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Journal of the American Heart... May 2024
Topics: Neutrophils; Humans; Lymphocytes; Apolipoprotein A-I; Myocardial Infarction; Male; Lymphocyte Count
PubMed: 38700008
DOI: 10.1161/JAHA.123.033541 -
Protein Science : a Publication of the... May 2024Serum amyloid A (SAA) is a highly conserved acute-phase protein that plays roles in activating multiple pro-inflammatory pathways during the acute inflammatory response...
Serum amyloid A (SAA) is a highly conserved acute-phase protein that plays roles in activating multiple pro-inflammatory pathways during the acute inflammatory response and is commonly used as a biomarker of inflammation. It has been linked to beneficial roles in tissue repair through improved clearance of lipids and cholesterol from sites of damage. In patients with chronic inflammatory diseases, elevated levels of SAA may contribute to increased severity of the underlying condition. The majority of circulating SAA is bound to lipoproteins, primarily high-density lipoprotein (HDL). Interaction with HDL not only stabilizes SAA but also alters its functional properties, likely through altered accessibility of protein-protein interaction sites on SAA. While high-resolution structures for lipid-free, or apo-, forms of SAA have been reported, their relationship with the HDL-bound form of the protein, and with other possible mechanisms of SAA binding to lipids, has not been established. Here, we have used multiple biophysical techniques, including SAXS, TEM, SEC-MALS, native gel electrophoresis, glutaraldehyde crosslinking, and trypsin digestion to characterize the lipid-free and lipid-bound forms of SAA. The SAXS and TEM data show the presence of soluble octamers of SAA with structural similarity to the ring-like structures reported for lipid-free ApoA-I. These SAA octamers represent a previously uncharacterized structure for lipid-free SAA and are capable of scaffolding lipid nanodiscs with similar morphology to those formed by ApoA-I. The SAA-lipid nanodiscs contain four SAA molecules and have similar exterior dimensions as the lipid-free SAA octamer, suggesting that relatively few conformational rearrangements may be required to allow SAA interactions with lipid-containing particles such as HDL. This study suggests a new model for SAA-lipid interactions and provides new insight into how SAA might stabilize protein-lipid nanodiscs or even replace ApoA-I as a scaffold for HDL particles during inflammation.
Topics: Serum Amyloid A Protein; Humans; Lipoproteins, HDL; Nanostructures; Models, Molecular; Apolipoprotein A-I; Protein Binding
PubMed: 38659173
DOI: 10.1002/pro.4983 -
Diabetes & Metabolism May 2024The catabolism of high density lipoprotein (HDL) apolipoprotein AI (apoAI) is accelerated in patients with type 2 diabetes (T2D), related to hypertriglyceridemia,...
AIM
The catabolism of high density lipoprotein (HDL) apolipoprotein AI (apoAI) is accelerated in patients with type 2 diabetes (T2D), related to hypertriglyceridemia, insulin resistance and low plasma adiponectin levels. Since liraglutide is likely to partly correct these abnormalities, we hypothesized that it might have a beneficial effect on HDL apoAI kinetics in patients with T2D.
METHODS
An in vivo kinetic study of HDL apoAI was performed in 10 patients with T2D before and after 6 months of treatment with 1.2 mg/day of liraglutide, using a bolus of l-[1-C]leucine followed by a 16-hour constant infusion.
RESULTS
Liraglutide reduced BMI (34.9 ± 4.7 vs 36.6 ± 4.9 kg/m, P = 0.012), HbA1c (7.1 ± 1.1 vs 9.6 ± 2.6%, P = 0.003), HOMA-IR (5.5 ± 1.9 vs 11.6 ± 11.2, P = 0.003), fasting triglycerides (1.76 ± 0.37 vs 2.48 ± 0.69 mmol/l, P < 0.001) and triglycerides during kinetics (2.34 ± 0.81 vs 2.66 ± 0.65 mmol/l, P = 0.053). Plasma HDL cholesterol and adiponectin concentrations were unchanged (respectively 0.97 ± 0.26 vs 0.97 ± 0.19 mmol/l, P = 1; 3169 ± 1561 vs 2618 ± 1651 µg/l, P = 0.160), similar to triglyceride content in HDL (5.13 ± 1.73 vs 5.39 ± 1.07%, P = 0.386). Liraglutide modified neither HDL apoAI fractional catabolic rate (0.35 ± 0.11 vs 0.38 ± 0.11 pool/day, P = 0.375), nor its production rate (0.44 ± 0.13 vs 0.49 ± 0.15 g/l/day, P = 0.375), nor its plasma concentration (1.26 ± 0.19 vs 1.29 ± 0.14 g/l, P = 0.386).
CONCLUSION
Six months of treatment with 1.2 mg/day of liraglutide had no effect on the kinetics of HDL apoAI in patients with T2D. The lack of decrease in triglyceride content in HDL related to an only moderate decrease in triglyceridemia, probably greatly explains these results. Insufficient improvement of insulin sensitivity and adiponectinemia may also be implied.
Topics: Humans; Liraglutide; Diabetes Mellitus, Type 2; Male; Female; Middle Aged; Apolipoprotein A-I; Aged; Hypoglycemic Agents; Kinetics; Lipoproteins, HDL
PubMed: 38653365
DOI: 10.1016/j.diabet.2024.101535 -
Lipids in Health and Disease Apr 2024The present study was performed to assess the association between the neutrophil-to-apolipoprotein A1 ratio (NAR) and outcomes in patients with acute decompensated heart...
The neutrophil-to-apolipoprotein A1 ratio is associated with adverse outcomes in patients with acute decompensated heart failure at different glucose metabolic states: a retrospective cohort study.
BACKGROUND
The present study was performed to assess the association between the neutrophil-to-apolipoprotein A1 ratio (NAR) and outcomes in patients with acute decompensated heart failure (ADHF) at different glucose metabolism states.
METHODS
We recruited 1233 patients with ADHF who were admitted to Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University from December 2014 to October 2019. The endpoints were defined as composites of cardiovascular death, nonfatal myocardial infarction, nonfatal ischemic stroke and exacerbation of chronic heart failure. The restricted cubic spline was used to determine the best cutoff of NAR, and patients were divided into low and high NAR groups. Kaplan-Meier plots and multivariable Cox proportional hazard models were used to investigate the association between NAR and the risk of adverse outcomes.
RESULTS
During the five-year follow-up period, the composite outcome occurred in 692 participants (56.1%). After adjusting for potential confounding factors, a higher NAR was associated with a higher incidence of composite outcomes in the total cohort (Model 1: HR = 1.42, 95% CI = 1.22-1.65, P<0.001; Model 2: HR = 1.29, 95% CI = 1.10-1.51, P = 0.002; Model 3: HR = 1.20, 95% CI = 1.01-1.42, P = 0.036). At different glucose metabolic states, a high NAR was associated with a high risk of composite outcomes in patients with diabetes mellitus (DM) (Model 1: HR = 1.54, 95% CI = 1.25-1.90, P<0.001; Model 2: HR = 1.40, 95% CI = 1.13-1.74, P = 0.002; Model 3: HR = 1.31, 95% CI = 1.04-1.66, P = 0.022), and the above association was not found in patients with prediabetes mellitus (Pre-DM) or normal glucose regulation (NGR) (both P>0.05).
CONCLUSIONS
The NAR has predictive value for adverse outcomes of ADHF with DM, which implies that the NAR could be a potential indicator for the management of ADHF.
Topics: Humans; Male; Female; Heart Failure; Apolipoprotein A-I; Middle Aged; Retrospective Studies; Aged; Neutrophils; Blood Glucose; Proportional Hazards Models; Kaplan-Meier Estimate; Risk Factors; Prognosis
PubMed: 38649986
DOI: 10.1186/s12944-024-02104-1 -
Journal of Orthopaedic Surgery and... Apr 2024To analyze the relationship between lipid metabolism, coagulation function, and bone metabolism and the contributing factor and staging of non-traumatic femoral head...
Relationship between lipid metabolism, coagulation and other blood indices and etiology and staging of non-traumatic femoral head necrosis: a multivariate logistic regression-based analysis.
BACKGROUND
To analyze the relationship between lipid metabolism, coagulation function, and bone metabolism and the contributing factor and staging of non-traumatic femoral head necrosis, and to further investigate the factors influencing the blood indicators related to the staging of non-traumatic femoral head necrosis.
METHODS
The medical records of patients with femoral head necrosis were retrieved from the inpatient medical record management system, and the lipid metabolism, bone metabolism, and coagulation indices of non-traumatic femoral head necrosis (including alcoholic, hormonal, and idiopathic group) were obtained according to the inclusion and exclusion criteria, including Low-Density Lipoprotein Cholesterol, Triglycerides, Non-High-Density Lipoprotein Cholesterol, Apolipoprotein A1, Apolipoprotein (B), Apolipoprotein (E), Uric Acid, Alkaline Phosphatase, Bone-specific Alkaline Phosphatase, Activated Partial Thromboplastin Time, Prothrombin Time, D-dimer, Platelet count. The relationship between these blood indices and the different stages under different causative factors was compared, and the factors influencing the stages of non-traumatic femoral head necrosis were analyzed using multivariate logistic regression.
RESULTS
(i) Gender, Age and BMI stratification, Low-density Lipoprotein Cholesterol, Triglycerides, Non-High-density Lipoprotein Cholesterol, Apolipoprotein (B), Apolipoprotein (E), Uric Acid, Bone-specific Alkaline Phosphatase, Activated Partial Thromboplastin Time, Plasminogen Time, D-dimer, and Platelet count of the alcohol group were statistically different when compared among the different ARCO staging groups; (ii) The differences in Age and BMI stratification, Triglycerides, Non-High-density Lipoprotein Cholesterol, Apolipoprotein A1, Apolipoprotein B, Apolipoprotein E, Uric Acid, Bone-specific Alkaline Phosphatase, Activated Partial Thromboplastin Time, Plasminogen Time, D-dimer, and Platelet count were statistically significant when compared among the different phases in the hormone group (P < 0.05); (iii) The differences in Age and BMI stratification, Non-High-Density Lipoprotein Cholesterol, Apolipoprotein A1, Apolipoprotein (B), Apolipoprotein (E), Uric Acid, Activated Partial Thromboplastin Time, D-dimer, and Platelet count were statistically significant when compared among the different stages in the idiopathic group (P < 0.05); (v) Statistically significant indicators were included in the multivariate logistic regression analysis, excluding the highly correlated bone-specific alkaline phosphatase, and the results showed that Low-density lipoprotein was negatively correlated with changes in the course of ARCO, and Non-High-Density Lipoprotein cholesterol, Apo B, Activated Partial Thromboplastin Time, and Platelet count were significantly and positively correlated with disease progression.
CONCLUSION
An abnormal hypercoagulable state as well as an abnormal hyperlipidemic state are risk factors for the progression of non-traumatic femoral head necrosis under various exposure factors, as indicated by Non-High-Density Lipoprotein Cholesterol, Apolipoprotein B, Activated Fractional Thromboplastin Time, and Platelet Counts.
Topics: Humans; Apolipoprotein A-I; Logistic Models; Lipid Metabolism; Femur Head Necrosis; Alkaline Phosphatase; Uric Acid; Cholesterol; Triglycerides; Cholesterol, LDL; Plasminogen
PubMed: 38643101
DOI: 10.1186/s13018-024-04715-x -
Journal of Lipid Research May 2024AapoA-I, the main protein of high-density lipoprotein, plays a key role in the biogenesis and atheroprotective properties of high-density lipoprotein. We showed...
AapoA-I, the main protein of high-density lipoprotein, plays a key role in the biogenesis and atheroprotective properties of high-density lipoprotein. We showed previously that a naturally occurring apoA-I mutation, L178P, induces major defects in protein's structural integrity and functions that may underlie the increased cardiovascular risk observed in carriers of the mutation. Here, a library of marketed drugs (956 compounds) was screened against apoA-I[L178P] to identify molecules that can stabilize the normal conformation of apoA-I. Screening was performed by the thermal shift assay in the presence of fluorescent dye SYPRO Orange. As an orthogonal assay, we monitored the change in fluorescence intensity of 8-anilinonaphthalene-1-sulfonic acid upon binding on hydrophobic sites on apoA-I. Screening identified four potential structure correctors. Subsequent analysis of the concentration-dependent effect of these compounds on secondary structure and thermodynamic stability of WT apoA-I and apoA-I[L178P] (assessed by thermal shift assay and circular dichroism spectroscopy), as well as on macrophage viability, narrowed the potential structure correctors to two, the drugs atorvastatin and bexarotene. Functional analysis showed that these two compounds can restore the defective capacity of apoA-I[L178P] to promote cholesterol removal from macrophages, an important step for atheroprotection. Computational docking suggested that both drugs target a positively charged cavity in apoA-I, formed between helix 1/2 and helix 5, and make extensive interactions that could underlie thermodynamic stabilization. Overall, our findings indicate that small molecules can correct defective apoA-I structure and function and may lead to novel therapeutic approaches for apoA-I-related dyslipidemias and increased cardiovascular risk.
Topics: Apolipoprotein A-I; Humans; Animals; Mice; Drug Evaluation, Preclinical; Small Molecule Libraries
PubMed: 38641010
DOI: 10.1016/j.jlr.2024.100543 -
Polski Przeglad Chirurgiczny Sep 2023<b><br>Introduction:</b> Neoadjuvant chemotherapy (NAC) is a part of the current standard of care in a locally advanced gastric adenocarcinoma (GA) and...
ApoA-I and ApoB levels, and ApoB-to-ApoA-I ratio as candidate pre-treatment biomarkers of pathomorphological response to neoadjuvant therapy in gastric and esophago-gastric junction adenocarcinoma.
<b><br>Introduction:</b> Neoadjuvant chemotherapy (NAC) is a part of the current standard of care in a locally advanced gastric adenocarcinoma (GA) and esophagogastric junction adenocarcinoma (EGJA), but only patients with good pathomorphological response (pR) to NAC benefit from prolonged overall survival.</br> <b><br>Aim:</b> The study aims to evaluate ApoA-I and ApoB as candidate pre-treatment biomarkers of pR to NAC in patients with GA and EGJA.</br> <b><br>Materials and methods:</b> Serum samples were collected from 18 patients with GA and 9 with EGJA before the initiation of NAC to determine the ApoA-I and ApoB levels. After NAC tumor regression grade (TRG) was evaluated in resected specimens according to the Mandard's tumor regression grading system and correlated with pre-treatment ApoA-I and ApoB serum concentration, and ApoB-to-ApoA-I serum concentration ratio.</br> <b><br>Results:</b> We found a positive correlation of ApoA-I level and pR (95% CI: -0.863 to -0.467; P < 0.0001), a negative correlation of ApoB level and pR (95% CI: 0.445 to 0.857; P < 0.0001), a negative correlation of ApoB-to-ApoA-I ratio and pR (95% CI: 0.835 to 0.964; P < 0.0001).</br> <b><br>Conclusions:</b> ApoA-I and ApoB levels, and ApoB-to-ApoA-I ratio are candidate pre-treatment predictors of pR to NAC in GA and may help to guide personalized therapy.</br>Our work fits into the dynamically developing trend of personalized treatment. It describes a potentially important rationale for further evaluation of apolipoprotein A-I and apolipoprotein B as predictors of cancer response to neoadjuvant therapy.
Topics: Humans; Adenocarcinoma; Apolipoprotein A-I; Apolipoproteins B; Biomarkers; Neoadjuvant Therapy; Stomach Neoplasms
PubMed: 38629280
DOI: 10.5604/01.3001.0053.8925 -
Protein Science : a Publication of the... May 2024High-density lipoproteins (HDLs) are responsible for removing cholesterol from arterial walls, through a process known as reverse cholesterol transport. The main protein...
High-density lipoproteins (HDLs) are responsible for removing cholesterol from arterial walls, through a process known as reverse cholesterol transport. The main protein in HDL, apolipoprotein A-I (ApoA-I), is essential to this process, and changes in its sequence significantly alter HDL structure and functions. ApoA-I amyloidogenic variants, associated with a particular hereditary degenerative disease, are particularly effective at facilitating cholesterol removal, thus protecting carriers from cardiovascular disease. Thus, it is conceivable that reconstituted HDL (rHDL) formulations containing ApoA-I proteins with functional/structural features similar to those of amyloidogenic variants hold potential as a promising therapeutic approach. Here we explored the effect of protein cargo and lipid composition on the function of rHDL containing one of the ApoA-I amyloidogenic variants G26R or L174S by Fourier transformed infrared spectroscopy and neutron reflectometry. Moreover, small-angle x-ray scattering uncovered the structural and functional differences between rHDL particles, which could help to comprehend higher cholesterol efflux activity and apparent lower phospholipid (PL) affinity. Our findings indicate distinct trends in lipid exchange (removal vs. deposition) capacities of various rHDL particles, with the rHDL containing the ApoA-I amyloidogenic variants showing a markedly lower ability to remove lipids from artificial membranes compared to the rHDL containing the native protein. This effect strongly depends on the level of PL unsaturation and on the particles' ultrastructure. The study highlights the importance of the protein cargo, along with lipid composition, in shaping rHDL structure, contributing to our understanding of lipid-protein interactions and their behavior.
Topics: Lipoproteins, HDL; Apolipoprotein A-I; Membranes, Artificial; Cholesterol; Phospholipids
PubMed: 38607188
DOI: 10.1002/pro.4987 -
Scientific Reports Apr 2024The current state of knowledge on the relationship between lifestyle factors, glycemic traits, lipoprotein traits with liver cancer risk is still uncertain despite some...
The current state of knowledge on the relationship between lifestyle factors, glycemic traits, lipoprotein traits with liver cancer risk is still uncertain despite some attempts made by observational studies. This study aims to investigate the causal genetic relationship between factors highly associated with liver cancer incidence by using Mendelian randomization (MR) analysis. Employing MR analysis, this study utilized previously published GWAS datasets to investigate whether lifestyle factors, glycemic traits, and lipoprotein traits would affect the risk of liver cancer. The study utilized three MR methods, including inverse variance-weighted model (IVW), MR Egger, and weighted median. Furthermore, MR-Egger analyses were performed to detect heterogeneity in the MR results. The study also conducted a leave-one-out analysis to assess the potential influence of individual SNPs on the MR analysis results. MR-PRESSO was used to identify and remove SNP outliers associated with liver cancer. MR analyses revealed that 2-h glucose (odds ratio, OR 2.33, 95% confidence interval, CI 1.28-4.21), type 2 diabetes mellitus (T2DM, OR 1.67, 95% CI 1.18-2.37), body mass index (BMI, OR 1.67, 95% CI 1.18-2.37), waist circumference (OR 1.78, 95% CI 1.18-2.37) were associated with increased risk of liver cancer. On the contrary, apolipoproteins B (APOB, OR 0.67, 95% CI 0.47-0.97), and low-density lipoprotein (LDL, OR 0.62, 95% CI 0.42-0.92) were negatively related to liver cancer risk. Additionally, after adjusting for BMI, apolipoproteins A-I (APOA-I, OR 0.56, 95% CI, 0.38-0.81), total cholesterol (TC, OR 0.72, 95% CI, 0.54-0.94), and total triglycerides (TG, OR 0.57, 95% CI, 0.40-0.78) exhibited a significant inverse correlation with the risk of liver cancer. This study supports a causal relationship between 2-h glucose, T2DM, BMI, and waist circumference with the increased risk of liver cancer. Conversely, the study reveals a cause-effect relationship between TC, TG, LDL, APOA-I, and APOB with a decreased risk of liver cancer.
Topics: Humans; Apolipoprotein A-I; Mendelian Randomization Analysis; Diabetes Mellitus, Type 2; Lipoproteins; Liver Neoplasms; Apolipoproteins B; Glucose; Genome-Wide Association Study; Risk Factors
PubMed: 38605235
DOI: 10.1038/s41598-024-59211-3 -
Journal of the American College of... Jun 2024The AEGIS-II trial hypothesized that CSL112, an intravenous formulation of human apoA-I, would lower the risk of plaque disruption, decreasing the risk of recurrent... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
The AEGIS-II trial hypothesized that CSL112, an intravenous formulation of human apoA-I, would lower the risk of plaque disruption, decreasing the risk of recurrent events such as myocardial infarction (MI) among high-risk patients with MI.
OBJECTIVES
This exploratory analysis evaluates the effect of CSL112 therapy on the incidence of cardiovascular (CV) death and recurrent MI.
METHODS
The AEGIS-II trial was an international, multicenter, randomized, double-blind, placebo-controlled trial that randomized 18,219 high-risk acute MI patients to 4 weekly infusions of apoA-I (6 g CSL112) or placebo.
RESULTS
The incidence of the composite of CV death and type 1 MI was 11% to 16% lower in the CSL112 group over the study period (HR: 0.84; 95% CI: 0.7-1.0; P = 0.056 at day 90; HR: 0.86; 95% CI: 0.74-0.99; P = 0.048 at day 180; and HR: 0.89; 95% CI: 0.79-1.01; P = 0.07 at day 365). Similarly, the incidence of CV death or any MI was numerically lower in CSL112-treated patients throughout the follow-up period (HR: 0.92; 95% CI: 0.80-1.05 at day 90, HR: 0.89; 95% CI: 0.79-0.996 at day 180, HR: 0.91; 95% CI: 0.83-1.01 at day 365). The effect of CSL112 treatment on MI was predominantly observed for type 1 MI and type 4b (MI due to stent thrombosis).
CONCLUSIONS
Although CSL112 did not significantly reduce the occurrence of the primary study endpoints, patients treated with CSL112 infusions had numerically lower rates of CV death and MI, type-1 MI, and stent thrombosis-related MI compared with placebo. These findings could suggest a role of apoA-I in reducing subsequent plaque disruption events via enhanced cholesterol efflux. Further prospective data would be needed to confirm these observations.
Topics: Humans; Male; Female; Double-Blind Method; Myocardial Infarction; Apolipoprotein A-I; Middle Aged; Aged; Recurrence; Infusions, Intravenous; Lipoproteins, HDL
PubMed: 38588930
DOI: 10.1016/j.jacc.2024.03.396