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Diacylglycerols and lysophosphatidic acid, enriched on Lipoprotein(a), contribute to monocyte inflammation

ABSTRACT: Background: OxPLs play a key role in the atherogenic potential of Lp(a), however Lp(a) is a complex particle that warrants research into additional pro-inflammatory mediators. We hypothesized that additional Lp(a)-associated lipids contribute to the atherogenicity of Lp(a). Methods: Untargeted lipidomics was performed on plasma and isolated lipoprotein fractions. The atherogenicity of the observed Lp(a)-associated lipids was tested ex vivo in primary human monocytes by RNAseq, ELISA, Western Blot and transendothelial migratory assays. Using immunofluorescence staining and single-cell RNA sequencing, the phenotype of macrophages was investigated in human atherosclerotic lesions. Results: Compared to healthy individuals with low/normal Lp(a) levels [median 7 mg/dL (18 nmol/L); N=13], individuals with elevated Lp(a) levels [median 87 mg/dL (218 nmol/L); N=12] demonstrated an increase in lipid species, particularly diacylglycerols (DGs) and lysophosphatidic acid (LPA). DG and the LPA precursor lysophosphatidylcholine were enriched in the Lp(a) fraction. Ex vivo stimulation with DG(40:6) demonstrated a significant upregulation in pro-inflammatory pathways related to leukocyte migration, chemotaxis, NF-κB signalling and cytokine production. Functional assessment showed a dose-dependent increase in the secretion of IL-6, IL-8 and IL-1β after DG(40:6) and DG(38:4) stimulation, which was in part mediated via the NLRP3-inflammasome. Conversely, LPA-stimulated monocytes did not exhibit an inflammatory phenotype. Furthermore, activation of monocytes by DGs and LPA increased their transendothelial migratory capacity. Human atherosclerotic plaques from patients with high Lp(a) levels demonstrated co-localisation of Lp(a) with M1 macrophages, and an enrichment of CD68+IL18+TLR4+TREM2+ resident macrophages and CD68+CASP1+IL1B+SELL+ inflammatory macrophages compared to patients with low Lp(a). Finally, potent Lp(a) lowering treatment (pelacarsen), resulted in a reduction in specific circulating DG lipid subspecies in cardiovascular disease patients with elevated Lp(a) levels [median 82 mg/dL (205 nmol/L)]. Conclusions: Lp(a)-associated DGs and LPA have a potential role in Lp(a)-induced monocyte inflammation by increasing cytokine secretion and monocyte transendothelial migration. This DG-induced inflammation is in part NLRP3-inflammasome dependent.

ORGANISM(S): Homo sapiens

PROVIDER: GSE249911 | GEO | 2024/01/25

REPOSITORIES: GEO

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Project description:An increased level of Lp(a) lipoprotein has been identified as a risk factor for coronary artery disease that is highly heritable. The genetic determinants of the Lp(a) lipoprotein level and their relevance for the risk of coronary disease are incompletely understood. METHODS: We used a novel gene chip containing 48,742 single-nucleotide polymorphisms (SNPs) in 2100 candidate genes to test for associations in 3145 case subjects with coronary disease and 3352 control subjects. Replication was tested in three independent populations involving 4846 additional case subjects with coronary disease and 4594 control subjects. RESULTS: Three chromosomal regions (6q26-27, 9p21, and 1p13) were strongly associated with the risk of coronary disease. The LPA locus on 6q26-27 encoding Lp(a) lipoprotein had the strongest association. We identified a common variant (rs10455872) at the LPA locus with an odds ratio for coronary disease of 1.70 (95% confidence interval [CI], 1.49 to 1.95) and another independent variant (rs3798220) with an odds ratio of 1.92 (95% CI, 1.48 to 2.49). Both variants were strongly associated with an increased level of Lp(a) lipoprotein, a reduced copy number in LPA (which determines the number of kringle IV-type 2 repeats), and a small Lp(a) lipoprotein size. Replication studies confirmed the effects of both variants on the Lp(a) lipoprotein level and the risk of coronary disease. A meta-analysis showed that with a genotype score involving both LPA SNPs, the odds ratios for coronary disease were 1.51 (95% CI, 1.38 to 1.66) for one variant and 2.57 (95% CI, 1.80 to 3.67) for two or more variants. After adjustment for the Lp(a) lipoprotein level, the association between the LPA genotype score and the risk of coronary disease was abolished. CONCLUSIONS: We identified two LPA variants that were strongly associated with both an increased level of Lp(a) lipoprotein and an increased risk of coronary disease. Our findings provide support for a causal role of Lp(a) lipoprotein in coronary disease.

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Diacylglycerols and lysophosphatidic acid, enriched on Lipoprotein(a), contribute to monocyte inflammation

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