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Clinical Laboratory Nov 2022The purpose of this study was to investigate the association between lipoprotein(a) [Lp(a)] concentrations, apolipoprotein(a) [apo(a)] isoform, and coronary artery...
BACKGROUND
The purpose of this study was to investigate the association between lipoprotein(a) [Lp(a)] concentrations, apolipoprotein(a) [apo(a)] isoform, and coronary artery disease (CAD) stratification in Han Chinese.
METHODS
Logistic regression analysis was performed to analyze the association between Lp(a) concentrations, apo(a) isoform and CAD stratification. Lp(a) concentrations and apo(a) isoforms were combined with other risk factors to establish the optimal prediction model of CAD risk.
RESULTS
Individuals with the top quarter of Lp(a) concentrations had more than a two-fold higher risk of stable CAD and three-fold higher risk of acute coronary syndrome (ACS) compared with those in the bottom quarter. This association was no longer significant after adjustment for apo(a) isoforms in stable CAD (OR 2.198, 95% CI 0.991 - 4.875, p = 0.053), but remained significant in the ACS (OR 3.583, 95% CI 1.278 - 5.614, p < 0.05). Individuals with small apo(a) isoforms had more than a two-fold higher risk of stable CAD and almost three-fold higher risk of ACS compared with those carrying larger apo(a) isoforms; however, this association was significantly alleviated after adjustment for Lp(a) concentrations (OR 2.133, 95% CI 0.964 - 4.742, p = 0.098; OR 2.642, 95% CI 1.032 - 5.833, p = 0.298, respectively). A combination of Lp(a) concentrations and apo(a) isoforms with other risk factors was the optimal prediction model of CAD risk (AUC 0.800, 95% CI 0.752 - 0.848, p < 0.001).
CONCLUSIONS
Elevated Lp(a) concentrations and small apo(a) isoforms were significant risk factors for CAD stratification, and their effects on CAD risk were mediated by each other. Combined application of Lp(a) concentrations and apo(a) isoform with conventional risk factors could aid in the assessment and prediction of CAD.
Topics: Humans; Lipoprotein(a); Apoprotein(a); Coronary Artery Disease; Apolipoproteins A; Risk Factors; Protein Isoforms; China
PubMed: 36377991
DOI: 10.7754/Clin.Lab.2022.211232 -
Apolipoprotein A-1 as a Potential Biomarker for Solid Tumors: A Systematic Review and Meta-Analysis.Current Medicinal Chemistry 2023The diagnostic value of apolipoprotein A-I (ApoA-I) as a marker of different malignancies has been reported in several investigations; however, the results have been... (Meta-Analysis)
Meta-Analysis
BACKGROUND
The diagnostic value of apolipoprotein A-I (ApoA-I) as a marker of different malignancies has been reported in several investigations; however, the results have been contradictory. The current meta-analysis examined the association between ApoA-I levels and human malignancies.
METHODS
We reviewed the databases and retrieved papers for analysis until November 1, 2021. Random-effects meta-analysis was performed to construct the pooled diagnostic parameters. To find the causes of heterogeneity, we utilized Spearman threshold effect analysis and subgroup analysis. The I2 and Chi-square tests were used to examine the heterogeneity. Moreover, subgroup analyses were performed based on sample type (serum/urine) and geographical region of study. Finally, publication bias was explored using Begg's and Egger's tests.
RESULTS
A total of 11 articles involving 4,121 participants (2,430 cases and 1,691 controls) were included. The overall pooled sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR), and area under the curve (AUC) were 0.764 (95% CI: 0.746 - 0.781), 0.795 (95% CI: 0.775 - 0.814), 5.105 (95% CI: 3.313 - 7.865), 0.251 (95% CI: 0.174 - 0.364), 24.61 (95% CI: 12.22 - 49.54), and 0.93, respectively. In subgroup analyses, better diagnostic values were found for urine samples and East Asian Countries (China, Korea, and Taiwan).
CONCLUSION
Urinary ApoA-I levels may serve as a favorable diagnostic marker for cancer.
Topics: Humans; Apolipoprotein A-I; Biomarkers; Neoplasms; China
PubMed: 36809959
DOI: 10.2174/0929867330666230210112700 -
Atherosclerosis May 2022High lipoprotein(a) [Lp(a)] concentrations are one of the most important genetically determined risk factors for cardiovascular disease. Lp(a) concentrations are an... (Review)
Review
High lipoprotein(a) [Lp(a)] concentrations are one of the most important genetically determined risk factors for cardiovascular disease. Lp(a) concentrations are an enigmatic trait largely controlled by one single gene (LPA) that contains a complex interplay of several genetic elements with many surprising effects discussed in this review. A hypervariable coding copy number variation (the kringle IV type-2 repeat, KIV-2) generates >40 apolipoprotein(a) protein isoforms and determines the median Lp(a) concentrations. Carriers of small isoforms with up to 22 kringle IV domains have median Lp(a) concentrations up to 5 times higher than those with large isoforms (>22 kringle IV domains). The effect of the apo(a) isoforms are, however, modified by many functional single nucleotide polymorphisms (SNPs) distributed over the complete range of allele frequencies (<0.1% to >20%) with very pronounced effects on Lp(a) concentrations. A complex interaction is present between the apo(a) isoforms and LPA SNPs, with isoforms partially masking the effect of functional SNPs and, vice versa, SNPs lowering the Lp(a) concentrations of affected isoforms. This picture is further complicated by SNP-SNP interactions, a poorly understood role of other polymorphisms such as short tandem repeats and linkage structures that are poorly captured by common R values. A further layer of complexity derives from recent findings that several functional SNPs are located in the KIV-2 repeat and are thus not accessible to conventional sequencing and genotyping technologies. A critical impact of the ancestry on correlation structures and baseline Lp(a) values becomes increasingly evident. This review provides a comprehensive overview on the complex genetic architecture of the Lp(a) concentrations in plasma, a field that has made tremendous progress with the introduction of new technologies. Understanding the genetics of Lp(a) might be a key to many mysteries of Lp(a) and booster new ideas on the metabolism of Lp(a) and possible interventional targets.
Topics: Apolipoproteins A; Apoprotein(a); DNA Copy Number Variations; Kringles; Lipoprotein(a); Polymorphism, Single Nucleotide; Protein Isoforms
PubMed: 35606073
DOI: 10.1016/j.atherosclerosis.2022.04.003 -
Journal of Clinical Lipidology 2020The role of cholesterol homeostasis in neuroaxonal injury in multiple sclerosis is not known.
BACKGROUND
The role of cholesterol homeostasis in neuroaxonal injury in multiple sclerosis is not known.
OBJECTIVE
The objective of the study is to investigate the associations of cerebrospinal fluid (CSF) and serum neurofilament light chain levels (CSF-NfL and sNfL, respectively), which are biomarkers of neuroaxonal injury, with cholesterol biomarkers at the clinical onset of multiple sclerosis.
METHODS
sNfL, serum cholesterol profile (total cholesterol, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol), serum apolipoprotein (Apo) levels (ApoA-I, ApoA-II, ApoB, and ApoE), and albumin quotient were obtained for 133 patients (63% female, age: 29.9 ± 8.0 years) during the first demyelinating event. CSF-NfL was available for 103 (77%) patients.
RESULTS
CSF-NfL and sNfL were negatively associated with serum ApoA-II (P = .005, P < .001) and positively associated with albumin quotient (P < .001, P < .0001). In addition, higher CSF-NfL was associated with lower serum ApoA-I (P = .009) levels and higher sNfL was associated with lower high-density lipoprotein cholesterol (P = .010). In stepwise regression, age (P = .045), serum ApoA-II (P = .022), and albumin quotient (P < .001) were associated with CSF-NfL; albumin quotient (P = .002) and ApoA-II (P = .001) were associated with sNfL. Path analysis identified parallel pathways from ApoA-II (P = .009) and albumin quotient (P < .001) to the sNfL outcome that were mediated by CSF-NfL (P < .001). The associations of CSF-NfL with ApoA-I (P = .014) and ApoA-II (P = .015) and sNfL with ApoA-II (P < .001) remained significant after adjusting for number of contrast-enhancing lesions and T2 lesion volume.
CONCLUSION
Lower serum ApoA-II and ApoA-I levels are associated with greater neuroaxonal injury as measured by CSF-NfL.
Topics: Adult; Apolipoprotein A-I; Apolipoprotein A-II; Female; Humans; Longitudinal Studies; Male; Multiple Sclerosis; Neurofilament Proteins; Neuroprotective Agents; Prognosis; Prospective Studies
PubMed: 32758395
DOI: 10.1016/j.jacl.2020.07.001 -
Arthritis Research & Therapy Jan 2024The etiology of giant cell arteritis (GCA) and its predictors are incompletely understood. Previous studies have indicated reduced risk of future development of GCA in...
BACKGROUND
The etiology of giant cell arteritis (GCA) and its predictors are incompletely understood. Previous studies have indicated reduced risk of future development of GCA in individuals with obesity and/or diabetes mellitus. There is limited information on blood lipids before the onset of GCA. The objective of the study was to investigate the relation between apolipoprotein levels and future diagnosis of GCA in a nested case-control analysis.
METHODS
Individuals who developed GCA after inclusion in a population-based health survey (the Malmö Diet Cancer Study; N = 30,447) were identified by linking the health survey database to the local patient administrative register and the national patient register. A structured review of medical records was performed. Four controls for every validated case, matched for sex, year of birth, and year of screening, were selected from the database. Anthropometric measures, self-reported physical activity, based on a comprehensive, validated questionnaire, and non-fasting blood samples had been obtained at health survey screening. Concentrations of apolipoprotein A-I (ApoA-I) and apolipoprotein B (ApoB) in stored serum were measured using an immunonephelometric assay. Potential predictors of GCA were examined in conditional logistic regression models.
RESULTS
There were 100 cases with a confirmed clinical diagnosis of GCA (81% female; mean age at diagnosis 73.6 years). The median time from screening to diagnosis was 12 years (range 0.3-19.1). The cases had significantly higher ApoA-I at baseline screening compared to controls (mean 168.7 vs 160.9 mg/dL, odds ratio [OR] 1.57 per standard deviation (SD); 95% confidence interval [CI] 1.18-2.10) (SD 25.5 mg/dL). ApoB levels were similar between cases and controls (mean 109.3 vs 110.4 mg/dL, OR 0.99 per SD; 95% CI 0.74-1.32) (SD 27.1 mg/dL). The ApoB/ApoA1 ratio tended to be lower in cases than in controls, but the difference did not reach significance. The association between ApoA-I and GCA development remained significant in analysis adjusted for body mass index and physical activity (OR 1.48 per SD; 95% CI 1.09-1.99).
CONCLUSION
Subsequent development of GCA was associated with significantly higher levels of ApoA-I. These findings suggest that a metabolic profile associated with lower risk of cardiovascular disease may predispose to GCA.
Topics: Humans; Female; Aged; Male; Giant Cell Arteritis; Risk Factors; Apolipoprotein A-I; Case-Control Studies; Apolipoproteins; Apolipoproteins B
PubMed: 38281009
DOI: 10.1186/s13075-024-03273-1 -
Arteriosclerosis, Thrombosis, and... Mar 2022Elevated plasma Lp(a) (lipoprotein(a)) levels are associated with increased risk for atherosclerotic cardiovascular disease and aortic valve stenosis. However, the cell...
BACKGROUND
Elevated plasma Lp(a) (lipoprotein(a)) levels are associated with increased risk for atherosclerotic cardiovascular disease and aortic valve stenosis. However, the cell biology of Lp(a) biosynthesis remains poorly understood, with the locations of the noncovalent and covalent steps of Lp(a) assembly unclear and the nature of the apoB-containing particle destined for Lp(a) unknown. We, therefore, asked if apo(a) and apoB interact noncovalently within hepatocytes and if this impacts Lp(a) biosynthesis.
METHODS
Using human hepatocellular carcinoma cells expressing 17K (17 kringle) apo(a), or a 17KΔLBS7,8 variant with a reduced ability to bind noncovalently to apoB, we performed coimmunoprecipitation, coimmunofluorescence, and proximity ligation assays to document intracellular apo(a):apoB interactions. We used a pulse-chase metabolic labeling approach to measure apo(a) and apoB secretion rates.
RESULTS
Noncovalent complexes containing apo(a)/apoB are present in lysates from cells expressing 17K but not 17KΔLBS7,8, whereas covalent apo(a)/apoB complexes are absent from lysates. 17K and apoB colocalized intracellularly, overlapping with staining for markers of endoplasmic reticulum trans-Golgi, and early endosomes, and less so with lysosomes. The 17KΔLBS7,8 had lower colocalization with apoB. Proximity ligation assays directly documented intracellular 17K/apoB interactions, which were dramatically reduced for 17KΔLBS7,8. Treatment of cells with PCSK9 (proprotein convertase subtilisin/kexin type 9) enhanced, and lomitapide reduced, apo(a) secretion in a manner dependent on the noncovalent interaction between apo(a) and apoB. Apo(a) secretion was also reduced by siRNA-mediated knockdown of .
CONCLUSIONS
Our findings explain the coupling of apo(a) and Lp(a)-apoB production observed in human metabolic studies using stable isotopes as well as the ability of agents that inhibit apoB biosynthesis to lower Lp(a) levels.
Topics: Apolipoprotein B-100; Apolipoproteins A; Binding Sites; Hep G2 Cells; Hepatocytes; Humans; Kringles; Lipoprotein(a); Lysine; Metabolic Networks and Pathways; Multiprotein Complexes; Protein Binding; Recombinant Proteins
PubMed: 35045727
DOI: 10.1161/ATVBAHA.121.317335 -
Pharmacological Research Aug 2020Angiogenesis is a finely co-ordinated, multi-step developmental process of the new vascular structure. Even though angiogenesis is regularly occurring in physiological... (Review)
Review
Angiogenesis is a finely co-ordinated, multi-step developmental process of the new vascular structure. Even though angiogenesis is regularly occurring in physiological events such as embryogenesis, in adults, it is restricted to specific tissue sites where rapid cell-turnover and membrane synthesis occurs. Both excessive and insufficient angiogenesis lead to vascular disorders such as cancer, ocular diseases, diabetic retinopathy, atherosclerosis, intra-uterine growth restriction, ischemic heart disease, stroke etc. Occurrence of altered lipid profile and vascular lipid deposition along with vascular disorders is a hallmark of impaired angiogenesis. Among lipoproteins, lipoprotein(a) needs special attention due to the presence of a multi-kringle protein subunit, apolipoprotein(a) [apo(a)], which is structurally homologous to many naturally occurring anti-angiogenic proteins such as plasminogen and angiostatin. Researchers have constructed different recombinant forms of apo(a) (rhLK68, rhLK8, RHACK2, KV-11, and AU-6) and successfully exploited its potential to inhibit unwanted angiogenesis during tumor metastasis and retinal neovascularization. Similar to naturally occurring anti-angiogenic proteins, apo(a) can directly interfere with angiogenic signaling pathways. Besides this, apo(a) can also exert its anti-angiogenic effect indirectly by inducing endothelial cell apoptosis, by inhibiting endothelial progenitor cell functions or by upregulating nuclear factors in endothelial cells via apo(a)-bound oxPLs. However, the impact of the anti-angiogenic potential of native apo(a) during physiological angiogenesis in embryos and wounded tissues is not yet explored. In this context, we review the studies so far done to demonstrate the anti-angiogenic activity of apo(a) and the recent developments in using apo(a) as a therapeutic agent to treat impaired angiogenesis during vascular disorders, with emphasis on the gaps in the literature.
Topics: Angiogenesis Inhibitors; Animals; Apolipoproteins A; Humans; Neovascularization, Pathologic; Neovascularization, Physiologic
PubMed: 32430285
DOI: 10.1016/j.phrs.2020.104858 -
The Journal of Pharmacology and... Jan 2020Obesity is a pathologic condition generated by an energy imbalance, that is, excess caloric consumption, leading to weight gain and metabolic disturbances characterized... (Review)
Review
Obesity is a pathologic condition generated by an energy imbalance, that is, excess caloric consumption, leading to weight gain and metabolic disturbances characterized by adipose tissue inflammation and hyperglycemic conditions. In line with these observations, increasing evidence causally links inflammation, or the molecules and networks integral to inflammatory response, to the development of obesity and the complications that emerge from this pathology, such as cardiovascular, neurologic, respiratory, and metabolic illnesses, as well as sepsis and cancer. Not surprisingly, this chronic and abnormal metabolic background leads to constant derangements in innate and adaptive immunity. It is well known that high-density lipoprotein (HDL) possesses anti-inflammatory and antioxidant properties, and various studies have highlighted an emerging role of HDL in modulating immune function. The efficacy of synthetic HDL (sHDL) containing the recombinant form of apoA-I (sHDL-apoA-I), originating from the observation that carriers of this mutation have low levels of HDL cholesterol without increased atherosclerosis, has been largely proved in diverse animal models of atherosclerosis; however, the therapeutic use of sHDL-apoA-I still needs clinical validation. One of the main limitations to the use of recombinant proteins in clinical studies lies in the unsustainable purification costs. Unpurified rice-milk-apoA-I demonstrated anti-inflammatory and antiatherogenic properties in a mouse model, even though administrated by an unconventional way: by oral gavage. Additionally, recent data have uncovered new therapeutic applications for this sHDL-apoA-I This review provides an overview of all potential application of sHDL-apoA-I in some inflammatory-based diseases. SIGNIFICANCE STATEMENT: A recent study demonstrated that oral administration of rice-seed protein extracts containing the apoA-I (i.e., the milk-apoA-I) reduced atherosclerosis development in a mouse model. Moreover, the rice-milk-apoA-I preserved both in vitro and in vivo anti-inflammatory properties, as observed when sHDL-apoA-I was given by intravascular infusion. Besides, various studies suggested that sHDL-apoA-I could positively affect other inflammatory-based diseases. Together, these data might represent a new starting point for "sHDL-apoA-I-based therapies" in chronic degenerative disease.
Topics: Animals; Anti-Inflammatory Agents; Anticholesteremic Agents; Apolipoprotein A-I; Atherosclerosis; Humans
PubMed: 31649050
DOI: 10.1124/jpet.119.261719 -
Molecules (Basel, Switzerland) Aug 2019Lipoproteins are endogenous nanoparticles which are the major transporter of fats and cholesterol in the human body. They play a key role in the regulatory mechanisms of... (Review)
Review
Lipoproteins are endogenous nanoparticles which are the major transporter of fats and cholesterol in the human body. They play a key role in the regulatory mechanisms of cardiovascular events. Lipoproteins can be modified and manipulated to act as drug delivery systems or nanocarriers for contrast agents. In particular, high density lipoproteins (HDL), which are the smallest class of lipoproteins, can be synthetically engineered either as nascent HDL nanodiscs or spherical HDL nanoparticles. Reconstituted HDL (rHDL) particles are formed by self-assembly of various lipids and apolipoprotein AI (apo-AI). A variety of substances including drugs, nucleic acids, signal emitting molecules, or dyes can be loaded, making them efficient nanocarriers for therapeutic applications or medical diagnostics. This review provides an overview about synthesis techniques, physicochemical properties of rHDL nanoparticles, and structural determinants for rHDL function. We discuss recent developments utilizing either apo-AI or apo-AI mimetic peptides for the design of pharmaceutical rHDL formulations. Advantages, limitations, challenges, and prospects for clinical translation are evaluated with a special focus on promising strategies for the treatment and diagnosis of atherosclerosis and cardiovascular diseases.
Topics: Animals; Apolipoprotein A-I; Biomimetic Materials; Biomimetics; Cardiovascular Diseases; Cardiovascular System; Chemical Phenomena; Disease Susceptibility; Drug Carriers; Drug Delivery Systems; Humans; Lipoproteins; Lipoproteins, HDL; Nanoparticles; Peptides; Research; Theranostic Nanomedicine
PubMed: 31382521
DOI: 10.3390/molecules24152829 -
Methods in Molecular Biology (Clifton,... 2022More than three decades ago, as a test for the amphipathic helix theory, an 18 amino acid residue peptide and its analogs were designed with no sequence homology to any...
More than three decades ago, as a test for the amphipathic helix theory, an 18 amino acid residue peptide and its analogs were designed with no sequence homology to any of the exchangeable apolipoproteins. Based on the apolipoprotein A-I (the major protein component of high density lipoproteins, HDL) mimicking properties, they were termed as ApoA-I mimicking peptides. Several laboratories around the world started studying such de novo-designed peptides for their antiatherogenic properties. The present chapter describes the efforts in bringing these peptides as therapeutic agents for atherosclerosis and several lipid-mediated disorders.
Topics: Apolipoprotein A-I; Apolipoproteins; Atherosclerosis; Humans; Lipoproteins, HDL; Peptides
PubMed: 35237960
DOI: 10.1007/978-1-0716-1924-7_6