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Results for “Lipoprotein metabolism”

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17 records
All sourcesNASA NTRSDOE OSTI
DOE OSTI2025

Lipid and lipoprotein metabolism in microglia: Alzheimer’s disease mechanisms and interventions

Alzheimer's disease (AD) presents a significant challenge owing to its widespread prevalence and complex neuropathogenesis, affecting millions worldwide. Current therapeutic strategies that predominantly target amyloid-beta accumulation are insufficient, particularly for ApoE4 carriers. Alterations in lipid composition are well documented in AD, characterized by reductions in phospholipids and sulfatides, along with increases in cholesterol, cholesteryl esters, and triglycerides (TGs). Microglia, the brain's resident immune cells, link dysfunctional lipid processing to AD neuropathogenesis. For example, genetic studies have pointed to microglial lipid and lipoprotein processing gene variants as some of the strongest risk factors for AD. In addition, microglial dysfunction, characterized by lipid droplet accumulation, increased cholesterol and TG levels, and altered lipid transport, may exacerbate the pathological hallmarks of AD, such as amyloid-beta and tau accumulation. Conversely, emerging studies have shown that strategies aimed at inhibiting lipid droplet accumulation in microglia, reducing TG synthesis, and promoting the activity of lipoprotein receptors expressed by microglia can improve cell functions and markers of AD pathology. This review dissects the interplay between microglial lipid metabolism and AD, highlighting the significance of lipid transport and trafficking within the CNS. Given the intrinsic link between microglial metabolism and AD progression, emerging and potential therapeutic strategies aimed at restoring lipid handling and improving microglial function are explored. This review provides a comprehensive examination of the emerging literature, detailing the current state of knowledge on microglial lipid metabolism, its genetic underpinnings, and the potential for novel interventions targeting these mechanisms to ameliorate AD pathology.

Alzheimer's disease↗
DOE OSTI2021

Pregnancy is accompanied by larger high density lipoprotein particles and compositionally distinct subspecies

Pregnancy is accompanied by significant physiological changes, which can impact the health and development of the fetus and mother. Pregnancy-induced changes in plasma lipoproteins are well documented, with modest to no impact observed on the generic measure of high density lipoprotein (HDL) cholesterol. However, the impact of pregnancy on the concentration and composition of HDL subspecies has not been examined in depth. In this prospective study, we collected plasma from 24 nonpregnant and 19 pregnant women in their second trimester. Using nuclear magnetic resonance (NMR), we quantified 11 different lipoprotein subspecies from plasma by size, including three in the HDL class. We observed an increase in the number of larger HDL particles in pregnant women, which were confirmed by tracking phospholipids across lipoproteins using high-resolution gel-filtration chromatography. Using liquid chromatography-mass spectrometry (LC-MS), we identified 87 lipid-associated proteins across size-speciated fractions. We report drastic shifts in multiple protein clusters across different HDL size fractions in pregnant females compared with nonpregnant controls that have major implications on HDL function. These findings significantly elevate our understanding of how changes in lipoprotein metabolism during pregnancy could impact the health of both the fetus and the mother.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2021

Molecular chaperone RAP interacts with LRP1 in a dynamic bivalent mode and enhances folding of ligand-binding regions of other LDLR family receptors

The low-density lipoprotein receptor (LDLR) family of receptors are cell-surface receptors that internalize numerous ligands and play crucial role in various processes, such as lipoprotein metabolism, hemostasis, fetal development, etc. Previously, receptor-associated protein (RAP) was described as a molecular chaperone for LDLR-related protein 1 (LRP1), a prominent member of the LDLR family. We aimed to verify this role of RAP for LRP1 and two other LDLR family receptors, LDLR and vLDLR, and to investigate the mechanisms of respective interactions using a cell culture model system, purified system, and in silico modelling. Upon coexpression of RAP with clusters of the ligand-binding complement repeats (CRs) of the receptors in secreted form in insect cells culture, the isolated proteins had increased yield, enhanced folding, and improved binding properties compared with proteins expressed without RAP, as determined by circular dichroism and surface plasmon resonance. Within LRP1 CR-clusters II and IV, we identified multiple sites comprised of adjacent CR doublets, which provide alternative bivalent binding combinations with specific pairs of lysines on RAP. Mutational analysis of these lysines within each of isolated RAP D1/D2 and D3 domains having high affinity to LRP1 and of conserved tryptophans on selected CR-doublets of LRP1, as well as in silico docking of a model LRP1 CR-triplet with RAP, indicated a universal role for these residues in interaction of RAP and LRP1. Consequently, we propose a new model of RAP interaction with LDLR family receptors based on switching of the bivalent contacts between molecules over time in a dynamic mode.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2024

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

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 cholesterol efflux capacity. APOA2 likewise increased the cholesterol efflux capacity of isolated HDL with the maximum effect occurring when equal masses of APOA1 and APOA2 coexisted on the particles. Follow-up experiments with reconstituted HDL corroborated that the presence of both APOA1 and APOA2 were necessary for the increased efflux. Using limited proteolysis and chemical cross-linking mass spectrometry, we found that APOA2 induced a conformational change in the N- and C-terminal helices of APOA1. Using reconstituted HDL with APOA1 deletion mutants, we further showed that APOA2 lost its ability to stimulate ABCA1 efflux to HDL if the C-terminal domain of APOA1 was absent, but retained this ability when the N-terminal domain was absent. Based on these findings, we propose a model in which APOA2 displaces the C-terminal helix of APOA1 from the HDL surface which can then interact with ABCA1—much like it does in lipid-poor APOA1. These findings suggest APOA2 may be a novel therapeutic target given this ability to open a large, high-capacity pool of HDL particles to enhance ABCA1-mediated cholesterol efflux.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2024

High-density Lipoprotein (HDL) Structure and Function Proteomics (JM-DP1)

The purpose of this experiment was to investigate how the interactions between APOA1 and APOA2 on the surface of high-density lipoproteins (HDL) impact particle function by studying the effect of exogenous APOA2 on HDL structure through limited proteolysis. Interactions were investigated on HDL isolated from human blood plasma using structural proteomics tools such as chemical cross-linking and limited proteolysis (LiP). The structural proteomics data was acquired using a Q-Exactive HF-X mass spectrometer and processed using MaxQuant software (v.1.6.17.0).

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2024

PPI DataHub Project Data Package: High-density Lipoprotein (HDL) Structure and Function Proteomics

The purpose of this experiment was to investigate how the interactions between APOA1 and APOA2 on the surface of high-density lipoproteins (HDL) impact particle function. Interactions were investigated on HDL isolated from human blood plasma using structural proteomics tools such as chemical cross-linking and limited proteolysis (LiP). The structural proteomics data was acquired using a Q-Exactive HF-X mass spectrometer and data was processed and compiled using MaxQuant sofware (v.1.6.17.0). Processed datasets are openly accessible from the download button (~2.8 GB) and contain secondary processed LiP and global proteomic results files and supporting metadata materials. Processed data downloads include a sample naming key, processed MaxQuant results/parameters, and protein annotated relative abundance files.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2025

Apolipoprotein A5 reduces clearance of VLDL by altering apolipoprotein E content

Apolipoprotein A-V (APOA5) is a critical regulator of circulating triglyceride (TG) levels. Its deletion leads to elevated plasma TG concentrations by altering the metabolism of very low-density lipoprotein (VLDL) particles in vivo. One way APOA5 exerts its effects is through modulation of lipoprotein lipase (LPL) activity, specifically by disrupting inhibitory interactions between LPL and angiopoietin-like proteins (ANGPTLs). However, the impact of APOA5 on VLDL composition and its potential to alter VLDL metabolism in other ways remains poorly understood. To address this, we investigated the influence of APOA5 on the VLDL proteome, LPL activation, and hepatic remnant uptake. Using VLDL from Apoa5 knockout (KO) and wild-type (WT) mice, we found no evidence that APOA5 directly enhances LPL activity in purified or plasma systems. However, VLDL from Apoa5 K mice was cleared significantly more slowly by cultured hepatocytes. Proteomics experiments from two independent laboratories identified consistent depletion of 17 proteins involved in lipoprotein metabolism, inflammation, and immune response in Apoa5 KO VLDL, including APOE and serum amyloid A1 (SAA1). Remarkably, reintroduction of recombinant mouse APOA5 to the KO plasma partially restored the WT VLDL proteome, including APOE, and normalized VLDL uptake by hepatocytes without altering LPL lipolysis. These findings reveal that APOA5 influences hepatic clearance of VLDL remnants by modulating particle composition, particularly APOE content. This study expands the functional scope of APOA5 in TG metabolism and underscores its role in VLDL remodeling and remnant clearance, offering new insights with implications for understanding hypertriglyceridemia and its roles in inflammation and immune response.

LPL↗
DOE OSTI2024

Lipoprotein Particles in Cerebrospinal Fluid

The brain is the most lipid-rich organ in the body, and the intricate interplay between lipid metabolism and pathologies associated with neurodegenerative disorders is being increasingly recognized. The brain is bathed in cerebrospinal fluid (CSF), which, like plasma, contains lipid-protein complexes called lipoproteins that are responsible for extracellular lipid transport. Multiple CSF lipoprotein populations exist, some of which are produced de novo in the central nervous system and others that appear to be generated from protein constituents that are produced in the periphery. These CSF lipoproteins are thought to play key roles in maintaining lipid homeostasis in the central nervous system, while little else is known due to their limited accessibility and their low abundance in CSF. Recent work has provided new insights into the compositional complexity of CSF lipoprotein families and their metabolism in cerebral circulation. Finally, the purpose of this review is to summarize our current state of knowledge on the composition, origin, and metabolism of CSF lipoproteins.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2025

The congenital APOA1 K107del mutation disrupts the lipid-free conformation of monomeric APOA1 and impairs oligomerization

Apolipoprotein A-I (APOA1) oligomerization is thought to be essential for high-density lipoprotein (HDL) formation and metabolism. Naturally occurring mutations can disrupt normal APOA1 folding and self-association, leading to dysfunctional HDL formation and cardiovascular disease. The congenital APOA1 variant p.K131del (APOA1 K107del ) has been associated with cardiovascular pathologies such as low HDL-cholesterol levels and aortic amyloidosis, and multiple studies indicate structural changes in APOA1 conformation underlie associated dysfunction. In the current study, we confirmed that APOA1 K107del exhibits no notable defect in lipid-binding. However, using polyacrylamide gel electrophoresis (PAGE) and size-exclusion chromatography (SEC), we found that loss of lysine 107 resulted in a remarkable shift in the distribution of APOA1 oligomers with a much higher proportion of monomers present in APOA1 K107del compared to wild-type APOA1. Further investigation using quantitative cross-linking revealed a major disruption of interactions in helical regions reported to participate in domain swaps necessary for proper self-association. This structural disruption appears to impair N- and C-termini interactions and dynamics that lead to non-specific aggregation. In conclusion, these findings support the hypothesis that lysine 107 is critical for proper folding and self-association of lipid-free APOA1 which could impact HDL biogenesis.

APOA1 (p.K131del)↗
DOE OSTI2022

Extracellular electron transfer increases fermentation in lactic acid bacteria via a hybrid metabolism

Energy conservation in microorganisms is classically categorized into respiration and fermentation; however, recent work shows some species can use mixed or alternative bioenergetic strategies. We explored the use of extracellular electron transfer for energy conservation in diverse lactic acid bacteria (LAB), microorganisms that mainly rely on fermentative metabolism and are important in food fermentations. The LAB Lactiplantibacillus plantarum uses extracellular electron transfer to increase its NAD + /NADH ratio, generate more ATP through substrate-level phosphorylation, and accumulate biomass more rapidly. This novel, hybrid metabolism is dependent on a type-II NADH dehydrogenase (Ndh2) and conditionally requires a flavin-binding extracellular lipoprotein (PplA) under laboratory conditions. It confers increased fermentation product yield, metabolic flux, and environmental acidification in laboratory media and during kale juice fermentation. The discovery of a single pathway that simultaneously blends features of fermentation and respiration in a primarily fermentative microorganism expands our knowledge of energy conservation and provides immediate biotechnology applications.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2023

Biophysical and biochemical studies support TP0094 as a phosphotransacetylase in an acetogenic energy-conservation pathway in Treponema pallidum

The mechanisms of energy generation and carbon-source utilization in the syphilis spirochete Treponema pallidum have remained enigmatic despite complete genomic sequence information. Whereas the bacterium harbors enzymes for glycolysis, the apparatus for more efficient use of glucose catabolites, namely the citric-acid cycle, is apparently not present. Yet, the organism’s energy needs likely exceed the modest output from glycolysis alone. Recently, building on our structure-function studies of T . pallidum lipoproteins, we proposed a “flavin-centric” metabolic lifestyle for the organism that partially resolves this conundrum. As a part of the hypothesis, we have proposed that T . pallidum contains an acetogenic energy-conservation pathway that catabolizes D-lactate, yielding acetate, reducing equivalents for the generation and maintenance of chemiosmotic potential, and ATP. We already have confirmed the D-lactate dehydrogenase activity in T . pallidum necessary for this pathway to operate. In the current study, we focused on another enzyme ostensibly involved in treponemal acetogenesis, phosphotransacetylase (Pta). This enzyme is putatively identified as TP0094 and, in this study, we determined a high-resolution (1.95 Å) X-ray crystal structure of the protein, finding that its fold comports with other known Pta enzymes. Further studies on its solution behavior and enzyme activity confirmed that it has the properties of a Pta. These results are consistent with the proposed acetogenesis pathway in T . pallidum , and we propose that the protein be referred to henceforth as TpPta.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2023

Lipoprotein subfraction patterns throughout gestation in The Gambia: changes in subfraction composition and their relationships with infant birth weights

Lipoprotein subfraction concentrations have been shown to change as gestation progresses in resource-rich settings. The objective of the current study was to evaluate the impact of pregnancy on different-sized lipoprotein particle concentrations and compositions in a resource-poor setting. Samples were collected from pregnant women in rural Gambia at enrollment (8–20 weeks), 20 weeks, and 30 weeks of gestation. Concentrations of different-sized high-density, low-density, and triglyceride-rich lipoprotein particles (HDL, LDL, and TRL, respectively) were measured by nuclear magnetic resonance in 126 pooled plasma samples from a subset of women. HDL was isolated and the HDL proteome evaluated using mass spectroscopy. Subfraction concentrations from women in The Gambia were also compared to concentrations in women in the U.S. in mid gestation. Total lipoprotein particles and all-sized TRL, LDL, and HDL particle concentrations increased during gestation, with the exception of medium-sized LDL and HDL particles which decreased. Subfraction concentrations were not associated with infant birth weights, though relationships were found between some lipoprotein subfraction concentrations in women with normal versus low birth weight infants (< 2500 kg). HDL’s proteome also changed during gestation, showing enrichment in proteins associated with metal ion binding, hemostasis, lipid metabolism, protease inhibitors, proteolysis, and complement activation. Compared to women in the U.S., Gambian women had lower large- and small-sized LDL and HDL concentrations, but similar medium-sized LDL and HDL concentrations. Most lipoprotein subfraction concentrations increase throughout pregnancy in Gambian women and are lower in Gambian vs U.S. women, the exception being medium-sized LDL and HDL particle concentrations which decrease during gestation and are similar in both cohorts of women. The proteomes of HDL also change in ways to support gestation. These changes warrant further study to determine how a lack of change or different changes could impact negative pregnancy outcomes.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

Apolipoprotein A-I modulates HDL particle size in the absence of apolipoprotein A-II

Human high-density lipoproteins (HDLs) are a complex mixture of structurally related nanoparticles that perform distinct physiological functions. We previously showed that human HDL containing apolipoprotein A-I (APOA1) but not apolipoprotein A-II (APOA2), designated LpA-I, is composed primarily of two discretely sized populations. Here, we isolated these particles directly from human plasma by antibody affinity chromatography, separated them by high-resolution size-exclusion chromatography and performed a deep molecular characterization of each species. The large and small LpA-I populations were spherical with mean diameters of 109 Å and 91 Å, respectively. Unexpectedly, isotope dilution MS/MS with [ 15 N]-APOA1 in concert with quantitation of particle concentration by calibrated ion mobility analysis demonstrated that the large particles contained fewer APOA1 molecules than the small particles; the stoichiometries were 3.0 and 3.7 molecules of APOA1 per particle, respectively. MS/MS experiments showed that the protein cargo of large LpA-I particles was more diverse. Human HDL and isolated particles containing both APOA1 and APOA2 exhibit a much wider range and variation of particle sizes than LpA-I, indicating that APOA2 is likely the major contributor to HDL size heterogeneity. We propose a ratchet model based on the trefoil structure of APOA1 whereby the helical cage maintaining particle structure has two “settings”—large and small—that accounts for these findings. This understanding of the determinants of HDL particle size and protein cargo distribution serves as a basis for determining the roles of HDL subpopulations in metabolism and disease states.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2024

Relationship Between Radiation Dose and Markers of Insulin Resistance and Inflammation in Atomic Bomb Survivors

Abstract Context In recent studies of childhood cancer survivors, diabetes has been considered a late effect associated with high therapeutic doses of radiation therapy. Our recent study of atomic bomb (A-bomb) survivors also suggested an association between radiation dose and diabetes incidence, with exposure city and age at exposure as radiation dose effect modifiers. Insulin resistance mediated by systemic inflammation and abnormal body composition has been suggested as a possible primary mechanism for the incidence of diabetes after total body irradiation; however, no studies have examined low to moderate radiation exposure (<4 Gy) and insulin resistance in A-bomb survivors. Objective To examine the association between radiation dose and markers of inflammation and insulin resistance. Methods This study investigated 3152 survivors who underwent a health examination between 2008 and 2012 and who were younger than 15 years at exposure. Multivariate linear regression analyses were used to evaluate the radiation effects on levels of markers of inflammation and insulin resistance. Results Radiation dose was significantly and positively associated with levels of C-reactive protein, triglycerides, homeostasis model assessment of β-cell function (HOMA-β), and HOMA of insulin resistance (HOMA-IR) after adjustment for relevant covariates including sex, city, and age at exposure. Adiponectin and high-density lipoprotein cholesterol levels were also associated significantly and negatively with radiation dose. However, city was not a dose modifier of the radiation response on these markers of inflammation and insulin resistance. Conclusion Insulin resistance might be a possible factor in radiation-related diabetes incidence in A-bomb survivors.

Endocrinology & Metabolism↗
DOE OSTI2024

Expression, purification, and characterization of diacylated Lipo-YcjN from Escherichia coli

YcjN is a putative substrate binding protein expressed from a cluster of genes involved in carbohydrate import and metabolism in Escherichia coli. Here, we determine the crystal structure of YcjN to a resolution of 1.95 Å, revealing that its three-dimensional structure is similar to substrate binding proteins in subcluster D-I, which includes the well-characterized maltose binding protein. Furthermore, we found that recombinant overexpression of YcjN results in the formation of a lipidated form of YcjN that is posttranslationally diacylated at cysteine 21. Comparisons of size-exclusion chromatography profiles and dynamic light scattering measurements of lipidated and nonlipidated YcjN proteins suggest that lipidated YcjN aggregates in solution via its lipid moiety. Additionally, bioinformatic analysis indicates that YcjN-like proteins may exist in both Bacteria and Archaea, potentially in both lipidated and nonlipidated forms. Together, our results provide a better understanding of the aggregation properties of recombinantly expressed bacterial lipoproteins in solution and establish a foundation for future studies that aim to elucidate the role of these proteins in bacterial physiology.

Escherichia coli↗
DOE OSTI2022

A Surface Exposed, Two-Domain Lipoprotein Cargo of a Type XI Secretion System Promotes Colonization of Host Intestinal Epithelia Expressing Glycans

The only known required component of the newly described Type XI secretion system (TXISS) is an outer membrane protein (OMP) of the DUF560 family. TXISS OMPs are broadly distributed across proteobacteria, but properties of the cargo proteins they secrete are largely unexplored. We report biophysical, histochemical, and phenotypic evidence that Xenorhabdus nematophila NilC is surface exposed. Biophysical data and structure predictions indicate that NilC is a two-domain protein with a C-terminal, 8-stranded β-barrel. This structure has been noted as a common feature of TXISS effectors and may be important for interactions with the TXISS OMP . The NilC N-terminal domain is more enigmatic, but our results indicate it is ordered and forms a β-sheet structure, and bioinformatics suggest structural similarities to carbohydrate-binding proteins. X. nematophila NilC and its presumptive TXISS OMP partner NilB are required for colonizing the anterior intestine of Steinernema carpocapsae nematodes: the receptacle of free-living, infective juveniles and the anterior intestinal cecum (AIC) in juveniles and adults. We show that, in adult nematodes, the AIC expresses a Wheat Germ Agglutinin (WGA)-reactive material, indicating the presence of N-acetylglucosamine or N-acetylneuraminic acid sugars on the AIC surface. A role for this material in colonization is supported by the fact that exogenous addition of WGA can inhibit AIC colonization by X. nematophila. Conversely, the addition of exogenous purified NilC increases the frequency with which X. nematophila is observed at the AIC, demonstrating that abundant extracellular NilC can enhance colonization. NilC may facilitate X. nematophila adherence to the nematode intestinal surface by binding to host glycans, it might support X. nematophila nutrition by cleaving sugars from the host surface, or it might help protect X. nematophila from nematode host immunity. Proteomic and metabolomic analyses of wild type X. nematophila compared to those lacking nilB and nilC revealed differences in cell wall and secreted polysaccharide metabolic pathways. Additionally, purified NilC is capable of binding peptidoglycan, suggesting that periplasmic NilC may interact with the bacterial cell wall. Overall, these findings support a model that NilB-regulated surface exposure of NilC mediates interactions between X. nematophila and host surface glycans during colonization. This is a previously unknown function for a TXISS.

59 BASIC BIOLOGICAL SCIENCES↗