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Apolipoprotein A-II Increases Cholesterol Efflux Capacity of Mature High-Density Lipoproteins Via the Apolipoprotein A-I C-terminus

ABSTRACT: Samples were processed using Global and Limited Proteolysis (LiP). Peptides and proteins were identified using MaxQuant (v1.6.17.0), then summarized using R package RomicsProcessor.

INSTRUMENT(S): Orbitrap Fusion Lumos, Q Exactive HF-X

ORGANISM(S): Homo Sapiens (ncbitaxon:9606)

SUBMITTER: John T. Melchior

PROVIDER: MSV000095479 | MassIVE | Mon Jul 29 16:56:00 BST 2024

REPOSITORIES: MassIVE

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Publications

APOA2 increases cholesterol efflux capacity to plasma HDL by displacing the C-terminus of resident APOA1.

Sarkar Snigdha S Morris Jamie J You Youngki Y Sexmith Hannah H Street Scott E SE Thibert Stephanie M SM Attah Isaac K IK Hutchinson Bunch Chelsea M CM Novikova Irina V IV Evans James E JE Shah Amy S AS Gordon Scott M SM Segrest Jere P JP Bornfeldt Karin E KE Vaisar Tomas T Heinecke Jay W JW Davidson W Sean WS Melchior John T JT

Journal of lipid research 20241028 12

The ability of high-density lipoprotein (HDL) to promote cellular cholesterol efflux is a more robust predictor of cardiovascular disease protection than HDL-cholesterol levels in plasma. Previously, we found that lipidated HDL containing both apolipoprotein A-I (APOA1) and A-II (APOA2) promotes cholesterol efflux via the ATP-binding cassette transporter (ABCA1). In the current study, we directly added purified, lipid-free APOA2 to human plasma and found a dose-dependent increase in whole plasma ...[more]

PMID: 39490930

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Structure of apolipoprotein A-I N terminus on nascent high density lipoproteins.

Project description:Apolipoprotein A-I (apoA-I) is the major protein component of high density lipoproteins (HDL) and a critical element of cholesterol metabolism. To better elucidate the role of the apoA-I structure-function in cholesterol metabolism, the conformation of the apoA-I N terminus (residues 6-98) on nascent HDL was examined by electron paramagnetic resonance (EPR) spectroscopic analysis. A series of 93 apoA-I variants bearing single nitroxide spin label at positions 6-98 was reconstituted onto 9.6-nm HDL particles (rHDL). These particles were subjected to EPR spectral analysis, measuring regional flexibility and side chain solvent accessibility. Secondary structure was elucidated from side-chain mobility and molecular accessibility, wherein two major ?-helical domains were localized to residues 6-34 and 50-98. We identified an unstructured segment (residues 35-39) and a ?-strand (residues 40-49) between the two helices. Residues 14, 19, 34, 37, 41, and 58 were examined by EPR on 7.8, 8.4, and 9.6 nm rHDL to assess the effect of particle size on the N-terminal structure. Residues 14, 19, and 58 showed no significant rHDL size-dependent spectral or accessibility differences, whereas residues 34, 37, and 41 displayed moderate spectral changes along with substantial rHDL size-dependent differences in molecular accessibility. We have elucidated the secondary structure of the N-terminal domain of apoA-I on 9.6 nm rHDL (residues 6-98) and identified residues in this region that are affected by particle size. We conclude that the inter-helical segment (residues 35-49) plays a role in the adaptation of apoA-I to the particle size of HDL.

| S-EPMC3024791 | biostudies-literature

Genetic loci associated with plasma concentration of low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides, apolipoprotein A1, and Apolipoprotein B among 6382 white women in genome-wide analysis with replication.

Project description:Genome-wide genetic association analysis represents an opportunity for a comprehensive survey of the genes governing lipid metabolism, potentially revealing new insights or even therapeutic strategies for cardiovascular disease and related metabolic disorders.We have performed large-scale, genome-wide genetic analysis among 6382 white women with replication in 2 cohorts of 970 additional white men and women for associations between common single-nucleotide polymorphisms and low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides, apolipoprotein(Apo) A1, and ApoB. Genome-wide associations (P < 5 x 10(-8)) were found at the PCSK9 gene, the APOB gene, theLPL gene, the APOA1-APOA5 locus, the LIPC gene, the CETP gene, the LDLR gene, and the APOE locus. In addition,genome-wide associations with triglycerides at the GCKR gene confirm and extend emerging links between glucose and lipid metabolism. Still other genome-wide associations at the 1p13.3 locus are consistent with emerging biological properties for a region of the genome, possibly related to the SORT1 gene. Below genome-wide significance, our study provides confirmatory evidence for associations at 5 novel loci with low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, or triglycerides reported recently in separate genome-wide association studies. The total proportion of variance explained by common variation at the genome-wide candidate loci ranges from 4.3% for triglycerides to 12.6% for ApoB.Genome-wide associations at the GCKR gene and near the SORT1 gene, as well as confirmatory associations at 5 additional novel loci, suggest emerging biological pathways for lipid metabolism among white women.

| S-EPMC2630707 | biostudies-literature

The effects of apolipoprotein F deficiency on high density lipoprotein cholesterol metabolism in mice.

Project description:Apolipoprotein F (apoF) is 29 kilodalton secreted sialoglycoprotein that resides on the HDL and LDL fractions of human plasma. Human ApoF is also known as Lipid Transfer Inhibitor protein (LTIP) based on its ability to inhibit cholesteryl ester transfer protein (CETP)-mediated transfer events between lipoproteins. In contrast to other apolipoproteins, ApoF is predicted to lack strong amphipathic alpha helices and its true physiological function remains unknown. We previously showed that overexpression of Apolipoprotein F in mice reduced HDL cholesterol levels by 20-25% by accelerating clearance from the circulation. In order to investigate the effect of physiological levels of ApoF expression on HDL cholesterol metabolism, we generated ApoF deficient mice. Unexpectedly, deletion of ApoF had no substantial impact on plasma lipid concentrations, HDL size, lipid or protein composition. Sex-specific differences were observed in hepatic cholesterol content as well as serum cholesterol efflux capacity. Female ApoF KO mice had increased liver cholesteryl ester content relative to wild type controls on a chow diet (KO: 3.4+/-0.9 mg/dl vs. WT: 1.2+/-0.3 mg/dl, p<0.05). No differences were observed in ABCG1-mediated cholesterol efflux capacity in either sex. Interestingly, ApoB-depleted serum from male KO mice was less effective at promoting ABCA1-mediated cholesterol efflux from J774 macrophages relative to WT controls.

| S-EPMC3282742 | biostudies-literature

Apolipoprotein B is associated with CT-angiographic progression beyond low-density lipoprotein cholesterol and non-high-density lipoprotein cholesterol in patients with coronary artery disease.

Project description:BackgroundAccumulating evidence indicated that apolipoprotein B (apoB) was the principal lipid determinant of coronary artery disease (CAD). Nevertheless, the connection between apoB and angiographic progression of CAD remained undetermined.MethodsFive hundred and forty-four CAD patients with twice coronary computed tomography angiography experiences were enrolled. The Gensini scoring system was used to assess angiographic progression. Incident angiographic progression was defined as an annual change rate of the Gensini score of > 1 point. The predictive efficacy of baseline apoB levels for angiographic progression was assessed using a receiver operating characteristic (ROC) curve. For comparative purposes, patients were categorized into three groups according to their baseline apoB tertiles. Furthermore, discordance analyses defined by the median were performed to assess the superiority of apoB over lipoprotein cholesterol in predicting angiographic progression of CAD.ResultsAngiographic progression was observed in 184 patients (33.8%) during a follow-up period of 2.2-year. The area under the ROC curve was 0.565 (0.522-0.607, P = 0.013). The incidence of angiographic progression was elevated with increasing apoB tertile after adjusting for confounding factors [odds ratio (OR) for the medium apoB tertile: 1.92, 95% confidence interval (CI): 1.15-3.19, P = 0.012; OR for the high apoB tertile: 2.05, 95%CI:1.17-3.60, P = 0.013]. Additionally, discordance analyses showed that the higher apoB group had a significantly higher risk of CAD progression in the fully adjusted model (all P < 0.05).ConclusionsApoB could be used as an accurate and comprehensive indicator of angiographic progression in patients with CAD.

| S-EPMC10410799 | biostudies-literature

Apolipoprotein B discordance with low-density lipoprotein cholesterol and non-high-density lipoprotein cholesterol in relation to coronary artery calcification in the Multi-Ethnic Study of Atherosclerosis (MESA).

Project description:BackgroundDiscordant levels of apolipoprotein B (apo B) relative to low-density lipoprotein cholesterol (LDL-C) or non-high-density lipoprotein cholesterol (non-HDL-C) may be associated with subclinical atherosclerotic cardiovascular disease (ASCVD).ObjectiveThe present study investigated whether discordance between apo B and LDL-C or non-HDL-C levels was associated with subclinical ASCVD measured by coronary artery calcium (CAC).MethodsThis study was conducted in a subpopulation of the Multi-Ethnic Study of Atherosclerosis (MESA) cohort, aged 45 to 84 years, free of ASCVD, and not taking lipid-lowering medications at the baseline (2000-2002) (prevalence analytic N = 4623; incidence analytic N = 2216; progression analytic N = 3947). Apo B discordance relative to LDL-C and non-HDL-C was defined using residuals and percentile rankings (>5/10/15 percentile). Associations with prevalent and incident CAC (CAC > 0 vs CAC = 0) were assessed using prevalence ratio/relative risk regression and CAC progression (absolute increase/year) using multinomial logistic regression.ResultsHigher apo B levels were associated with CAC prevalence, incidence, and progression. Apo B discordance relative to LDL-C or non-HDL-C was inconsistently associated with CAC prevalence and progression. Discordantly high apo B relative to LDL-C and non-HDL-C was associated with CAC progression. Associations for apo B discordance with non-HDL-C remained after further adjustment for metabolic syndrome components.ConclusionApo B was associated with CAC among adults aged ≥45 years not taking statins, but provided only modest additional predictive value of apo B for CAC prevalence, incidence, or progression beyond LDL-C or non-HDL-C. Apo B discordance may still be important for ASCVD risk assessment and further research is needed to confirm findings.

| S-EPMC7085429 | biostudies-literature

Low-density lipoprotein cholesterol, apolipoprotein B, and risk of coronary heart disease: from familial hyperlipidemia to genomics.

Project description:Coronary heart disease (CHD) affects 17 million people in the United States and accounts for over a million hospital stays each year. Technological advances, especially in genetics and genomics, have changed our understanding of the risk factors for developing CHD. The purpose of this article is to review low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (apo B), and risk of CHD. The article focuses on five topics: (1) a description of lipoprotein classes, normal lipoprotein metabolism, and the biological mechanism of atherosclerosis; (2) a review of selected epidemiologic and clinical trial studies examining the associations between elevated LDL-C and apo B with CHD; (3) a brief review of the familial forms of hyperlipidemia; (4) a description of variants in genes that have been associated with higher LDL-C levels in candidate gene studies and genome-wide association studies (GWAS); and (5) nursing implications, including a discussion on how genetic tests are evaluated and the current clinical utility and validity of genetic tests for CHD.

| S-EPMC4031677 | biostudies-literature

ABCA1 mediates unfolding of apolipoprotein AI N terminus on the cell surface before lipidation and release of nascent high-density lipoprotein.

Project description:To gain insight into the mechanism by which ABCA1 generates nascent high-density lipoprotein.HEK293 cells were stably transfected with ABCA1 vectors, encoding wild type, and the W590S and C1477R Tangier disease mutation isoforms, along with the K939M ATP-binding domain mutant. Apolipoprotein AI (ApoAI) binding, plasma membrane remodeling, cholesterol efflux, apoAI cell surface unfolding, and apoAI cell surface lipidation were determined, the latter 2 measured using novel fluorescent apoAI indicators. The W590S isoform had decreased plasma membrane remodeling and lipid efflux activities, and the C1477R isoform had decreased apoAI binding, and lipid efflux activities, whereas the K939M isoform did not bind apoAI, remodel the membrane, or efflux cholesterol. However, all ABCA1 isoforms led to apoAI unfolding at the cell surface, which was higher for the isoforms that increased apoAI binding. ApoAI lipidation was not detected on ABCA1-expressing cells, only in the conditioned medium, consistent with rapid release of nascent high-density lipoprotein from ABCA1-expressing cells.We identified a third activity of ABCA1, the ability to unfold the N terminus of apoAI on the cell surface. Our results support a model in which unfolded apoAI on the cell surface is an intermediate in its lipidation and that, once apoAI is lipidated, it forms an unstable structure that is rapidly released from the cells to generate high-density lipoprotein.

| S-EPMC3701943 | biostudies-literature

Hyperhomocysteinemia decreases circulating high-density lipoprotein by inhibiting apolipoprotein A-I Protein synthesis and enhancing HDL cholesterol clearance.

Project description:We previously reported that hyperhomocysteinemia (HHcy), an independent risk factor of coronary artery disease (CAD), is associated with increased atherosclerosis and decreased plasma high-density lipoprotein cholesterol (HDL-C) in cystathionine beta-synthase-/apolipoprotein E-deficient (CBS(-/-)/apoE(-/-)) mice. We observed that plasma homocysteine (Hcy) concentrations are negatively correlated with HDL-C and apolipoprotein A1 (apoA-I) in patients with CAD. We found the loss of large HDL particles, increased HDL-free cholesterol, and decreased HDL protein in CBS(-/-)/apoE(-/-) mice, and attenuated cholesterol efflux from cholesterol-loaded macrophages to plasma in CBS(-/-)/apoE(-/-) mice. ApoA-I protein was reduced in the plasma and liver, but hepatic apoA-I mRNA was unchanged in CBS(-/-)/apoE(-/-) mice. Moreover, Hcy (0.5 to 2 mmol/L) reduced the levels of apoA-I protein but not mRNA and inhibited apoA-1 protein synthesis in mouse primary hepatocytes. Further, plasma lecithin:cholesterol acyltransferase (LCAT) substrate reactivity was decreased, LCAT specific activity increased, and plasma LCAT protein levels unchanged in apoE(-/-)/CBS(-/-) mice. Finally, the clearance of plasma HDL cholesteryl ester, but not HDL protein, was faster in CBS(-/-)/apoE(-/-) mice, correlated with increased scavenger receptor B1, and unchanged ATP-binding cassette transporter A1 protein expression in the liver. These findings indicate that HHcy inhibits reverse cholesterol transport by reducing circulating HDL via inhibiting apoA-I protein synthesis and enhancing HDL-C clearance.

| S-EPMC4400841 | biostudies-literature

Site-specific 5-hydroxytryptophan incorporation into apolipoprotein A-I impairs cholesterol efflux activity and high-density lipoprotein biogenesis.

Project description:Apolipoprotein A-I (apoA-I) is the major protein constituent of high-density lipoprotein (HDL) and a target of myeloperoxidase-dependent oxidation in the artery wall. In atherosclerotic lesions, apoA-I exhibits marked oxidative modifications at multiple sites, including Trp72 Site-specific mutagenesis studies have suggested, but have not conclusively shown, that oxidative modification of Trp72 of apoA-I impairs many atheroprotective properties of this lipoprotein. Herein, we used genetic code expansion technology with an engineered Saccharomyces cerevisiae tryptophanyl tRNA-synthetase (Trp-RS):suppressor tRNA pair to insert the noncanonical amino acid 5-hydroxytryptophan (5-OHTrp) at position 72 in recombinant human apoA-I and confirmed site-specific incorporation utilizing MS. In functional characterization studies, 5-OHTrp72 apoA-I (compared with WT apoA-I) exhibited reduced ABC subfamily A member 1 (ABCA1)-dependent cholesterol acceptor activity in vitro (41.73 ± 6.57% inhibition; p < 0.01). Additionally, 5-OHTrp72 apoA-I displayed increased activation and stabilization of paraoxonase 1 (PON1) activity (μmol/min/mg) when compared with WT apoA-I and comparable PON1 activation/stabilization compared with reconstituted HDL (WT apoA-I, 1.92 ± 0.04; 5-OHTrp72 apoA-I, 2.35 ± 0.0; and HDL, 2.33 ± 0.1; p < 0.001, p < 0.001, and p < 0.001, respectively). Following injection into apoA-I-deficient mice, 5-OHTrp72 apoA-I reached plasma levels comparable with those of native apoA-I yet exhibited significantly reduced (48%; p < 0.01) lipidation and evidence of HDL biogenesis. Collectively, these findings unequivocally reveal that site-specific oxidative modification of apoA-I via 5-OHTrp at Trp72 impairs cholesterol efflux and the rate-limiting step of HDL biogenesis both in vitro and in vivo.

| S-EPMC7152772 | biostudies-literature

A map of protein-metabolite interactions reveals principles of chemical communication

Project description:Application of a novel mass spectrometry-based high-throughput workflow (LiP-SMap) and data resource based on limited proteolysis (LiP) of complex samples. Proteome-wide limited proteolysis sites were obtained in different conditions to infer ligand-induced and protein-protein interaction induced conformational changes. This information was used to identify unknown ligand binding proteins, small molecule-protein binding sites and the remodeling of protein complexes directly in cells.

2018-01-04 | PXD006543 | Pride

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