Diacylglycerols and lysophosphatidic acid, enriched on Lipoprotein(a), contribute to monocyte inflammation
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ABSTRACT:
PROVIDER: PRJNA1051121 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR27183220_1.fastq.gz | Fastqsanger.gz | |||
| SRR27183220_2.fastq.gz | Fastqsanger.gz | |||
| SRR27183221_1.fastq.gz | Fastqsanger.gz | |||
| SRR27183221_2.fastq.gz | Fastqsanger.gz | |||
| SRR27183222_1.fastq.gz | Fastqsanger.gz |
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Project description: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.
2024-01-25 | GSE249911 | GEO
Project description:BackgroundOxidized phospholipids play a key role in the atherogenic potential of lipoprotein(a) (Lp[a]); however, Lp(a) is a complex particle that warrants research into additional proinflammatory mediators. We hypothesized that additional Lp(a)-associated lipids contribute to the atherogenicity of Lp(a).MethodsUntargeted 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 RNA sequencing, 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.ResultsCompared with 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 proinflammatory pathways related to leukocyte migration, chemotaxis, NF-κB (nuclear factor kappa B) signaling, and cytokine production. Functional assessment showed a dose-dependent increase in the secretion of IL (interleukin)-6, IL-8, and IL-1β after DG(40:6) and DG(38:4) stimulation, which was, in part, mediated via the NLRP3 (NOD [nucleotide-binding oligomerization domain]-like receptor family pyrin domain containing 3) 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 colocalization of Lp(a) with M1 macrophages, and an enrichment of CD68+IL-18+TLR4+ (toll-like receptor) TREM2+ (triggering receptor expressed on myeloid cells) resident macrophages and CD68+CASP1+ (caspase) IL-1B+SELL+ (selectin L) inflammatory macrophages compared with patients with low Lp(a). Finally, potent Lp(a)-lowering treatment (pelacarsen) resulted in a reduction in specific circulating DG lipid subspecies in patients with cardiovascular disease with elevated Lp(a) levels (median, 82 mg/dL [205 nmol/L]).ConclusionsLp(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.
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Project description:Although therapies for atherosclerotic cardiovascular disease (ASCVD) have advanced, substantial residual risk of cardiovascular (CV) events remains. Lipoprotein (a) [Lp(a)] is a low-density lipoprotein (LDL) particle that is causally linked to both ASCVD and CV events. Lp(a) is thought to drive ASCVD through multiple mechanisms including its effects on cholesterol accumulation, inflammation, and thrombosis. Although the associations between Lp(a) and ASCVD drivers are clear, the mechanisms that integrate Lp(a)-mediated cholesterol accumulation, inflammation, and thrombosis remain largely unknown. In this study, we employed systems biology approaches consisting of proteomics, transcriptomics, and mass cytometry to define the immune cellular and molecular phenotypes in ASCVD subjects with high and low Lp(a) levels and the mechanisms through which Lp(a) mediates monocyte activation. In a cohort of stable ASCVD subjects (n=64 [41 with high Lp(a) and 23 with low Lp(a]), we found that circulating markers of inflammation (CCL28, IL-17D) and vascular dysfunction (BNP), tissue factor [TF]) was elevated in subjects with high Lp(a) levels compared with those with low Lp(a) levels. Additionally, although total monocytes levels and hs-CRP levels were similar between the groups, CD14+ monocytes from ASCVD subjects with an elevated Lp(a) were primed and expressed more TF at baseline and in response to stress. Mechanistically, we found that Lp(a) itself can activate monocytes through Toll-like receptors (TLR) and nuclear factor kappa B (NFκB) signaling, driving both the induction of TF and TF activity. Overall, these studies are the first to link Lp(a) to monocyte-mediated inflammation and thrombosis, demonstrating a novel mechanism through TLR2, NFκB, and monocyte TF which Lp(a) amplifies immunothrombotic risk.
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Project description:Lysophosphatidic acid (LPA) acts through high-affinity G protein-coupled receptors to mediate a plethora of physiological and pathological activities associated with tumorigenesis. LPA receptors and autotaxin (ATX/LysoPLD), the primary enzyme producing LPA, are aberrantly expressed in multiple cancer lineages. However, the role of ATX and LPA receptors in the initiation and progression of breast cancer has not been evaluated. We demonstrate that expression of ATX or each edg family LPA receptor in mammary epithelium of transgenic mice is sufficient to induce a high frequency of late-onset, estrogen receptor (ER)-positive, invasive, and metastatic mammary cancer. Thus, ATX and LPA receptors can contribute to the initiation and progression of breast cancer.
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2024-12-31 | E-MTAB-13993 | biostudies-arrayexpress
Project description:Lipids are essential components of cancer cells due to their structural and signaling roles. To meet metabolic demands, many cancers take up extracellular lipids; however, how these lipids contribute to cancer growth and progression remains poorly understood. Here, using functional genetic screens, we identify lipoprotein uptake—the primary mechanism for lipid transport in circulation—as a key determinant of ferroptosis sensitivity in cancer. Lipoprotein supplementation robustly inhibits ferroptosis across diverse cancer types, primarily through the delivery of α-tocopherol (α-toc), the most abundant form of vitamin E in human lipoproteins. Mechanistically, cancer cells take up lipoproteins through a pathway dependent on sulfated glycosaminoglycans (GAGs) linked to cell-surface proteoglycans. Disrupting GAG biosynthesis or acutely degrading surface GAGs reduces lipoprotein uptake, sensitizes cancer cells to ferroptosis, and impairs tumour growth in mice. Notably, human clear cell renal cell carcinomas, a lipid-rich malignancy, exhibit elevated levels of chondroitin sulfate and increased lipoprotein-derived α-toc compared to normal kidney tissue. Altogether, our work establishes lipoprotein uptake as a critical anti-ferroptotic mechanism in cancer and implicates GAG biosynthesis as a therapeutic target.
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