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At least 19 records
All sourcesNASA NTRSDOE OSTI
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 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 OSTI2022

Synthetic apolipoproteins, and related compositions methods and systems for nanolipoprotein particles formation

Synthetic apolipoproteins based on native/naturally occurring homolog proteins can be prepared using solid-phase peptide synthesis approaches combined with native chemical ligation methods to create analogs of full length apolipoproteins. The chemical synthesis is expected to allow introduction of non-natural amino acids, e.g., α,α′-dialkyl amino acids, with a periodicity that encourages both helix formation and amphipathicity. Such apolipoprotein analogs are expected to encourage, in some embodiments, facile and more complete NLP formation, enabling consideration of full spectrum of nanoparticle-based biotechnology applications ranging from therapeutic sequestration and delivery to energy/biofuel production to biopolymer production.

Source record↗
DOE OSTI2021

Apolipoprotein nanodiscs with telodendrimer

The present invention provides a nanodisc with a membrane scaffold protein. The nanodisc includes a membrane scaffold protein, a telodendrimer and a lipid. The membrane scaffold protein can be apolipoprotein. The telodendrimer has the general formula PEG-L-D-(R)n, wherein D is a dendritic polymer; L is a bond or a linker linked to the focal point group of the dendritic polymer; each PEG is a polyethylene glycol) polymer; each R is and end group of the dendritic polymer, or and end group with a covalently bound hydrophobic group, hydrophilic group, amphiphilic compound, or drug; and subscript n is an integer from 2 to 20. Cell free methods of making the nanodiscs are also provided.

Luo, Juntao↗
DOE OSTI2023

Apolipoprotein nanodiscs with telodendrimer

The present invention provides a nanodisc with a membrane scaffold protein. The nanodisc includes a membrane scaffold protein, a telodendrimer and a lipid. The membrane scaffold protein can be apolipoprotein. The telodendrimer has the general formula PEG-L-D-(R)n, wherein D is a dendritic polymer; L is a bond or a linker linked to the focal point group of the dendritic polymer; each PEG is a poly(ethylene glycol) polymer, each R is and end group of the dendritic polymer, or and end group with a covalently bound hydrophobic group, hydrophilic group, amphiphilic compound, or drug; and subscript n is an integer from 2 to 20. Cell free methods of making the nanodiscs are also provided.

Luo, Juntao↗
DOE OSTI2022

Computational Engineering of Human Apolipoprotein for Enhanced Interaction with Bacterial Toxins

Sepsis is caused by an over-activation of the immune system in response to the presence of bacterial endotoxins in the bloodstream. LPS exemplifies a potent immune stimulator which can lead to an excessive activation leading to an overly pro-inflammatory reaction and if left untreated results in multi-organ failure and death. Human lipoproteins (HLP) have been shown to neutralize LPS and facilitate its clearance from circulation via the liver. However, host-derived lipoproteins are inhomogeneous in content and size, presenting a challenge for therapeutic applications. In this work, we have used IC facilities in order to computationally engineer HLP for an enhanced interaction with LPS. This work is a continuation of our previous efforts to derive an optimal Nanodisc (ND) lipid mixture for enhanced association with the endotoxin. We have performed fully atomistic Molecular dynamic (MD) simulations in order to carefully identify the most optimal residues in HLP, which can potentially lead to a stronger association to LPS.

42 ENGINEERING↗
DOE OSTI2024

Deciphering ApoE Genotype-Driven Proteomic and Lipidomic Alterations in Alzheimer’s Disease Across Distinct Brain Regions

Alzheimer’s disease (AD) is a neurodegenerative disease with a complex etiology influenced by confounding factors such as genetic polymorphisms, age, sex, and race. Traditionally, AD research has not prioritized these influences, resulting in dramatically skewed cohorts such as three times the number of Apolipoprotein E (APOE) e4-allele carriers in AD relative to healthy cohorts. Thus, the resulting molecular changes of AD have previously been complicated by the influence of apolipoprotein E disparities. To explore how apolipoprotein E polymorphism influences AD progression, 62 post-mortem patients consisting of 33 Alzheimer’s disease (AD) and 29 controls (Ctrl) were studied to balance the number of e4-allele carriers and facilitate a molecular comparison of the apolipoprotein E genotype. Lipid and protein perturbations were assessed across AD diagnosed brains compared to Ctrl brains, e4 allele carriers (APOE4+ for those carrying 1 or 2 e4s and APOE4- for non-e4 carriers), and differences in e3e3 and e3e4 Ctrl brains across two brain regions (frontal cortex (FCX) and cerebellum (CBM)). In conclusion, the region-specific influences of apolipoprotein E on AD mechanisms showcased mitochondrial dysfunction and cell proteostasis at the core of AD pathophysiology in the post-mortem brains, indicating these two processes may be influenced by genotypic differences and brain morphology.

Alzheimer’s disease↗
DOE OSTI2024

The POINTER Imaging baseline cohort: Associations between multimodal neuroimaging biomarkers, cardiovascular health, and cognition

Abstract INTRODUCTION The U.S. Study to Protect Brain Health Through Lifestyle Intervention to Reduce Risk (U.S. POINTER) is evaluating lifestyle interventions in older adults at risk for cognitive decline and dementia. Here we characterize the baseline data set of the POINTER Imaging ancillary study. METHODS Participants underwent health and cognitive assessments and neuroimaging with multimodal positron emission tomography (PET) (beta‐amyloid [Aβ] and tau) and magnetic resonance imaging (MRI). Framingham risk score (FRS) was used to quantify cardiovascular disease (CVD) risk. RESULTS A total of 1052 participants (31% from underrepresented ethnoracial groups) were enrolled. Compared to Aβ−, Aβ+ (29%) participants were older, had higher apolipoprotein E (APOE) ε4 carriage rate and white matter hyperintensity volume, and greater temporal tau. FRS was related to MRI measures, but not AD biomarkers. FRS and tau had independent effects on cognition. DISCUSSION In this heterogenous, at‐risk cohort, CVD risk was related to more abnormal brain structure and poorer cognition, representing a putative non‐AD (Alzheimer's disease) pathway to brain injury and cognitive decline. Highlights The U.S. Study to Protect Brain Health Through Lifestyle Intervention to Reduce Risk (U.S. POINTER) cohort is enriched for cardiovascular disease (CVD) and poor lifestyle POINTER Imaging collected multimodal neuroimaging data in this unique, at‐risk cohort Amyloid burden was related to age, apolipoprotein E (APOE) ε4 carriage, and measures of disease progression Associations between amyloid and tau, and tau and cognition, were relatively weak CVD risk and tau pathology were independently related to memory

Neurosciences & Neurology↗
DOE OSTI2026

Excipient screening by lyophilization provides insights into spray drying formulations for nanoparticle vaccines

Nanoparticles have shown great promise as delivery platforms in the development of tunable and safe vaccines. Nanolipoprotein particles (NLPs), also known as nanodiscs, are discoidal nanoparticles composed of a lipid bilayer stabilized at their periphery by apolipoproteins. Under the right conditions, the NLP self-assembly process is highly customizable in terms of lipids and apolipoprotein constituents, allowing for tunable physical and chemical characteristics. This flexibility allows a wide range of vaccine antigens and adjuvants to be incorporated onto the NLP platform for tailored vaccine design. The stability of NLPs during long term storage is a very important factor in developing a vaccine delivery platform suitable for widespread global use. When stored in a solution for extended periods of time, NLPs dissociate into their corresponding lipids and protein constituents, leading to particle degradation. Proper stabilization of NLPs can often be achieved by lyophilization (i.e. freeze-drying), a method widely used for various applications including pharmaceuticals. This process, however, can be damaging to particles without the presence of lyoprotectants or excipients that help maintain particle stability during lyophilization. Another method used to stabilize vaccines and pharmaceuticals is spray drying, a process that converts liquid formulations into dry powders through controlled heating and airflow. While spray drying is rapid, scalable, and cost-effective, lyophilization is typically a gentler process that better retains biomolecule structure and function. Both processes use excipients for particle stabilization, so lyophilization can be used as a surrogate to test stability of NLPs, to down-select formulations that may withstand the harsher conditions of spray drying. To screen different formulations, NLPs were synthesized and purified to homogeneity by size exclusion chromatography (SEC) and samples were prepared with a wide range of lyoprotectants and/or excipients. To assess the protective effects of excipients on NLPs upon spray drying, both pre- and post-lyophilized samples were analyzed by SEC. To assess the protective effects upon heating (encountered during the spray drying process), NLP samples were incubated at elevated temperatures prior to SEC analysis. The lyoprotectants and excipients evaluated in this study had different efficiencies in protecting NLPs during lyophilization and heating tests. Trehalose, for example, exhibits stabilization on NLPs both upon lyophilization and heating whereas leucine accelerated NLP dissociation. Although some lyoprotectants are effective by themselves, different combinations can decrease the stabilization of NLPs. Shelf-stable vaccines that do not require cold-chain storage are essential for global accessibility and our findings provide fundamental insight into how to advance NLP-based vaccines for these applications.

Serrano, Litzay J [Lawrence Livermore National Lab↗
DOE OSTI2024

Discovery of potent small-molecule inhibitors of lipoprotein(a) formation

Lipoprotein(a) (Lp(a)), an independent, causal cardiovascular risk factor, is a lipoprotein particle that is formed by the interaction of a low-density lipoprotein (LDL) particle and apolipoprotein(a) (apo(a)). Apo(a) first binds to lysine residues of apolipoprotein B-100 (apoB-100) on LDL through the Kringle IV (K IV ) 7 and 8 domains, before a disulfide bond forms between apo(a) and apoB-100 to create Lp(a). Here we show that the first step of Lp(a) formation can be inhibited through small-molecule interactions with apo(a) K IV 7–8. We identify compounds that bind to apo(a) K IV 7–8, and, through chemical optimization and further application of multivalency, we create compounds with subnanomolar potency that inhibit the formation of Lp(a). Oral doses of prototype compounds and a potent, multivalent disruptor, LY3473329 (muvalaplin), reduced the levels of Lp(a) in transgenic mice and in cynomolgus monkeys. Although multivalent molecules bind to the Kringle domains of rat plasminogen and reduce plasmin activity, species-selective differences in plasminogen sequences suggest that inhibitor molecules will reduce the levels of Lp(a), but not those of plasminogen, in humans. These data support the clinical development of LY3473329—which is already in phase 2 studies—as a potent and specific orally administered agent for reducing the levels of Lp(a).

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2020

Peptides having reduced toxicity that stimulate cholesterol efflux

The present invention provides a family of non-naturally occurring polypeptides having cholesterol efflux activity that parallels that of full-length apolipoproteins (e.g., Apo AI and Apo E), and having high selectivity for ABCA1 that parallels that of full-length apolipoproteins. Further, the peptides of the invention have little or no toxicity when administered at therapeutic and higher doses. The invention also provides compositions comprising such polypeptides, methods of identifying, screening and synthesizing such polypeptides, and methods of treating, preventing or diagnosing diseases and disorders associated with dyslipidemia, hypercholesterolemia, or inflammation; or diseases involving abnormal glucose metabolism, e.g., diabetes, metabolic syndrome; or Alzheimer's Disease or frontotemporal dementia.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2021

Peptides having reduced toxicity that stimulate cholesterol efflux

The present invention provides a family of non-naturally occurring polypeptides having cholesterol efflux activity that parallels that of full-length apolipoproteins (e.g., Apo AI and Apo E), and having high selectivity for ABCA1 that parallels that of full-length apolipoproteins. Further, the peptides of the invention have little or no toxicity when administered at therapeutic and higher doses. The invention also provides compositions comprising such polypeptides, methods of identifying, screening and synthesizing such polypeptides, and methods of treating, preventing or diagnosing diseases and disorders associated with dyslipidemia, hypercholesterolemia, or inflammation; or diseases involving abnormal glucose metabolism, e.g., diabetes, metabolic syndrome; or Alzheimers Disease or frontotemporal dementia.

Bielicki, John K.↗
DOE OSTI2022

Peptides having reduced toxicity that stimulate cholesterol efflux

The present invention provides a family of non-naturally occurring polypeptides having cholesterol efflux activity that parallels that of full-length apolipoproteins (e.g., Apo AI and Apo E), and having high selectivity for ABCA1 that parallels that of full-length apolipoproteins. Further, the peptides of the invention have little or no toxicity when administered at therapeutic and higher doses. The invention also provides compositions comprising such polypeptides, methods of identifying, screening and synthesizing such polypeptides, and methods of treating, preventing or diagnosing diseases and disorders associated with dyslipidemia, hypercholesterolemia, or inflammation; or diseases involving abnormal glucose metabolism, e.g., diabetes, metabolic syndrome; or Alzheimer's Disease or frontotemporal dementia.

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 OSTI2021

Mitoferrin 2 deficiency prevents mitochondrial iron overload-induced endothelial injury and alleviates atherosclerosis

Endothelial dysfunction is an early step in the development of atherosclerotic cardiovascular disease. Iron overload can lead to excessive mitochondrial reactive oxygen species (mtROS) production, resulting in mitochondrial dysfunction and vascular endothelial cell (EC) damage. Mitoferrin 2 (Mfrn2) is an iron transporter in the inner mitochondrial membrane. This study aimed to assess whether Mfrn2 and mitochondrial iron overload were involved in atherosclerosis progression and to explore the potential mechanism. We observed significant upregulation of Mfrn2 in the arteries of high-fat diet (HFD)-fed Apolipoprotein E{sup −/-} (ApoE{sup −/-}) mice and in TNF-α-induced mouse aortic endothelial cells (MAECs). Mfrn2 gene silencing inhibited mitochondrial iron overload, stabilized mitochondrial membrane potential and improved mitochondrial function in TNF-α-induced MAECs. Vascular EC-specific knockdown of Mfrn2 in ApoE{sup −/-} mice markedly decreased atherosclerotic lesion formation and the levels of ICAM-1 in aortas and reduced monocyte infiltration into the vascular wall. Furthermore, TNF-α increased the binding of 14-3-3 epsilon (ε) and Mfrn2, preventing Mfrn2 degradation and leading to mitochondrial iron overload in ECs, while 14-3-3ε overexpression increased Mfrn2 stability by inhibiting its ubiquitination. Together, our results reveal that Mfrn2 deficiency attenuates endothelial dysfunction by decreasing iron levels within the mitochondria and mitochondrial dysfunction. These findings may provide new insights into preventive and therapeutic strategies against vascular endothelial dysfunction in atherosclerotic disease.

60 APPLIED LIFE SCIENCES↗