0
selected
-
1.
Sphingolipids in HDL - Potential markers for adaptation to pregnancy?
Patanapirunhakit, P, Karlsson, H, Mulder, M, Ljunggren, S, Graham, D, Freeman, D
Biochimica et biophysica acta. Molecular and cell biology of lipids. 2021;(8):158955
Abstract
Plasma high density lipoprotein (HDL) exhibits many functions that render it an effective endothelial protective agent and may underlie its potential role in protecting the maternal vascular endothelium during pregnancy. In non-pregnant individuals, the HDL lipidome is altered in metabolic disease compared to healthy individuals and is linked to reduced cholesterol efflux, an effect that can be reversed by lifestyle management. Specific sphingolipids such as sphingosine-1-phosphate (S1P) have been shown to mediate the vaso-dilatory effects of plasma HDL via interaction with the endothelial nitric oxide synthase pathway. This review describes the relationship between plasma HDL and vascular function during healthy pregnancy and details how this is lost in pre-eclampsia, a disorder of pregnancy associated with widespread endothelial dysfunction. Evidence of a role for HDL sphingolipids, in particular S1P and ceramide, in cardiovascular disease and in healthy pregnancy and pre-eclampsia is discussed. Available data suggest that HDL-S1P and HDL-ceramide can mediate vascular protection in healthy pregnancy but not in preeclampsia. HDL sphingolipids thus are of potential importance in the healthy maternal adaptation to pregnancy.
-
2.
The Alcohol-High-Density Lipoprotein Athero-Protective Axis.
Rosales, C, Gillard, BK, Gotto, AM, Pownall, HJ
Biomolecules. 2020;(7)
Abstract
Ingestion of alcohol is associated with numerous changes in human energy metabolism, especially that of plasma lipids and lipoproteins. Regular moderate alcohol consumption is associated with reduced atherosclerotic cardiovascular disease (ASCVD), an effect that has been attributed to the concurrent elevations of plasma high-density lipoprotein-cholesterol (HDL-C) concentrations. More recent evidence has accrued against the hypothesis that raising plasma HDL concentrations prevents ASCVD so that other metabolic processes associated with alcohol consumption have been considered. This review explored the roles of other metabolites induced by alcohol consumption-triglyceride-rich lipoproteins, non-esterified free fatty acids, and acetate, the terminal alcohol metabolite in athero-protection: Current evidence suggests that acetate has a key role in athero-protection but additional studies are needed.
-
3.
High-Density Lipoprotein in Lupus: Disease Biomarkers and Potential Therapeutic Strategy.
Kim, SY, Yu, M, Morin, EE, Kang, J, Kaplan, MJ, Schwendeman, A
Arthritis & rheumatology (Hoboken, N.J.). 2020;(1):20-30
-
-
Free full text
-
Abstract
Systemic lupus erythematosus (SLE) patients exhibit accelerated development of atherosclerosis and increased incidents of cardiovascular disease (CVD) that cannot be explained by traditional risk factors alone. Accumulating evidence suggests that reduced levels of high-density lipoproteins (HDLs), along with altered HDL composition and function, may contribute to the accelerated atherosclerosis in SLE patients. Normally, HDLs play various atheroprotective roles through facilitating cholesterol efflux, inhibiting vascular inflammation, and scavenging oxidative species. However, systemic inflammation, oxidative stress, and autoimmunity in SLE patients induce changes in HDL size distribution and proteomic and lipidomic signatures. These compositional changes in HDLs result in the formation of proinflammatory, dysfunctional HDL. These lupus-altered HDLs have impaired antiatherogenic function with reduced cholesterol efflux capacities, impaired antioxidation abilities, and diminished antiinflammatory properties. In fact, dysfunctional HDL may promote atherogenesis by inducing inflammation. Thus, dysfunctional HDLs could be an important biomarker of accelerated atherosclerosis in lupus. Additionally, HDL-targeted therapies, especially infusion of reconstituted HDLs, may serve as a potential therapeutic intervention for SLE patients with CVD.
-
4.
High-Density Lipoprotein Subspecies in Health and Human Disease: Focus on Type 2 Diabetes.
Davidson, WS, Shah, AS
Methodist DeBakey cardiovascular journal. 2019;(1):55-61
Abstract
Plasma cholesterol levels of high-density lipoproteins (HDL) have been associated with cardioprotection for decades. However, there is an evolving appreciation that this lipoprotein class is highly heterogeneous with regard to composition and functionality. With the advent of advanced lipid-testing techniques and methods that allow both the quantitation and recovery of individual particle populations, we are beginning to connect the functionality of HDL subspecies with chronic metabolic diseases. In this review, we examine type 2 diabetes (T2D) and explore our current understanding of how obesity, insulin resistance, and hyperglycemia affect, and may be affected by, HDL subspeciation. We discuss mechanistic aspects of how insulin resistance may alter lipoprotein profiles and how this may impact the ability of HDL to mitigate both atherosclerotic disease and diabetes itself. Finally, we call for more detailed studies examining the impact of T2D on specific HDL subspecies and their functions. If these particles can be isolated and their compositions and functions fully elucidated, it may become possible to manipulate the levels of these specific particles or target the protective functions to reduce the incidence of coronary heart disease.
-
5.
High-density lipoprotein carbamylation and dysfunction in vascular disease.
Santana, JM, Brown, CD
Frontiers in bioscience (Landmark edition). 2018;(12):2227-2234
Abstract
High-density lipoprotein (HDL) is cardioprotective because of its anti-atherogenic properties. Nevertheless, our goal to optimize HDL cholesterol (HDL-C) levels have had little effects on the atherothrombotic burden and suggests a closer look be taken at HDL function and dysfunction. HDL is a group of complex macromolecules composed of a lipid- and proteome that work in synergy to execute its anti-inflammatory, anti-atherogenic, and anti-thrombotic effects. However, throughout its life-span in circulation, HDL undergoes significant modification. Carbamylation, a non-enzymatic and irreversible post-translational modification of protein, is one effector of HDL which has growing evidence that it plays a crucial role in the development and progression of atherosclerotic cardiovascular disease (ASCVD), particularly in chronic kidney disease (CKD). We summarize HDL's function, susceptibility to modification, and discuss HDL carbamylation and its effect in cardiovascular disease.
-
6.
Therapeutics for APOL1 nephropathies: putting out the fire in the podocyte.
Heymann, J, Winkler, CA, Hoek, M, Susztak, K, Kopp, JB
Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association. 2017;(suppl_1):i65-i70
-
-
Free full text
-
Abstract
APOL1 nephropathies comprise a range of clinical and pathologic syndromes, which can be summarized as focal segmental glomerulosclerosis, in various guises, and arterionephrosclerosis, otherwise known as hypertensive kidney diseases. Current therapies for these conditions may achieve therapeutic targets, reduction in proteinuria and control of blood pressure, respectively, but often fail to halt the progressive decline in kidney function. It appears that current therapies fail to address certain underlying critical pathologic processes that are driven, particularly in podocytes and microvascular cells, by the APOL1 renal risk genetic variants. Mechanisms hypothesized to be responsible for APOL1 variant-associated cell injury can be summarized in five domains: increased APOL1 gene expression, activation of inflammasomes, activation of protein kinase R, electrolyte flux across plasma or intracellular membranes, and altered endolysosomal trafficking associated with endoplasmic reticulum stress. We briefly review the available evidence for these five mechanisms and suggest possible novel therapeutic approaches.
-
7.
RVX 208: A novel BET protein inhibitor, role as an inducer of apo A-I/HDL and beyond.
Ghosh, GC, Bhadra, R, Ghosh, RK, Banerjee, K, Gupta, A
Cardiovascular therapeutics. 2017;(4)
-
-
Free full text
-
Abstract
Low-density cholesterol (LDL) has been the prime target of currently available lipid-lowering therapies although current research is expanding the focus beyond LDL lowering and has included high-density cholesterol (HDL) also as the target. Bromo and extra-terminal (BET) proteins are implicated in the regulation of transcription of several regulatory genes and regulation of proinflammatory pathways. As atherosclerosis is an inflammatory pathway and studies showed that BET inhibition has a role in inhibiting inflammation, the concept of BET inhibition came in the field of atherosclerosis. RVX 208 is a novel, orally active, BET protein inhibitor and the only BET inhibitor currently available in the field of atherosclerosis. RVX 208 acts primarily by increasing apo A-I (apolipoprotein A-I) and HDL levels. RVX 208 has a novel action of increasing larger, more cardio-protective HDL particles. Post hoc analysis of Phase II trials also showed that RVX 208 reduced major adverse cardiovascular events (MACE) in treated patients, over and above that of apo A-I/HDL increasing action. This MACE reducing actions of RVX 208 were largely due to its novel anti-inflammatory actions. Currently, a phase III trial, BETonMACE, is recruiting patients to look for the effects of RVX 208 in patients with increased risk of atherosclerotic cardiovascular disease. So BET inhibitors act in multiple ways to inhibit and modulate atherosclerosis and would be an emerging and potential option in the management of multifactorial disease like coronary artery disease by inhibiting a single substrate. But we need long-term phase III trial data's to look for effects on real-world patients.
-
8.
High-density Lipoprotein and Low-density Lipoprotein Therapeutic Approaches in Acute Coronary Syndromes.
Androulakis, E, Zacharia, E, Papageorgiou, N, Lioudaki, E, Bertsias, D, Charakida, M, Siasos, G, Tousoulis, D
Current cardiology reviews. 2017;(3):168-182
-
-
Free full text
-
Abstract
BACKGROUND Low-density lipoprotein cholesterol (LDL), and especially its oxidized form, renders the atherosclerotic plaque vulnerable to rupture in acute coronary syndromes (ACS). On the other hand, high-density lipoprotein (HDL) is considered an anti-atherogenic molecule. The more recent HDL-targeted drugs may prove to be superior to those used before. Indeed, delipidated HDL and HDL mimetics are efficient in increasing HDL levels, while the apoA-I upregulation with RVX-208 appears to offer a clinical benefit which is beyond the HDL related effects. HDL treatment however has not shown a significant improvement in the outcomes of patients with ACS so far, studies have therefore focused again on LDL. In addition to statins and ezetimibe, novel drugs such as PSCK9 inhibitors and apolipoprotein B inhibitors appear to be both effective and safe for patients with hyperlipidemia. CONCLUSION Data suggest these could potentially improve the cardiovascular outcomes of patient with ACS. Yet, there is still research to be done, in order to confirm whether ACS patients would benefit from LDL- or HDL-targeted therapies or a combination of both.
-
9.
Dysfunctional high-density lipoproteins in coronary heart disease: implications for diagnostics and therapy.
Annema, W, von Eckardstein, A
Translational research : the journal of laboratory and clinical medicine. 2016;:30-57
-
-
Free full text
-
Abstract
Low plasma levels of high-density lipoprotein (HDL) cholesterol are associated with increased risks of coronary heart disease. HDL mediates cholesterol efflux from macrophages for reverse transport to the liver and elicits many anti-inflammatory and anti-oxidative activities which are potentially anti-atherogenic. Nevertheless, HDL has not been successfully targeted by drugs for prevention or treatment of cardiovascular diseases. One potential reason is the targeting of HDL cholesterol which does not capture the structural and functional complexity of HDL particles. Hundreds of lipid species and dozens of proteins as well as several microRNAs have been identified in HDL. This physiological heterogeneity is further increased in pathologic conditions due to additional quantitative and qualitative molecular changes of HDL components which have been associated with both loss of physiological function and gain of pathologic dysfunction. This structural and functional complexity of HDL has prevented clear assignments of molecules to the functions of normal HDL and dysfunctions of pathologic HDL. Systematic analyses of structure-function relationships of HDL-associated molecules and their modifications are needed to test the different components and functions of HDL for their relative contribution in the pathogenesis of atherosclerosis. The derived biomarkers and targets may eventually help to exploit HDL for treatment and diagnostics of cardiovascular diseases.
-
10.
Lipid-free Apolipoprotein A-I Structure: Insights into HDL Formation and Atherosclerosis Development.
Mei, X, Atkinson, D
Archives of medical research. 2015;(5):351-60
-
-
Free full text
-
Abstract
Apolipoprotein A-I is the major protein in high-density lipoprotein (HDL) and plays an important role during the process of reverse cholesterol transport (RCT). Knowledge of the high-resolution structure of full-length apoA-I is vital for a molecular understanding of the function of HDL at the various steps of the RCT pathway. Due to the flexible nature of apoA-I and aggregation properties, the structure of full-length lipid-free apoA-I has evaded description for over three decades. Sequence analysis of apoA-I suggested that the amphipathic α-helix is the structural motif of exchangeable apolipoprotein, and NMR, X-ray and MD simulation studies have confirmed this. Different laboratories have used different methods to probe the secondary structure distribution and organization of both the lipid-free and lipid-bound apoA-I structure. Mutation analysis, synthetic peptide models, surface chemistry and crystal structures have converged on the lipid-free apoA-I domain structure and function: the N-terminal domain [1-184] forms a helix bundle while the C-terminal domain [185-243] mostly lacks defined structure and is responsible for initiating lipid-binding, aggregation and is also involved in cholesterol efflux. The first 43 residues of apoA-I are essential to stabilize the lipid-free structure. In addition, the crystal structure of C-terminally truncated apoA-I suggests a monomer-dimer conversation mechanism mediated through helix 5 reorganization and dimerization during the formation of HDL. Based on previous research, we have proposed a structural model for full-length monomeric apoA-I in solution and updated the HDL formation mechanism through three states. Mapping the known natural mutations on the full-length monomeric apoA-I model provides insight into atherosclerosis development through disruption of the N-terminal helix bundle or deletion of the C-terminal lipid-binding domain.