Association of apolipoprotein A1 levels with lumbar bone mineral density and ß-CTX in osteoporotic fracture individuals: a cross-sectional investigation.

Background: The relationship between the levels of high-density lipoprotein (HDL) and bone mineral density (BMD) is controversial. Furthermore, the specific role of apolipoprotein A1 (APOA1), a primary HDL component, in regulating BMD remains unclear. This study aimed to elucidate the correlation between APOA1 levels and lumbar BMD in patients with osteoporotic fracture (OPF) for novel insights into potential therapeutic strategies against osteoporosis. Methods: This study included 587 OPF patients enrolled at the Kunshan Hospital, Affiliated with Jiangsu University between January 2017 and July 2022. The patient's serum APOA1 levels were determined, followed by the assessment of lumbar BMD and C-terminal telopeptide of type I collagen (ß-CTX) as outcome variables. The association of APOA1 levels with lumbar BMD and ß-CTX was assessed via Generalized Estimating Equations (GEE) and spline smoothing plot analyses. A generalized additive model (GAM) helped ascertain non-linear correlations. Moreover, a subgroup analysis was also conducted to validate the result's stability. Results: It was observed that APOA1 levels were positively correlated with lumbar BMD (ß = 0.07, 95% CI: 0.02 to 0.11, p = 0.0045), indicating that increased APOA1 levels were linked with enhanced lumbar BMD. Furthermore, APOA1 levels were negatively related to ß-CTX (ß = -0.19, 95% CI: -0.29 to -0.09, p = 0.0003), suggesting APOA1 might reduce osteolysis. In addition, these findings were robustly supported by subgroup and threshold effect analyses. Conclusion: This study indicated that increased APOA1 levels were correlated with enhanced lumbar BMD and decreased osteolysis in OPF patients. Therefore, APOA1 may inhibit osteoclast activity to prevent further deterioration in osteoporotic patients. However, further research I warranted to validate these conclusions and elucidate the underlying physiologies.

A new risk factor for coronary artery disease can be detected by an ApoA1 mAb-based assay.

BACKGROUND: This study aimed to find coronary artery disease (CAD) related apolipoprotein A1 (ApoA1) monoclonal antibody (mAb) and to evaluate the diagnostic value of the assay based on it. METHODS: Patients with CAD diagnosed by coronary angiography (disease group, n = 180) and healthy subjects (control group, n = 199) were recruited. The correlation between methods and CAD were evaluated by Spearman's rank correlation coefficients. Receiver operating characteristic (ROC) curve analysis was used to evaluate the auxiliary diagnostic value of methods for CAD. Odds ratios (ORs) of the test results in CAD were estimated using logistic regression analysis. RESULTS: Measurements from an ApoA1 mAb were found significantly positively correlated with CAD (r = 0.243, P < 0.01), unlike the measurements from the ApoA1 pAb were negatively correlated with CAD (r = -0.341, P < 0.001). The areas under the ROC curve of the ApoA1 mAb and pAb measurements were 0.704 and 0.563, respectively, in patients with normal HDL-C levels. ApoA1 values from the mAb assay had a significant positive impact on CAD risk. CONCLUSION: An ApoA1 mAb-based assay can distinguish a high-density lipoprotein (HDL) subclass positively related to CAD, which can be used to improve and reappraise CAD risk assessment.

Delineating the impact of pathogenic mutations on the conformational dynamics of HDL's vital protein ApoA1: a combined computational and molecular dynamic simulation approach.

Apolipoprotein A1 (ApoA1), is the important component of high-density lipoproteins (HDL), that has key role in HDL biogenesis, cholesterol trafficking, and reverse cholesterol transport (RCT). Non-synonymous Single Nucleotide Polymorphisms (nsSNPs) in ApoA1 have been linked to cardiovascular diseases and amyloidosis as they alter the protein's native structure and function. Therefore in this study, we attempted to understand the molecular pathogenicity profile of nsSNPs of ApoA1 using various computational approaches. We used state-of-the-art computational methods to thoroughly investigate the 295 ApoA1 nsSNPs at sequence and structural levels. Seven nsSNPs (L13R, L84R, L84P, L99P, R173P, L187P, and L238P) out of 295 were classified as the most deleterious and destabilizing. In order to estimate the effect of such destabilizing mutations on the protein conformation, all-atom molecular dynamics simulations (MDS) of ApoA1 wild-type (WT), L99P and R173P for 100 ns, was carried out using GROMACS 5.0.1 package. The MD simulation investigation revealed significant structural alterations in L99P and R173P. In addition, they had changed principal component analysis and electrostatic surface potential, decreased structural compactness, and intramolecular hydrogen bonds, which supported the rationale underpinning ApoA1 dysfunction with such mutations. This work sheds light on ApoA1 dysfunction due to single amino acid alterations, and offers new insight into the molecular basis of ApoA1-related diseases progression.Communicated by Ramaswamy H. Sarma.

Leveraging knowledge of HDLs major protein ApoA1: Structure, function, mutations, and potential therapeutics.

Apolipoprotein A1 (ApoA1) is a member of the Apolipoprotein family of proteins. It's a vital protein that helps in the production of high-density lipoprotein (HDL) particles, which are crucial for reverse cholesterol transport (RCT). It also has anti-inflammatory, anti-atherogenic, anti-apoptotic, and anti-thrombotic properties. These functions interact to give HDL particles their cardioprotective characteristics. ApoA1 has recently been investigated for its potential role in atherosclerosis, diabetes, neurological diseases, cancer, and certain infectious diseases. Since ApoA1's discovery, numerous mutations have been reported that affect its structural integrity and alter its function. Hence these insights have led to the development of clinically relevant peptides and synthetic reconstituted HDL (rHDL) that mimics the function of ApoA1. As a result, this review has aimed to provide an organized explanation of our understanding of the ApoA1 protein structure and its role in various essential pathways. Furthermore, we have comprehensively reviewed the important ApoA1 mutations (24 mutations) that are reported to be involved in various diseases. Finally, we've focused on the therapeutic potentials of some of the beneficial mutations, small peptides, and synthetic rHDL that are currently being researched or developed, since these will aid in the development of novel therapeutics in the future.

Low APOA-1 Expression in Hepatocellular Carcinoma Patients Is Associated With DNA Methylation and Poor Overall Survival.

Background: Hepatocellular carcinoma (HCC) is the most frequent fatal malignancy, and it has a poor prognosis. Apolipoprotein 1 (APOA-1), the main protein component of high-density lipoproteins, is involved in numerous biological processes. Thus, this study was performed to detect the clinical significance of APOA-1 mRNA, APOA-1 expression, and APOA-1DNA methylation in patients with HCC. Methods: Data mining was performed using clinical and survival data from the Cancer Genome Atlas (TCGA) and Oncomine databases. The serum concentration of APOA-1 was measured in 316 patients with HCC and 100 healthy individuals at Renmin Hospital of Wuhan University, and the intact clinical information was reviewed and determined using univariate and multivariate Cox hazard models. Results: Bioinformatic analysis revealed that APOA-1 mRNA was present at lower levels in the serum of patients with HCC than in that of healthy individuals, and there was a strong negative correlation between levels of APOA-1 mRNA and APOA-1 DNA methylation. High expression of APOA-1 transcription correlated with better overall survival (p = 0.003), and APOA-1 hypermethylation correlated with progress-free survival (p = 0.045) in HCC sufferers. Next, the clinical data analysis demonstrated that APOA-1 protein levels in the serum were significantly lower in patients with HCC than in healthy controls. Furthermore, the expression of APOA-1 was significantly associated with some significant clinical indexes, and elevated APOA-1 expression was significantly associated with favorable (OS; HR:1.693, 95% CI: 1.194-2.401, p = 0.003) and better progression-free survival (PFS; HR = 1.33, 95% CI = 1.194-2.401, p = 0.045). Finally, enrichment analysis suggested that co-expressed genes of APOA-1 were involved in lipoprotein metabolism and FOXA2/3 transcription factor networks. Conclusion: APOA-1 mRNA expression is negatively regulated by DNA methylation in HCC. Low expression of APOA-1 might be a potential risk biomarker to predict survival in patients with HCC.

ApoA-1 improves glucose tolerance by increasing glucose uptake into heart and skeletal muscle independently of AMPKα2.

OBJECTIVE: Acute administration of the main protein component of high-density lipoprotein, apolipoprotein A-I (ApoA-1), improves glucose uptake in skeletal muscle. The molecular mechanisms mediating this are not known, but in muscle cell cultures, ApoA-1 failed to increase glucose uptake when infected with a dominant-negative AMP-activated protein kinase (AMPK) virus. We therefore investigated whether AMPK is necessary for ApoA-1-stimulated glucose uptake in intact heart and skeletal muscle in vivo. METHODS: The effect of injection with recombinant human ApoA-1 (rApoA-1) on glucose tolerance, glucose-stimulated insulin secretion, and glucose uptake into skeletal and heart muscle with and without block of insulin secretion by injection of epinephrine (0.1 mg/kg) and propranolol (5 mg/kg), were investigated in 8 weeks high-fat diet-fed (60E%) wild-type and AMPKα2 kinase-dead mice in the overnight-fasted state. In addition, the effect of rApoA-1 on glucose uptake in isolated skeletal muscle ex vivo was studied. RESULTS: rApoA-1 lowered plasma glucose concentration by 1.7 mmol/l within 3 h (6.1 vs 4.4 mmol/l; p < 0.001). Three hours after rApoA-1 injection, glucose tolerance during a 40-min glucose tolerance test (GTT) was improved compared to control (area under the curve (AUC) reduced by 45%, p < 0.001). This was accompanied by an increased glucose clearance into skeletal (+110%; p < 0.001) and heart muscle (+100%; p < 0.001) and an increase in glucose-stimulated insulin secretion 20 min after glucose injection (+180%; p < 0.001). When insulin secretion was blocked during a GTT, rApoA-1 still enhanced glucose tolerance (AUC lowered by 20% compared to control; p < 0.001) and increased glucose clearance into skeletal (+50%; p < 0.05) and heart muscle (+270%; p < 0.001). These improvements occurred to a similar extent in both wild-type and AMPKα2 kinase-dead mice and thus independently of AMPKα2 activity in skeletal- and heart muscle. Interestingly, rApoA-1 failed to increase glucose uptake in isolated skeletal muscles ex vivo. CONCLUSIONS: In conclusion, ApoA-1 stimulates in vivo glucose disposal into skeletal and heart muscle independently of AMPKα2. The observation that ApoA-1 fails to increase glucose uptake in isolated muscle ex vivo suggests that additional systemic effects are required.

Development and Characterization of Monoclonal Antibodies Against Nitro-166Tyrosine of High-Density Lipoprotein: Apolipoprotein A1.

Apolipoprotein A1 (ApoA1) of the high-density lipoprotein (HDL) plays a cardinal role in alleviating atherosclerosis in various ways. Its role in reverse cholesterol transport is preeminent. However, the ApoA1 undergoes oxidation under chronic inflammatory conditions and these oxidations are mediated by myeloperoxidase. It has been reported that the oxidation of the amino acids such as methionine, tyrosine, and tryptophan residues at specific sites of ApoA1 renders it not only dysfunctional but also proinflammatory and proatherogenic. Thus, assessing the quality of ApoA1 and, in turn, that of HDL in circulating blood can serve as an early diagnostic tool for cardiovascular diseases (CVDs). In this study, we developed monoclonal antibodies (mAbs) specific to modified ApoA1 with its tyrosine residue at the 166th position nitrated to 3-nitrotyrosine. A 20 amino acid peptide around the modification of interest was designed using an antigenicity prediction tool. The peptide was custom synthesized with ovalbumin as conjugate and used as an antigen to immunize BALB/c mice. Hybridomas were obtained by fusion of Sp2/0 mouse myeloma cells with spleen cells from the immunized mouse. A hybridoma clone 2E5B7, thus developed and characterized, was found to secrete mAb of the desired specificity and sensitivity against nitrated 166Tyrosine. The lowest concentration of the antigen that could be detected by the mAb with confidence was 15 ng. The mAb was able to detect nitrated 166Tyrosine peptide ovalbumin conjugate antigen spiked in human plasma with high specificity. The generated mAb could be potentially used in immuno-based diagnostic systems to screen the quality of HDL and in turn assess CVD risks in humans.

Apolipoprotein A-1 Binding Protein Inhibits Inflammatory Signaling Pathways by Binding to Apolipoprotein A-1 in THP-1 Macrophages.

BACKGROUND: It has previously been demonstrated that apolipoprotein A-1 (apoA-1) binding protein (AIBP) promotes apoA-1 binding to ATP-binding cassette transporter A1 (ABCA1) and prevents ABCA1 protein degradation so as to inhibit foam cell formation. Because apoA-1 inhibits inflammatory signaling pathways, whether AIBP has an inhibitory effect on inflammatory signaling pathways in THP-1-derived macrophages is investigated.Methods and Results:Analysis of inflammation-related gene expression indicated that AIBP decreased lipopolysaccharide (LPS)-mediated macrophage inflammation. AIBP significantly prevented NF-κB nuclear translocation. Further, AIBP prevented the activation of mitogen-activated protein kinases (MAPKs), including p38 MAPK, extracellular-signal regulated kinase and c-Jun N-terminal kinase. AIBP decreased MyD88 expression at both mRNA and protein levels, but did not have any effect on TLR4 expression. Moreover, treatment with both AIBP and apoA-1 decreased the abundance of TLR4 in the lipid raft fraction. AIBP lacking 115-123 amino acids (∆115-123), however, did not have such effects as described for intact AIBP. In addition, knockdown of ABCA1 inhibited the effects of AIBP on inflammatory factor secretion. CONCLUSIONS: These results suggest that AIBP inhibits inflammatory signaling pathways through binding to apoA-1 and stabilizing ABCA1, and subsequent alteration of lipid rafts and TLR4 in the cell membrane.

Long-Term Survival and Apolipoprotein A1 Level in Chronic Heart Failure: Interaction With Tumor Necrosis Factor α -308 G/A Polymorphism.

BACKGROUND: Apolipoprotein A1 (ApoA1), a major constituent of high-density lipoprotein (HDL), has antiinflammatory and antioxidative properties and plays a prognostic role in chronic heart failure (CHF). Despite increased tumor necrosis factor α (TNFα) levels being linked to worse outcome of HF, the results are ambiguous about the association of functionally active 308 promoter polymorphism of the TNFα gene. The aims of our study were to investigate the association of ApoA1 and TNFα levels with mortality and to evaluate potential interaction between these factors and TNFα -308 polymorphism. METHODS: Together with several parameters ApoA1, TNFα levels and TNFα-308 polymorphism were determined in a cohort of 195 patients with CHF who were followed for 5 years. RESULTS: Low ApoA1 and high TNFα levels were associated with more severe disease, and ApoA1 showed the strongest relationship with HDL, total cholesterol, C-reactive protein, and N-terminal pro-B-type natriuretic peptide (NT-proBNP). TNFα -308 A carriers had significantly higher ApoA1 levels than wild-type (GG) patients (1.41 ± 0.268 vs 1.29 ± 0.324 g/L; P = .007), whereas levels of TNFα were the same in these groups. Decreased ApoA1 levels were significant predictors of 5-year mortality (NT-proBNP-adjusted HR for 1 decile decrease in ApoA1 level was 1.10 (P = .011). Interaction was found between the ApoA1 level and TNFα -308 polymorphism, because in patients with GG haplotype the adverse effect of low ApoA1 level on survival was more prevalent. CONCLUSIONS: Lower ApoA1 levels were strongly associated with adverse outcome in CHF patients in a TNFα -308 polymorphism dependent manner. These observations support the complex involvement of malnutrition and inflammation in the pathogenesis of CHF.

HDL in sepsis - risk factor and therapeutic approach.

High-density lipoprotein (HDL) is a key component of circulating blood and plays essential roles in regulation of vascular endothelial function and immunity. Clinical data demonstrate that HDL levels drop by 40-70% in septic patients, which is associated with a poor prognosis. Experimental studies using Apolipoprotein A-I (ApoAI) null mice showed that HDL deficient mice are susceptible to septic death, and overexpressing ApoAI in mice to increase HDL levels protects against septic death. These clinical and animal studies support our hypothesis that a decrease in HDL level is a risk factor for sepsis, and raising circulating HDL levels may provide an efficient therapy for sepsis. In this review, we discuss the roles of HDL in sepsis and summarize the efforts of using synthetic HDL as a potential therapy for sepsis.

Potential biomarkers in the sera of breast cancer patients from bahawalpur, pakistan.

Most of the approximately 90,000 cases of Breast Cancer (BC) documented annually in Pakistan are not diagnosed properly because of lack of suitable markers. We performed serum proteome expression profiling of BC and benign breast disease (BBD) patients with the aim to identify biomarkers that can be helpful for diagnosis and prognosis of the disease. Sera of patients were analyzed by one-dimensional SDS polyacrylamide gel electrophoresis (PAGE). Differentially expressed proteins were subjected to identification through LC-MS/MS analysis. In majority of the BC cases some acute phase proteins (APP) and some complement system components (C3 and C8) containing fractions were up-regulated with the exception of transthyretin (TTR) which was predominantly (68.75%) down-regulated (n = 33/48) in the sera of these patients. Varying expression patterns were observed in BBD patients and healthy controls. These differentially expressed proteins have the potential to serve as diagnostic biomarkers for BC as well as benign breast diseases.