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International Journal of Molecular... Jul 2023Target biomarkers for H at both the protein and genome levels are still unclear. In this study, quantitative proteomics acquired from a mouse model were first analyzed....
Target biomarkers for H at both the protein and genome levels are still unclear. In this study, quantitative proteomics acquired from a mouse model were first analyzed. At the same time, functional pathway analysis helped identify functional pathways at the protein level. Then, bioinformatics on mRNA sequencing data were conducted between sepsis and normal mouse models. Differential expressional genes with the closest relationship to disease status and development were identified through module correlation analysis. Then, common biomarkers in proteomics and transcriptomics were extracted as target biomarkers. Through analyzing expression quantitative trait locus (eQTL) and genome-wide association studies (GWAS), colocalization analysis on Apoa2 and sepsis phenotype was conducted by summary-data-based Mendelian randomization (SMR). Then, two-sample and drug-target, syndrome Mendelian randomization (MR) analyses were all conducted using the Twosample R package. For protein level, protein quantitative trait loci (pQTLs) of the target biomarker were also included in MR. Animal experiments helped validate these results. As a result, Apoa2 protein or mRNA was identified as a target biomarker for H with a protective, causal relationship with sepsis. HDL and type 2 diabetes were proven to possess causal relationships with sepsis. The agitation and inhibition of Apoa2 were indicated to influence sepsis and related syndromes. In conclusion, we first proposed Apoa2 as a target for H treatment.
Topics: Animals; Mice; Biomarkers; Diabetes Mellitus, Type 2; Genetic Predisposition to Disease; Genome-Wide Association Study; Genomics; Hydrogen; Lung Injury; Polymorphism, Single Nucleotide; Proteomics; Sepsis; Apolipoprotein A-II
PubMed: 37511084
DOI: 10.3390/ijms241411325 -
Current Opinion in Lipidology Aug 2014To summarize recent publications in the field of apolipoprotein mimetics. (Review)
Review
PURPOSE OF REVIEW
To summarize recent publications in the field of apolipoprotein mimetics.
RECENT FINDINGS
Apolipoprotein mimetic peptides continue to show efficacy in a number of animal models of disease and demonstrate properties that make them attractive as potential therapeutic agents. A number of new apolipoprotein mimetics have been described recently. A major site of action of apolipoprotein mimetic peptides was found to be in the small intestine in which they decrease the levels of proinflammatory bioactive lipids. A major problem related to the use of apolipoprotein mimetic peptides is their cost, particularly those that need to be generated by solid phase synthesis with chemical addition of end-blocking groups. Novel approaches to apolipoprotein mimetic therapy have emerged recently that show promise in overcoming these barriers.
SUMMARY
Despite the recent failure of therapies designed to raise HDL-cholesterol in humans, an approach to therapy using mimetics of HDL and its components continues to show promise.
Topics: Animals; Apolipoprotein A-I; Biomimetics; Disease; Humans; Peptidomimetics
PubMed: 24977978
DOI: 10.1097/MOL.0000000000000092 -
Journal of Lipid Research Sep 2016Lipoprotein (a) [Lp(a)] is a human plasma lipoprotein with unique structural and functional characteristics. Lp(a) is an assembly of two components: a central core with... (Review)
Review
Lipoprotein (a) [Lp(a)] is a human plasma lipoprotein with unique structural and functional characteristics. Lp(a) is an assembly of two components: a central core with apoB and an additional glycoprotein, called apo(a). Ever since the strong association between elevated levels of Lp(a) and an increased risk for CVD was recognized, interest in the therapeutic modulation of Lp(a) levels has increased. Here, the past and present therapies aiming to lower Lp(a) levels will be reviewed, demonstrating that these agents have had varying degrees of success. The next challenge will be to prove that Lp(a) lowering also leads to cardiovascular benefit in patients with elevated Lp(a) levels. Therefore, highly specific and potent Lp(a)-lowering strategies are awaited urgently.
Topics: Apolipoprotein B-100; Apolipoproteins A; Cardiovascular Diseases; Humans; Hypolipidemic Agents; Lipoprotein(a); Risk Factors
PubMed: 26637277
DOI: 10.1194/jlr.R053066 -
Journal of Lipid Research Apr 2016The high degree of size heterogeneity of apo(a), the distinct protein component of lipoprotein (a) [Lp(a)], renders the development and selection of specific antibodies... (Review)
Review
The high degree of size heterogeneity of apo(a), the distinct protein component of lipoprotein (a) [Lp(a)], renders the development and selection of specific antibodies directed to apo(a) more difficult and poses significant challenges to the development of immunoassays to measure its concentration in plasma or serum samples. Apo(a) is extremely variable in size not only between but also within individuals because of the presence of two different, genetically determined apo(a) isoform sizes. Therefore, the antigenic determinants per particle available to interact with the antibodies will vary in the samples and the calibrators, thus contributing to apo(a) size-dependent inaccuracy of different methods. The lack of rigorous validation of the immunoassays and common means of expressing Lp(a) concentrations hinder the harmonization of results obtained by different studies and contribute to the lack of common cut points for identification of individuals at risk for coronary artery disease or for interventions aimed at reducing Lp(a) levels. The aim of our review is to present and critically evaluate the issues surrounding the measurements of Lp(a), their impact on the clinical interpretation of the data, and the obstacles we need to overcome to achieve the standardization of Lp(a) measurements.
Topics: Apolipoproteins A; Cardiovascular Diseases; Data Interpretation, Statistical; Humans; Immunoassay; Lipoprotein(a); Reference Standards
PubMed: 26637278
DOI: 10.1194/jlr.R061648 -
ACS Nano Mar 2016High-density lipoproteins (HDL) are endogenous nanoparticles involved in the transport and metabolism of cholesterol, phospholipids, and triglycerides. HDL is well-known... (Review)
Review
High-density lipoproteins (HDL) are endogenous nanoparticles involved in the transport and metabolism of cholesterol, phospholipids, and triglycerides. HDL is well-known as the "good" cholesterol because it not only removes excess cholesterol from atherosclerotic plaques but also has anti-inflammatory and antioxidative properties, which protect the cardiovascular system. Circulating HDL also transports endogenous proteins, vitamins, hormones, and microRNA to various organs. Compared with other synthetic nanocarriers, such as liposomes, micelles, and inorganic and polymeric nanoparticles, HDL has unique features that allow them to deliver cargo to specific targets more efficiently. These attributes include their ultrasmall size (8-12 nm in diameter), high tolerability in humans (up to 8 g of protein per infusion), long circulating half-life (12-24 h), and intrinsic targeting properties to different recipient cells. Various recombinant ApoA proteins and ApoA mimetic peptides have been recently developed for the preparation of reconstituted HDL that exhibits properties similar to those of endogenous HDL and has a potential for industrial scale-up. In this review, we will summarize (a) clinical pharmacokinetics and safety of reconstituted HDL products, (b) comparison of HDL with inorganic and other organic nanoparticles,
Topics: Animals; Apolipoprotein A-I; Drug Carriers; Drug Delivery Systems; Humans; Lipoproteins, HDL; Nanomedicine; Nanoparticles; Recombinant Proteins
PubMed: 26889958
DOI: 10.1021/acsnano.5b07522 -
Journal of Lipid Research Jul 2016Levels of lipoprotein (a) [Lp(a)], a complex between an LDL-like lipid moiety containing one copy of apoB, and apo(a), a plasminogen-derived carbohydrate-rich... (Review)
Review
Levels of lipoprotein (a) [Lp(a)], a complex between an LDL-like lipid moiety containing one copy of apoB, and apo(a), a plasminogen-derived carbohydrate-rich hydrophilic protein, are primarily genetically regulated. Although stable intra-individually, Lp(a) levels have a skewed distribution inter-individually and are strongly impacted by a size polymorphism of the LPA gene, resulting in a variable number of kringle IV (KIV) units, a key motif of apo(a). The variation in KIV units is a strong predictor of plasma Lp(a) levels resulting in stable plasma levels across the lifespan. Studies have demonstrated pronounced differences across ethnicities with regard to Lp(a) levels and some of this difference, but not all of it, can be explained by genetic variations across ethnic groups. Increasing evidence suggests that age, sex, and hormonal impact may have a modest modulatory influence on Lp(a) levels. Among clinical conditions, Lp(a) levels are reported to be affected by kidney and liver diseases.
Topics: Age Factors; Apolipoproteins A; Apolipoproteins B; Ethnicity; Female; Genetic Variation; Humans; Kringles; Lipoprotein(a); Male; Polymorphism, Single Nucleotide; Risk Factors; Sex Characteristics
PubMed: 26637279
DOI: 10.1194/jlr.R051904 -
Current Opinion in Lipidology Jun 2021Lipoprotein(a) [Lp(a)] is a plasma circulating apoB100 (apoB) containing lipoprotein. It has a unique glycoprotein bound to the apoB100, apolipoprotein(a) [apo(a)]. The... (Review)
Review
PURPOSE OF REVIEW
Lipoprotein(a) [Lp(a)] is a plasma circulating apoB100 (apoB) containing lipoprotein. It has a unique glycoprotein bound to the apoB100, apolipoprotein(a) [apo(a)]. The majority of the population expresses two apo(a) isoforms, when bound to apoB100 they create two circulating Lp(a) particles. Lp(a) levels are genetically determined and epidemiological studies have established elevated levels of Lp(a) to be a causal risk factor of cardiovascular disease (CVD). Lp(a) levels differ across racial groups and Blacks of Sub-Saharan decent have higher levels when compared to white. In comparison to white populations, studies in minorities are less represented in the published literature. Additionally, there is a lack of standardization in the commercial assays used to measured Lp(a) levels, and hence it is difficult to assess risk based on individual Lp(a) levels, but risk seems to occur in the upper percentiles of the population.
RECENT FINDINGS
A recent study using data from the UK biobank highlights the racial differences in Lp(a) levels and the increase risk in CVD amongst all races.
SUMMARY
This review will highlight Lp(a) biology and physiology with a focus on available data from racially diverse cohorts. There is a need to perform studies in diverse populations to understand if they are at higher risk than whites are.
Topics: Apolipoproteins A; Cardiovascular Diseases; Ethnicity; Heart Disease Risk Factors; Humans; Lipoprotein(a); Risk Factors
PubMed: 33900275
DOI: 10.1097/MOL.0000000000000753 -
Journal of the American Heart... Aug 2023Concern continues about whether the measurement of apolipoprotein B (apoB) is adequately standardized, and therefore, whether apoB should be applied widely in clinical... (Review)
Review
Concern continues about whether the measurement of apolipoprotein B (apoB) is adequately standardized, and therefore, whether apoB should be applied widely in clinical care. This concern is misplaced. Our objective is to explain why and what the term "standardization" means. To produce clinically valid results, a test must accurately, precisely, and selectively measure the marker of interest. That is, it must be standardized. Accuracy refers to how closely the result obtained with 1 method corresponds to the result obtained with the standard method, precision to how reproducible the result is on repeated testing, and selectivity to how susceptible the method is to error by inclusion of other classes of lipoprotein particles. Multiple expert groups have determined that the measurement of apoB is adequately standardized for clinical care, and that apoB can be measured inexpensively, using widely available automated methods, more accurately, precisely, and selectively than low-density lipoprotein cholesterol or non-high-density lipoprotein cholesterol. ApoB is a standard superior to low-density lipoprotein cholesterol and high-density lipoprotein cholesterol because it is a defined molecule, whereas the cholesterol markers are the mass of cholesterol within lipoprotein particles defined by their density, not by their molecular structure. Nevertheless, the standardization of apoB is being further improved by the application of mass spectrophotometric methods, whereas the limitations in the standardization and, therefore, the accurate, precise, and selective measurement of low-density lipoprotein cholesterol and high-density lipoprotein cholesterol are unlikely to be overcome. We submit that greater accuracy, precision, and selectivity in measurement is a decisive advantage for apoB in the modern era of intensive lipid-lowering therapies.
Topics: Cholesterol, LDL; Cholesterol; Apolipoproteins B; Apolipoprotein B-100; Cholesterol, HDL; Lipoproteins; Apolipoprotein A-I
PubMed: 37489721
DOI: 10.1161/JAHA.123.030405 -
International Journal of Molecular... Mar 2022Lipoprotein(a) (Lp(a)) is one of the strongest causal risk factors of atherosclerotic disease. It is rich in cholesteryl ester and composed of apolipoprotein B and... (Review)
Review
Lipoprotein(a) (Lp(a)) is one of the strongest causal risk factors of atherosclerotic disease. It is rich in cholesteryl ester and composed of apolipoprotein B and apo(a). Plasma Lp(a) levels are determined by apo(a) transcriptional activity driven by a direct repeat (DR) response element in the apo(a) promoter under the control of (HNF)4α Farnesoid-X receptor (FXR) ligands play a key role in the downregulation of expression. In vitro studies on the catabolism of Lp(a) have revealed that Lp(a) binds to several specific lipoprotein receptors; however, their in vivo role remains elusive. There are more than 1000 publications on the role of diabetes mellitus (DM) in Lp(a) metabolism; however, the data is often inconsistent and confusing. In patients suffering from Type-I diabetes mellitus (T1DM), provided they are metabolically well-controlled, Lp(a) plasma concentrations are directly comparable to healthy individuals. In contrast, there exists a paradox in T2DM patients, as many of these patients have reduced Lp(a) levels; however, they are still at an increased cardiovascular risk. The Lp(a) lowering mechanism observed in T2DM patients is most probably caused by mutations in the mature-onset diabetes of the young (MODY) gene and possibly other polymorphisms in key transcription factors of the apolipoprotein (a) gene (APOA).
Topics: Apolipoproteins A; Apoprotein(a); Cardiovascular Diseases; Diabetes Mellitus, Type 2; Humans; Lipoprotein(a)
PubMed: 35408941
DOI: 10.3390/ijms23073584 -
Archives of Medical Research Jul 2015Apolipoprotein A-I is the major protein in high-density lipoprotein (HDL) and plays an important role during the process of reverse cholesterol transport (RCT).... (Review)
Review
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.
Topics: Apolipoprotein A-I; Apolipoproteins; Atherosclerosis; Cholesterol; Humans; Lipids; Lipoproteins, HDL; Protein Binding; Protein Structure, Secondary; Protein Structure, Tertiary
PubMed: 26048453
DOI: 10.1016/j.arcmed.2015.05.012