HDL from apoA1 transgenic mice expressing the 4WF isoform is resistant to oxidative loss of function

Berisha, Stela Z.; Brubaker, Greg; Kasumov, Takhar; Hung, Kimberly T.; DiBello, Patricia M.; Huang, Ying; Li, Ling; Willard, Belinda; Pollard, Katherine; Nagy, Laura E.; Hazen, Stanley A; Smith, Jonathan

doi:10.1194/jlr.m056754

Cited by 11 publications

(18 citation statements)

References 52 publications

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“…56 PIP2 carried on circulating HDL might also serve as a signaling molecule by the delivery of PIP2 to target cells via SR-BI. In wildtype mice we observed plasma PIP2 levels at ~0.4 μM; however, with plasma apoA1 of ~ 32 uM 57 , and assuming on average 2.5 apoA1 molecules per HDL, the final HDL concentration is ~13 μM. Thus, it appears that there is less than one PIP2 molecule per HDL particle in circulation.…”

Section: Discussionmentioning

confidence: 64%

PI(4,5)P2 Is Translocated by ABCA1 to the Cell Surface Where It Mediates Apolipoprotein A1 Binding and Nascent HDL Assembly

Gulshan

Brubaker

Conger

et al. 2016

Circulation Research

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Rationale The molecular mechanism by which ABCA1 mediates cellular binding of apolipoprotein A-I (apoA1) and nascent HDL assembly is not well understood. Objective To determine the cell surface lipid that mediates apoA1 binding to ABCA1 expressing cells and the role it plays in nascent HDL assembly. Methods and Results Using multiple biochemical and biophysical methods, we found that apoA1 binds specifically to phosphatidylinositol (4,5) bis-phosphate (PIP2). Flow cytometry and PIP2 reporter binding assays demonstrated that ABCA1 led to PIP2 redistribution from the inner to the outer leaflet of the plasma membrane. Enzymatic cleavage of cell surface PIP2 or decreased cellular PIP2 by knockdown of phosphatidylinositol-5-phosphate 4-kinase impaired apoA1 binding and cholesterol efflux to apoA1. PIP2 also increased the spontaneous solubilization of phospholipid liposomes by apoA1. Using site directed mutagenesis; we found that ABCA1's PIP2 and phosphatidylserine translocase activities are independent from each other. Furthermore, we discovered that PIP2 is effluxed from cells to apoA1, where it is associated with HDL in plasma, and that PIP2 on HDL is taken up by target cells in a scavenger receptor-BI (SR-BI) dependent manner. Mouse plasma PIP2 levels are apoA1 gene dosage dependent and are > 1 μM in apoA1 transgenic mice. Conclusions ABCA1 has a PIP2 floppase activity, which increases cell surface PIP2 levels that mediate apoA1 binding and lipid efflux during nascent HDL assembly. We found that PIP2 itself is effluxed to apoA1 and it circulates on plasma HDL, where it can be taken up via the HDL receptor SR-BI.

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Section: Discussionmentioning

confidence: 64%

PI(4,5)P2 Is Translocated by ABCA1 to the Cell Surface Where It Mediates Apolipoprotein A1 Binding and Nascent HDL Assembly

Gulshan

Brubaker

Conger

et al. 2016

Circulation Research

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“…2 H 2 O labeling-based HDL turnover method also was applied to assess the effect of different isoforms of apoAI and gender on in vivo HDL function in wild-type human transgenic apoAI mice and mice with 4WF isoform of human apoAI, in which 4 tryptophan residues are substituted with phenylalanine [86]. The in vitro cholesterol efflux assay demonstrated that the 4WF isoform of apoAI was resistant to myeloperoxidase-induced loss of function while human apoA1 transgenic HDL lost all ABCA1-dependent cholesterol acceptor activity.…”

Section: Animal Studiesmentioning

confidence: 99%

Proteome Dynamics with Heavy Water — Instrumentations, Data Analysis, and Biological Applications

Kasumov¹,

Willard²,

Li³

et al. 2015

Recent Advances in Proteomics Research

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The quantitative assessment of the synthesis of individual proteins has been greatly hindered by the lack of a high-throughput nonradioactive method. We recently developed a method that we call proteome dynamics and software that enables high-throughput kinetic analyses of peptides on a proteome-wide scale. Previous studies established that oral administration of heavy water H O or deuterium oxide, D O is safe and well tolerated in humans. "riefly, a loading dose of H O, a nonradioactive isotope, is administered in drinking water. H O rapidly labels body water and transfers H from H O to H-labeled amino acids, which incorporates into proteins dependent upon the rate of synthesis of the specific protein. Proteins are analyzed by high-resolution mass spectrometry and protein synthesis is calculated using specialized software. We have established the effectiveness of this method for plasma and mitochondrial proteins. We demonstrated that fasting has a differential effect on the synthesis rates of proteins. We also applied this method to assess the effect of heart failure on the stability of mitochondrial proteins. In this review, we describe the study design, instrumentation, data analysis, and biological application of heavy water-based proteome turnover studies. We summarize this chapter with the challenges in the field and future directions.

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“…In fact, the impact of MPO‐mediated oxidation on an apoA‐I variant in which all Tyr residues were conservatively replaced with Phe was equivalent to the impact on wild‐type apoA‐I (8). In contrast, an apoA‐I variant in which all 4 Trp were conservatively replaced with Phe (4WF‐ApoA‐I) was immune to MPO‐mediated impairment of the cholesterol acceptor function (9, 18, 19). This observation indicates that MPO‐mediated oxidation of Trp plays a central role in apoA‐I loss of function (9).…”

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confidence: 99%

“…In the case of ATP binding cassette transporter A1 (ABCA1)-mediated release of cellular cholesterol toward apoA-I, its extracellular recipient, the disagreement is even more pronounced (3,4,6,8,9,11,14,(16)(17)(18)(19). In vitro, chlorination levels of apoA-I Tyr residues tightly correlate with a reduction in cellular cholesterol release capacity (3,4,11) and in vivo, they correlate with the incidence of cardiovascular events and atherosclerosis (14,16,17).…”

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confidence: 99%

Methionine oxidized apolipoprotein A‐I at the crossroads of HDL biogenesis and amyloid formation

Witkowski¹,

Chan²,

Boatz

et al. 2018

FASEB j.

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Apolipoprotein A-I (apoA-I) shares with other exchangeable apolipoproteins a high level of structural plasticity. In the lipid-free state, the apolipoprotein amphipathic α-helices interact intra- and intermolecularly, providing structural stabilization by self-association. We have reported that lipid-free apoA-I becomes amyloidogenic upon physiologically relevant (myeloperoxidase-mediated) Met oxidation. In this study, we established that Met oxidation promotes amyloidogenesis by reducing the stability of apoA-I monomers and irreversibly disrupting self-association. The oxidized apoA-I monomers also exhibited increased cellular cholesterol release capacity and stronger association with macrophages, compared to nonoxidized apoA-I. Of physiologic relevance, preformed oxidized apoA-I amyloid fibrils induced amyloid formation in nonoxidized apoA-I. This process was enhanced when self-association of nonoxidized apoA-I was disrupted by thermal treatment. Solid state NMR analysis revealed that aggregates formed by seeded nonoxidized apoA-I were structurally similar to those formed by the oxidized protein, featuring a β-structure-rich amyloid fold alongside α-helices retained from the native state. In atherosclerotic lesions, the conditions that promote apoA-I amyloid formation are readily available: myeloperoxidase, active oxygen species, low pH, and high concentration of lipid-free apoA-I. Our results suggest that even partial Met oxidation of apoA-I can nucleate amyloidogenesis, thus sequestering and inactivating otherwise antiatherogenic and HDL-forming apoA-I.-Witkowski, A., Chan, G. K. L., Boatz, J. C., Li, N. J., Inoue, A. P., Wong, J. C., van der Wel, P. C. A., Cavigiolio, G. Methionine oxidized apolipoprotein A-I at the crossroads of HDL biogenesis and amyloid formation.

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HDL from apoA1 transgenic mice expressing the 4WF isoform is resistant to oxidative loss of function

Cited by 11 publications

References 52 publications

PI(4,5)P2 Is Translocated by ABCA1 to the Cell Surface Where It Mediates Apolipoprotein A1 Binding and Nascent HDL Assembly

PI(4,5)P2 Is Translocated by ABCA1 to the Cell Surface Where It Mediates Apolipoprotein A1 Binding and Nascent HDL Assembly

Proteome Dynamics with Heavy Water — Instrumentations, Data Analysis, and Biological Applications

Methionine oxidized apolipoprotein A‐I at the crossroads of HDL biogenesis and amyloid formation

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