scholarly journals An obesity model and corona multiomics analysis reveal high-density lipoprotein effects on lipid nanoparticle function

2021 ◽  
Author(s):  
Kai Liu ◽  
Ralf Nilsson ◽  
Elisa Lázaro-Ibáñez ◽  
Tasso Miliotis ◽  
Michael Lerche ◽  
...  
Keyword(s):  
Density Lipoprotein ◽  
Lipid Nanoparticles ◽  
High Density ◽  
High Density Lipoproteins ◽  
Nucleic Acid Delivery ◽  
Cargo Delivery ◽  
Corona Formation ◽  
Obese Rats ◽  
The Impact ◽  
The Relationship

Abstract Lipid nanoparticles (LNPs) are currently of great interest for therapeutic nucleic acid delivery. Lipid-based nanoparticles are, however, difficult to study analytically and so our understanding of the interaction between LNPs and biological systems remains obscure, particularly in terms of biomolecular corona formation and the impact this has on therapeutic efficacy and targeting. Ideally, we would like to engineer particles to acquire corona components that facilitate targeting, cargo delivery and improved safety. This requires studying the relationship between LNPs, biofluids and the resulting coronas. The particle-corona complexes are, however, fragile and biofluids also contain particles (such as lipoproteins) with sizes and biochemical characteristics similar to lipid nanoparticles, so contamination with biological components is a challenge. Here we describe a rapid, automated, and unbiased isolation method for LNP biomolecular coronas, coupled with proteomic and lipidomic analysis. Using these analytical methods, we systematically studied, in lean and obese rats, the variation in LNP-mediated mRNA delivery caused by individual physiology. A comprehensive multivariate model links LNP corona content to efficacy, identifying and validating high-density lipoproteins as a previously unidentified factor affecting particle efficacy.

scholarly journals High-Density Lipoproteins and the Kidney

Cells ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 764
Author(s):  
Arianna Strazzella ◽  
Alice Ossoli ◽  
Laura Calabresi
Keyword(s):  
Kidney Disease ◽  
Renal Disease ◽  
Cholesterol Acyltransferase ◽  
Density Lipoprotein ◽  
Hdl Cholesterol ◽  
High Density ◽  
High Density Lipoproteins ◽  
Lcat Deficiency ◽  
Progression Of Renal Disease ◽  
The Impact

Dyslipidemia is a typical trait of patients with chronic kidney disease (CKD) and it is typically characterized by reduced high-density lipoprotein (HDL)-cholesterol(c) levels. The low HDL-c concentration is the only lipid alteration associated with the progression of renal disease in mild-to-moderate CKD patients. Plasma HDL levels are not only reduced but also characterized by alterations in composition and structure, which are responsible for the loss of atheroprotective functions, like the ability to promote cholesterol efflux from peripheral cells and antioxidant and anti-inflammatory proprieties. The interconnection between HDL and renal function is confirmed by the fact that genetic HDL defects can lead to kidney disease; in fact, mutations in apoA-I, apoE, apoL, and lecithin–cholesterol acyltransferase (LCAT) are associated with the development of renal damage. Genetic LCAT deficiency is the most emblematic case and represents a unique tool to evaluate the impact of alterations in the HDL system on the progression of renal disease. Lipid abnormalities detected in LCAT-deficient carriers mirror the ones observed in CKD patients, which indeed present an acquired LCAT deficiency. In this context, circulating LCAT levels predict CKD progression in individuals at early stages of renal dysfunction and in the general population. This review summarizes the main alterations of HDL in CKD, focusing on the latest update of acquired and genetic LCAT defects associated with the progression of renal disease.

Abstract 260: Knockout of Apolipoprotein A-II Has Dramatic Effects on High-Density Lipoprotein Subspecies Distribution

2012 ◽  
Vol 32 (suppl_1) ◽  
Author(s):  
Scott M Gordon ◽  
Catherine A Reardon ◽  
Godfrey S Getz ◽  
W S Davidson
Keyword(s):  
Gel Filtration ◽  
Density Lipoprotein ◽  
High Density ◽  
Paraoxonase 1 ◽  
High Density Lipoproteins ◽  
Ionization Mass ◽  
Associated Proteins ◽  
Compositional Diversity ◽  
The Impact ◽  
Modest Effect

High density lipoproteins (HDL) are a highly heterogeneous population of particles composed of various lipids and proteins. They have been demonstrated to possess a diverse variety of functional properties which are thought to contribute to protection against cardiovascular disease (CVD). Proteomics studies have identified up to 75 different proteins which can associate with HDL. The basis for the compositional diversity of HDL is not known but a better understanding will yield important information about its broad functional diversity. To investigate the impact of common HDL apolipoproteins on the distribution of other apolipoproteins, we have begun to systematically fractionate plasma from various HDL apolipoprotein KO mice. Plasma from apoA-I, apoA-IV and apoA-II global KO mice was applied to gel filtration chromatography to distinguish HDL size populations. HDL particles sequestered by a phospholipid binding resin were proteomically analyzed by electrospray ionization mass spectrometry. By comparing elution volume shifts (i.e. particle size variations) for each HDL protein between WT controls and the KO models, we assessed the impact of the deleted protein on HDL size distributions. Ablation of apoA-I, while decreasing total HDL phospholipid by 70%, had a surprisingly small impact on the distribution of the majority of other HDL associated proteins - affecting only 9 of them. Genetic apoA-IV ablation had a similar modest effect shifting a distinct subset of 9 proteins. However, loss of apoA-II, in addition to causing a similar 70% reduction in overall HDL phospholipids, affected the size distribution of some 45 HDL proteins (including several complement proteins and paraoxonase-1). These data suggest that apoA-I, while associated with the majority of HDL phospholipid, may actually interact with relatively few of the lower abundance proteins known to be associated with HDL. ApoA-II on the other hand, may interact with many of these, perhaps acting as a docking site or adaptor molecule.

scholarly journals Current Therapies Focused on High-Density Lipoproteins Associated with Cardiovascular Disease

Molecules ◽  
2018 ◽  
Vol 23 (11) ◽  
pp. 2730 ◽  
Author(s):  
Diego Estrada-Luna ◽  
María Ortiz-Rodriguez ◽  
Lizett Medina-Briseño ◽  
Elizabeth Carreón-Torres ◽  
Jeannett Izquierdo-Vega ◽  
...  
Keyword(s):  
Cardiovascular Diseases ◽  
Molecular Mechanisms ◽  
Density Lipoprotein ◽  
Protein Composition ◽  
Inverse Correlation ◽  
Epidemiological Studies ◽  
High Density ◽  
High Density Lipoproteins ◽  
Current Therapies ◽  
The Impact

High-density lipoproteins (HDL) comprise a heterogeneous family of lipoprotein particles divided into subclasses that are determined by density, size and surface charge as well as protein composition. Epidemiological studies have suggested an inverse correlation between High-density lipoprotein-cholesterol (HDL-C) levels and the risk of cardiovascular diseases and atherosclerosis. HDLs promote reverse cholesterol transport (RCT) and have several atheroprotective functions such as anti-inflammation, anti-thrombosis, and anti-oxidation. HDLs are considered to be atheroprotective because they are associated in serum with paraoxonases (PONs) which protect HDL from oxidation. Polyphenol consumption reduces the risk of chronic diseases in humans. Polyphenols increase the binding of HDL to PON1, increasing the catalytic activity of PON1. This review summarizes the evidence currently available regarding pharmacological and alternative treatments aimed at improving the functionality of HDL-C. Information on the effectiveness of the treatments has contributed to the understanding of the molecular mechanisms that regulate plasma levels of HDL-C, thereby promoting the development of more effective treatment of cardiovascular diseases. For that purpose, Scopus and Medline databases were searched to identify the publications investigating the impact of current therapies focused on high-density lipoproteins.

scholarly journals Protection against Glucolipotoxicity by High Density Lipoprotein in Human PANC-1 Hybrid 1.1B4 Pancreatic Beta Cells: The Role of microRNA

Biology ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 218
Author(s):  
Jamie M.R. Tarlton ◽  
Richard J. Lightbody ◽  
Steven Patterson ◽  
Annette Graham
Keyword(s):  
High Density Lipoprotein ◽  
Beta Cells ◽  
Pancreatic Beta Cells ◽  
Cell Model ◽  
Density Lipoprotein ◽  
High Density ◽  
High Density Lipoproteins ◽  
Microrna Profile ◽  
Altered Gene ◽  
The Impact

High-density lipoproteins provide protection against the damaging effects of glucolipotoxicity in beta cells, a factor which sustains insulin secretion and staves off onset of type 2 diabetes mellitus. This study examines epigenetic changes in small non-coding microRNA sequences induced by high density lipoproteins in a human hybrid beta cell model, and tests the impact of delivery of a single sequence in protecting against glucolipotoxicity. Human PANC-1.1B4 cells were used to establish Bmax and Kd for [3H]cholesterol efflux to high density lipoprotein, and minimum concentrations required to protect cell viability and reduce apoptosis to 30mM glucose and 0.25 mM palmitic acid. Microchip array identified the microRNA signature associated with high density lipoprotein treatment, and one sequence, hsa-miR-21-5p, modulated via delivery of a mimic and inhibitor. The results confirm that low concentrations of high-density lipoprotein can protect against glucolipotoxicity, and report the global microRNA profile associated with this lipoprotein; delivery of miR-21-5p mimic altered gene targets, similar to high density lipoprotein, but could not provide sufficient protection against glucolipotoxicity. We conclude that the complex profile of microRNA changes due to HDL treatment may be difficult to replicate using a single microRNA, findings which may inform current drug strategies focused on this approach.

scholarly journals High-Density Lipoproteins and Cardiovascular Disease: The Good, the Bad and the Future

Biomedicines ◽  
2021 ◽  
Vol 9 (8) ◽  
pp. 857
Author(s):  
Josep Julve ◽  
Joan Carles Escolà-Gil
Keyword(s):  
Cardiovascular Disease ◽  
High Density Lipoprotein ◽  
High Density Lipoprotein Cholesterol ◽  
Density Lipoprotein ◽  
Epidemiological Studies ◽  
High Density ◽  
High Density Lipoproteins ◽  
Atherosclerotic Cardiovascular Disease ◽  
Plasma High Density ◽  
Low Levels

Epidemiological studies have shown that low levels of plasma high-density lipoprotein cholesterol (HDL-C) are associated with increased atherosclerotic cardiovascular disease (CVD) [...]

Involvement of high-density lipoprotein in stimulatory effect of hormones supporting function of the bovine corpus luteum.

2003 ◽  
Vol 51 (1) ◽  
pp. 111-120 ◽  
Author(s):  
D. Skarżyński ◽  
J. Młynarczuk ◽  
J. Kotwica
Keyword(s):  
Luteinising Hormone ◽  
Density Lipoprotein ◽  
High Density ◽  
High Density Lipoproteins ◽  
Luteal Cells ◽  
Progesterone Secretion ◽  
Bovine Corpus Luteum ◽  
Progesterone Synthesis ◽  
Deficient Medium ◽  
Intracellular Pathway

The hypothesis that epinephrine (noradrenaline, NA) enhances utilisation of high-density lipoproteins (HDL) by bovine luteal cells and that this process involves phospholipase (PL) C and protein kinase (PK) C intracellular pathway was tested. Luteal cells from days 2-4, 5-10 or 11-17 of the oestrous cycle were pre-incubated for 20h. Subsequently DMEM/Ham's F-12 medium was replaced by fresh medium and the cells were treated for 6 h as follows: In Experiment I with HDL (5-75μg cholesterol per ml), NA, isoprenaline (ISO) or luteinising hormone (LH). In Experiment II cells were incubated for further 24h in deficient medium (without FCS) and next treated as in Experiment I. In Experiment III cells were stimulated with NA, ISO or LH alone and together with HDL. In Experiment IV cells were treated with PLC inhibitor (U-73122) or with PKC inhibitor (staurosporine) or stimulator (phorbol 12-myristrate 13-acetate) and with either NA, insulin or LH. Only luteal cells from days 5-10 of the cycle responded on HDL and β-mimetics (P<0.05). LH stimulated progesterone secretion from the luteal cells during all stages of the cycle (P<0.001). Cells incubated in deficient medium and supplemented with HDL secreted as much progesterone as those stimulated by LH in all stages of the cycle. Beta-mimetics were unable to enhance the stimulatory effect of HDL. Blockade of PLC had no influence on progesterone secretion from cells treated with either NA or LH, but this did impair the stimulatory effect of insulin (P<0.05). Similarly, blockade of PKC by staurosporine impaired (P<0.05) the effect of insulin only but not that observed after LH or NA treatment. We suggest that: (a) noradrenergic stimulation does not enhance utilisation of cholesterol from HDL for progesterone secretion; (b) the fasting of luteal cells seems to activate enzymes responsible for the progesterone synthesis; (c) effect of NA on progesterone secretion from luteal cells does not involve the PLC-PKC pathway.

scholarly journals High serum non-high-density lipoprotein and the risk of ischemic stroke: A systematic review

2021 ◽  
Vol 20 (1) ◽  
pp. 15-20
Author(s):  
Nyoman Tyas Apsari ◽  
◽  
Kumara Tini ◽  
I Putu Eka Widyadharma ◽  
◽  
...  
Keyword(s):  
Systematic Review ◽  
Ischemic Stroke ◽  
High Density Lipoprotein ◽  
Large Population ◽  
Density Lipoprotein ◽  
High Serum ◽  
High Density ◽  
Inclusion Criteria ◽  
Increased Risk ◽  
The Relationship

Objectives. High levels of non high density lipoprotein cholesterol (non-HDL-C) are known to contribute to an increased risk of ischemic stroke. This systematic review was conducted to identify the relationship between high non-HDL-C levels and the risk of ischemic stroke. Material and methods. This systematic review using PRISMA (preferred reporting items for systematic reviews and meta-analyses) statement guideline, with a pre-determined search strategy. The search was conducted in Pubmed Central (PMC) and Pubmed from 2009 until 2020 with inclusion criteria, patients with a diagnosis of ischemic stroke, age >18 years, with non-HDL-C levels. The title and abstract of these articles were reviewed for relevance, based on inclusion criteria. This systematic review using STROBE to evaluate the quality in individual study which consists of 22 domains. Results. In the final stage, this systematic review identifies six cohort study consisting 166.720 participants. Overall, the quality in individual studies based on STROBE is good. We reported that there are two studies report that high non-HDL-C levels can significantly increase the risk of ischemic stroke. Meanwhile, there are four studies that report there was no significant relationship between high non-HDL-C levels and the risk of ischemic stroke. Conclusions. Overall, this systematic review provides the result about relationship between high levels of nonHDL-C and the risk of ischemic stroke, there are two studies with a larger population support that high levels of non-HDL-C can increase the risk of ischemic stroke. However, further studies is needed with a large population that specifically identify the relationship between non-HDL-C levels and risk of ischemic stroke and makes a better adjustments for confounding variables.

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