showed that the effects of HDL-C were mainly observed in elderly patients (≥65 years old), whereas those of ApoA1 and ApoB were mainly observed in elderly and obese patients (BMI≥24.00 kg/m[2]). Mediation analysis showed that HDL-C indirectly affected fractures through femoral neck and lumbar spine bone density (mediation ratios of 21.10% and 22.50%), while LDL-C was mediated by lumbar spine bone density (mediation ratio of 33.40%). After combining HDL-C, LDL-C, ApoA1, and ApoB indicators, the model's AUC increased significantly (P=0.010), and its predictive performance improved. Causal inference analysis supported that ApoA1 (maximum likelihood estimation: RR=0.83, 95%CI: 0.73-0.92, P=0.002; targeted maximum likelihood estimation: RR=0.81, 95%CI: 0.72-0.94, P<0.001) and ApoB (maximum likelihood estimation: RR=0.84, 95%CI: 0.74-0.94, P=0.004; targeted maximum likelihood estimation: RR=0.85, 95%CI: 0.74-0.96, P=0.009) were inversely associated with osteoporotic fracture risk, the association of HDL-C with osteoporotic fracture was only significant in the maximum likelihood estimation model (RR=1.20, 95%CI: 1.06-1.40, P=0.012). Conclusions: Elevated HDL-C levels were associated with increased risk of osteoporotic fractures, while elevated ApoA1 and ApoB levels were associated with decreased risk, and the association between the latter two was more robust in the causal inference analysis. Lipid indicators are useful for predicting and evaluating osteoporotic fracture risk and have potential clinical value for preventing osteoporotic fracture.