Site-specific glycations of apolipoprotein A-I lead to differentiated functional effects on lipid-binding and on glucose metabolism

Domingo-Espín, Joan; Nilsson, Oktawia; Bernfur, Katja; Giudice, Rita Del; Lagerstedt, Jens O.

doi:10.1016/j.bbadis.2018.05.014

Cited by 25 publications

(27 citation statements)

References 65 publications

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“…The ability of glycated apoA-IV by itself to efflux cholesterol from macrophages was conserved. This is consistent with what has been reported previously for the efflux of cholesterol by nonenzymatically glycated apoA-I from the J774 macrophage cell line [59], but is contrary to others that showed reduction in cholesterol efflux mediated by glycated apoA-I in THP-1 and J774 macrophages [36,38,60]. Figure 6: Abca1, Abcg1, Scarb1, Nr1h3, and Nr1h2 mRNA expression in macrophages treated with unmodified or AGE-apoA-IV and further stimulated with LPS.…”

supporting

confidence: 91%

“…Chemical alterations of HDL apolipoproteins, including their nonenzymatic glycation by reactive α-oxoaldehydes such as methylglyoxal, glycolaldehyde, and glyoxal, are detrimental to their function and role in atheroprotection [36,38,40,41]. Advanced glycation is independently related to cardiovascular disease, by inducing oxidative and inflammatory stress and disturbing the flux of cholesterol from the artery wall to the liver in the reverse cholesterol transport pathway.…”

Section: Discussionmentioning

confidence: 99%

“…Nonenzymatic glycation of apoA-I reduces HDL function as well as increases coronary artery plaque progression in patients with type 2 diabetes mellitus (T2DM) [36][37][38][39][40][41]. A recent study demonstrated that the extent of derivatization of apoA-IV by the AGE carboxymethyllysine (CML) is associated with coronary heart disease severity [42].…”

Section: Introductionmentioning

confidence: 99%

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Advanced Glycated apoA-IV Loses Its Ability to Prevent the LPS-Induced Reduction in Cholesterol Efflux-Related Gene Expression in Macrophages

Okuda

Iborra

Pinto

et al. 2020

Mediators of Inflammation

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We addressed how advanced glycation (AGE) affects the ability of apoA-IV to impair inflammation and restore the expression of genes involved in cholesterol efflux in lipopolysaccharide- (LPS-) treated macrophages. Recombinant human apoA-IV was nonenzymatically glycated by incubation with glycolaldehyde (GAD), incubated with cholesterol-loaded bone marrow-derived macrophages (BMDMs), and then stimulated with LPS prior to measurement of proinflammatory cytokines by ELISA. Genes involved in cholesterol efflux were quantified by RT-qPCR, and cholesterol efflux was measured by liquid scintillation counting. Carboxymethyllysine (CML) and pyrraline (PYR) levels, determined by Liquid Chromatography-Mass Spectrometry (LC-MS/MS), were greater in AGE-modified apoA-IV (AGE-apoA-IV) compared to unmodified-apoA-IV. AGE-apoA-IV inhibited expression of interleukin 6 (Il6), TNF-alpha (Tnf), IL-1 beta (Il1b), toll-like receptor 4 (Tlr4), tumor necrosis factor receptor-associated factor 6 (Traf6), Janus kinase 2/signal transducer and activator of transcription 3 (Jak2/Stat3), nuclear factor kappa B (Nfkb), and AGE receptor 1 (Ddost) as well as IL-6 and TNF-alpha secretion. AGE-apoA-IV alone did not change cholesterol efflux or ABCA-1 levels but was unable to restore the LPS-induced reduction in expression of Abca1 and Abcg1. AGE-apoA-IV inhibited inflammation but lost its ability to counteract the LPS-induced changes in expression of genes involved in macrophage cholesterol efflux that may contribute to atherosclerosis.

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supporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Advanced Glycated apoA-IV Loses Its Ability to Prevent the LPS-Induced Reduction in Cholesterol Efflux-Related Gene Expression in Macrophages

Okuda

Iborra

Pinto

et al. 2020

Mediators of Inflammation

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“…C2C12 myoblasts were differentiated to myotubes by switching from growth media to 2% FBS DMEM for 7 days, with the addition of cytosine arabinoside (Sigma, Stockholm, Sweden) from day 3 to 5 to eliminate proliferating cells [ 20 ]. Prior to stimulation, cells starved for 2 h in serum-free DMEM were treated as described and glucose uptake measurements were carried out.…”

Section: Methodsmentioning

confidence: 99%

ApoAI-derived peptide increases glucose tolerance and prevents formation of atherosclerosis in mice

et al. 2019

Self Cite

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Aims/hypothesis Finding new treatment alternatives for individuals with diabetes with severe insulin resistance is highly desired. To identify novel mechanisms that improve glucose uptake in skeletal muscle, independently from insulin levels and signalling, we have explored the therapeutic potential of a short peptide sequence, RG54, derived from apolipoprotein A-I (ApoA-I). Methods INS-1E rat clonal beta cells, C2C12 rat muscle myotubes and J774 mouse macrophages were used to study the impact of RG54 peptide on glucose-stimulated insulin secretion, glucose uptake and cholesterol efflux, respectively. GTTs were carried out on diet-induced insulin-resistant and Lepr db diabetic mouse models treated with RG54 peptide, and the impact of RG54 peptide on atherosclerosis was evaluated in Apoe −/− mice. Control mice received ApoA-I protein, liraglutide or NaCl. Results The synthetic RG54 peptide induced glucose uptake in cultured muscle myotubes by a similar amount as insulin, and also primed pancreatic beta cells for improved glucose-stimulated insulin secretion. The findings were verified in diet-induced insulin-resistant and Lepr db diabetic mice, jointly confirming the physiological effect. The RG54 peptide also efficiently catalysed cholesterol efflux from macrophages and prevented the formation of atherosclerotic plaques in Apoe −/− mice. Conclusions/interpretation The RG54 peptide exhibits good prospects for providing glucose control and reducing the risk of cardiovascular disease in individuals with severe insulin resistance. Electronic supplementary material The online version of this article (10.1007/s00125-019-4877-2) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

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“…The fifth most significant term, "lipoprotein remodeling" is part of the two aforementioned processes. The top 100 genes identified by the scDGN include apoa1 (main protein component of High-Density Lipoprotein cholesterol), apoa2, and apoc1, all of which encode lipoproteins that are primarily expressed in the liver [6,18]. These genes were not included in the top 100 genes by the NN.…”

Section: Analysis Of Key Genesmentioning

confidence: 99%

Supervised Adversarial Alignment of Single-Cell RNA-seq Data

Wang²,

Alavi³

et al. 2020

Preprint

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Dimensionality reduction is an important first step in the analysis of single cell RNA-seq (scRNA-seq) data. In addition to enabling the visualization of the profiled cells, such representations are used by many downstream analyses methods ranging from pseudo-time reconstruction to clustering to alignment of scRNA-seq data from different experiments, platforms, and labs. Both supervised and unsupervised methods have been proposed to reduce the dimension of scRNA-seq. However, all methods to date are sensitive to batch effects. When batches correlate with cell types, as is often the case, their impact can lead to representations that are batch rather than cell type specific. To overcome this we developed a domain adversarial neural network model for learning a reduced dimension representation of scRNA-seq data. The adversarial model tries to simultaneously optimize two objectives. The first is the accuracy of cell type assignment and the second is the inability to distinguish the batch (domain). We tested the method by using the resulting representation to align several different datasets. As we show, by overcoming batch effects our method was able to correctly separate cell types, improving on several prior methods suggested for this task. Analysis of the top features used by the network indicates that by taking the batch impact into account, the reduced representation is much better able to focus on key genes for each cell type.

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Site-specific glycations of apolipoprotein A-I lead to differentiated functional effects on lipid-binding and on glucose metabolism

Cited by 25 publications

References 65 publications

Advanced Glycated apoA-IV Loses Its Ability to Prevent the LPS-Induced Reduction in Cholesterol Efflux-Related Gene Expression in Macrophages

Advanced Glycated apoA-IV Loses Its Ability to Prevent the LPS-Induced Reduction in Cholesterol Efflux-Related Gene Expression in Macrophages

ApoAI-derived peptide increases glucose tolerance and prevents formation of atherosclerosis in mice

Supervised Adversarial Alignment of Single-Cell RNA-seq Data

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