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Background We previously showed that levels of prebeta‐1 high‐density lipoprotein (HDL), the principal acceptor of cholesterol effluxed from cells, including artery wall macrophages, are positively associated with coronary heart disease (CHD) and myocardial infarction (MI) risk. Methods and Results In a multiethnic follow‐up cohort of 1249 individuals from University of California–San Francisco clinics, we determined the degree to which prebeta‐1 HDL levels, both absolute and percentage of apolipoprotein AI, are associated with CHD and history of MI. Independent, strong, positive associations were found. Meta‐analysis revealed for the absolute prebeta‐1 HDL for the top tertile versus the lowest, unadjusted odds ratios of 1.90 (95% CI, 1.40–2.58) for CHD and 1.79 (95% CI, 1.35–2.36) for MI. For CHD, adjusting for established risk factors, the top versus bottom tertiles, quintiles, and deciles yielded sizable odds ratios of 2.37 (95% CI, 1.74–3.25, P P P Conclusions Analysis of 2507 subjects showed conclusively that levels of prebeta‐1 HDL are strongly associated with a history of CHD or MI, independently of traditional risk factors. Addition of prebeta‐1 HDL can significantly improve clinical assessment of risk of CHD and MI.

Summary A patient with atypical partial lipodystrophy who had a transient initial response to metreleptin experienced acute worsening of her metabolic state when neutralizing antibodies against metreleptin appeared. Because her metabolic status continued to deteriorate, a therapeutic trial with melanocortin-4 receptor agonist setmelanotide, that is believed to function downstream from leptin receptor in the leptin signaling system, was undertaken in an effort to improve her metabolic status for the first time in a patient with lipodystrophy. To achieve this, a compassionate use (investigational new drug application; IND) was initiated (NCT03262610). Glucose control, body fat by dual-energy X-ray absorptiometry and MRI, and liver fat by proton density fat fraction were monitored. Daily hunger scores were assessed by patient filled questionnaires. Although there was a slight decrease in hunger scales and visceral fat, stimulating melanocortin-4 receptor by setmelanotide did not result in any other metabolic benefit such as improvement of hypertriglyceridemia or diabetes control as desired. Targeting melanocortin-4 receptor to regulate energy metabolism in this setting was not sufficient to obtain a significant metabolic benefit. However, complex features of our case make it difficult to generalize these observations to all cases of lipodystrophy. It is still possible that melanocortin-4 receptor agonistic action may offer some therapeutic benefits in leptin-deficient patients. Learning points: A patient with atypical lipodystrophy with an initial benefit with metreleptin therapy developed neutralizing antibodies to metreleptin (Nab-leptin), which led to substantial worsening in metabolic control. The neutralizing activity in her serum persisted for longer than 3 years. Whether the worsening in her metabolic state was truly caused by the development of Nab-leptin cannot be fully ascertained, but there was a temporal relationship. The experience noted in our patient at least raises the possibility for concern for substantial metabolic worsening upon emergence and persistence of Nab-leptin. Further studies of cases where Nab-leptin is detected and better assay systems to detect and characterize Nab-leptin are needed. The use of setmelanotide, a selective MC4R agonist targeting specific neurons downstream from the leptin receptor activation, was not effective in restoring metabolic control in this complex patient with presumed diminished leptin action due to Nab-leptin. Although stimulating the MC4R pathway was not sufficient to obtain a significant metabolic benefit in lowering triglycerides and helping with her insulin resistance as was noted with metreleptin earlier, there was a mild reduction in reported food intake and appetite. Complex features of our case make it difficult to generalize our observation to all leptin-deficient patients. It is possible that some leptin-deficient patients (especially those who need primarily control of food intake) may still theoretically benefit from MC4R agonistic action, and further studies in carefully selected patients may help to tease out the differential pathways of metabolic regulation by the complex network of leptin signaling system.

Background Atherosclerosis is a slowly progressing, chronic multifactorial disease characterized by the accumulation of lipids, inflammatory cells, and fibrous tissue that drives to the formation of asymmetric focal thickenings in the tunica intima of large and mid-sized arteries. Despite the high therapeutic potential of ApoA-1 proteins, the purification and delivery into the disordered organisms of these drugs is still limited by low efficiency in these processes. Methods and results We report here a novel production and delivery system of anti-atherogenic APOA-1Milano muteins (APOA-1M) by means of genetically modified rice plants. APOA-1M, delivered as protein extracts from transgenic rice seeds, significantly reduced macrophage activation and foam cell formation in vitro in oxLDL-loaded THP-1 model. The APOA-1M delivery method and therapeutic efficacy was tested in healthy mice and in Apoe−/− mice fed with high cholesterol diet (Western Diet, WD). APOA-1M rice milk significantly reduced atherosclerotic plaque size and lipids composition in aortic sinus and aortic arch of WD-fed Apoe−/− mice as compared to wild type rice milk-treated, WD-fed Apoe−/− mice. APOA-1M rice milk also significantly reduced macrophage number in liver of WD-fed Apoe−/− mice as compared to WT rice milk treated mice. Translational impact The delivery of therapeutic APOA-1M full length proteins via oral administration of rice seeds protein extracts (the ‘rice milk’) to the disordered organism, without any need of purification, might overcome the main APOA1-based therapies' limitations and improve the use of this molecules as therapeutic agents for cardiovascular patients.

Objective— We aimed to determine whether autoantibodies against apoA-1 (apolipoprotein A-1; anti-apoA-1 IgG) predict incident coronary artery disease (CAD), defined as adjudicated incident myocardial infarction, angina, percutaneous coronary revascularization, or bypass grafting, in the general population. We further investigated whether this association is modulated by a functional CD14 receptor single nucleotide polymorphism. Approach and Results— In a prospectively studied, population-based cohort of 5220 subjects (mean age 52.6±10.7 years, 47.4% males), followed over a median period of 5.6 years, subjects positive versus negative for anti-apoA-1 IgG presented a total CAD rate of 3.9% versus 2.8% ( P =0.077) and a nonfatal CAD rate of 3.6% versus 2.3% ( P =0.018), respectively. After multivariate adjustment for established cardiovascular risk factors, the hazard ratios of anti-apoA-1 IgG for total and nonfatal CAD were: hazard ratio=1.36 (95% confidence interval, 0.94–1.97; P =0.105) and hazard ratio=1.53 (95% confidence interval, 1.03–2.26; P =0.034), respectively. In subjects with available genetic data for the C260T rs2569190 single nucleotide polymorphism in the CD14 receptor gene (n=4247), we observed a significant interaction between anti-apoA-1 IgG and rs2569190 allele status with regards to CAD risk, with anti-apoA-1 IgG conferring the highest risk for total and nonfatal CAD in non-TT carriers, whereas being associated with the lowest risk for total and nonfatal CAD in TT homozygotes ( P for interaction =0.011 and P for interaction =0.033, respectively). Conclusions— Anti-apoA-1 IgG are independent predictors of nonfatal incident CAD in the general population. The strength of this association is dependent on a functional polymorphism of the CD14 receptor gene, a finding suggesting a gene–autoantibody interaction for the development of CAD.

Decreased high-density lipoprotein (HDL) particle size, cholesterol poor, apolipoprotein A-I-rich HDL particles leading to smaller HDL particle size, may be associated with an anti-atherosclerotic effect. The data are sparse regarding the relationship between n-3 polyunsaturated fatty acids [n-3 PUFAs: eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA)] and HDL particle size. This study was designed as a hospital-based cross-sectional study to investigate the relationship between the serum levels of n-3 PUFAs and the HDL-cholesterol/apolipoprotein A-1 ratio, as estimated by the HDL particle size, in patients with the presence of one or more risk factors for atherosclerotic cardiovascular disease (ASCVD). Six hundred and forty sequential patients were enrolled in this study. The serum levels of EPA and DHA showed a strong correlation (r = 0.736, p β = − 0.745, p = 0.021), but not serum EPA (β = − 0.414, p = 0.139) or EPA + DHA (β = 0.330, p = 0.557) level, was identified as an independent indicator of decreased HDL particle size. In 476 patients followed up for at least 6 months, the absolute change (Δ) in the HDL-cholesterol/apolipoprotein A-1 ratio decreased significantly as the quartile of the Δ DHA level increased (p = 0.014), whereas no significant difference in the Δ HDL-cholesterol/apolipoprotein A-1 ratio was noted with the increase in the quartile of the Δ EPA level. Moreover, a multivariate regression analysis identified increased DHA level and decreased estimated low-density lipoprotein (LDL) particle size measured relative to the mobility value of LDL with polyacrylamide gel electrophoresis (i.e., relative LDL migration: LDL-Rm value), as independent predictors of decreased HDL-cholesterol/apolipoprotein A-1 ratio (β = − 0.171, p = 0.0003 and β = − 0.142, p = 0.002). The results suggest that increased serum DHA level, but not EPA level, might be associated with decreased HDL-cholesterol/apolipoprotein A-1 ratio, an indicator of estimated HDL particle size. Further studies are needed to investigate the useful clinical indices and outcomes of these patients.Clinical Trial Registration Information UMIN (http://www.umin.ac.jp/), Study ID: UMIN000010603.

Supplemental Digital Content is available in the text., Background: Total cholesterol and high-density lipoprotein cholesterol (HDL-C) measurements are central to cardiovascular disease (CVD) risk assessment, but there is continuing debate around the utility of other lipids for risk prediction. Methods: Participants from UK Biobank without baseline CVD and not taking statins, with relevant lipid measurements (n=346 686), were included in the primary analysis. An incident fatal or nonfatal CVD event occurred in 6216 participants (1656 fatal) over a median of 8.9 years. Associations of nonfasting lipid measurements (total cholesterol, HDL-C, non–HDL-C, direct and calculated low-density lipoprotein cholesterol [LDL-C], and apolipoproteins [Apo] A1 and B) with CVD were compared using Cox models adjusting for classical risk factors, and predictive utility was determined by the C-index and net reclassification index. Prediction was also tested in 68 649 participants taking a statin with or without baseline CVD (3515 CVD events). Results: ApoB, LDL-C, and non–HDL-C were highly correlated (r>0.90), while HDL-C was strongly correlated with ApoA1 (r=0.92). After adjustment for classical risk factors, 1 SD increase in ApoB, direct LDL-C, and non–HDL-C had similar associations with composite fatal/nonfatal CVD events (hazard ratio, 1.23, 1.20, 1.21, respectively). Associations for 1 SD increase in HDL-C and ApoA1 were also similar (hazard ratios, 0.81 [both]). Adding either total cholesterol and HDL-C, or ApoB and ApoA, to a CVD risk prediction model (C-index, 0.7378) yielded similar improvement in discrimination (C-index change, 0.0084; 95% CI, 0.0065, 0.0104, and 0.0089; 95% CI, 0.0069, 0.0109, respectively). Once total and HDL-C were in the model, no further substantive improvement was achieved with the addition of ApoB (C-index change, 0.0004; 95% CI, 0.0000, 0.0008) or any measure of LDL-C. Results for predictive utility were similar for a fatal CVD outcome, and in a discordance analysis. In participants taking a statin, classical risk factors (C-index, 0.7118) were improved by non–HDL-C (C-index change, 0.0030; 95% CI, 0.0012, 0.0048) or ApoB (C-index change, 0.0030; 95% CI, 0.0011, 0.0048). However, adding ApoB or LDL-C to a model already containing non–HDL-C did not further improve discrimination. Conclusions: Measurement of total cholesterol and HDL-C in the nonfasted state is sufficient to capture the lipid-associated risk in CVD prediction, with no meaningful improvement from addition of apolipoproteins, direct or calculated LDL-C.

Background Babesia canis infection induces a marked acute phase response (APR) that might be associated with alteration in lipid and lipoprotein metabolism and disease prognosis. Hypothesis Dogs with B. canis-induced APR develop dyslipidemia with altered lipoprotein concentration and morphology. Animals Twenty-nine client-owned dogs with acute B. canis infection and 10 clinically healthy control dogs. Methods Observational cross-sectional study. Serum amyloid A (SAA) was measured using ELISA. Cholesterol, phospholipids, and triglycerides were determined biochemically. Lipoproteins were separated using agarose gel electrophoresis. Lipoprotein diameter was assessed by polyacrylamide gradient gel electrophoresis; correlation with ApoA-1 (radioimmunoassay) and SAA was determined. Results Dogs with B. canis infection had a marked APR (median SAA, 168.3 mu g/mL; range, 98.1-716.2 mu g/mL) compared with controls (3.2 mu g/mL, 2.0-4.2 mu g/mL) (P < .001). Dogs with B. canis infection had significantly lower median cholesterol (4.79 mmol/L, 1.89-7.64 mmol/L versus 6.15 mmol/L, 4.2-7.4 mmol/L) (P = .02), phospholipid (4.64 mmol/L, 2.6-6.6 mmol/L versus 5.72 mmol/L, 4.68-7.0 mmol/L) (P = .02), and alpha-lipoproteins (77.5%, 27.7%-93.5% versus 89.2%, 75.1%-93.5%) (P = .04), and higher ApoA-1 (1.36 U, 0.8-2.56 U versus 0.95 U, 0.73-1.54 U) concentrations (P = .02). Serum amyloid A correlated with high-density lipoproteins (HDLs) diameter (rho = .43; P = .03) and ApoA-1 (rho = .63, P < .001). Conclusions and Clinical Importance Major changes associated with B. canis-induced APR in dogs are related to concentration, composition, and morphology of HDL particles pointing to an altered reverse cholesterol transport. Parallel ApoA-1 and SAA concentration increase is a unique still unexplained pathophysiological finding.

Background. No reliable tests or validated biomarkers exist to ensure parasitological cure following treatment of Chagas disease (CD) patients chronically infected with Trypanosoma cruzi. As seroreversion, the only marker of cure, happens more quickly in children, we investigated the correlation between previously identified biomarkers and seroreversion in children. Methods. Thirty CD children (age 1 month to 10 years) diagnosed as T. cruzi positive (time point S0) were treated with benznidazole (BZ) 5-8 mg/kg/d for 60 days. At least 2 serological tests were used to evaluate treatment efficacy from the end of treatment (S1) until seroreversion (S2). Thirty children (age 1 month to 10 years) and 15 adults were used as healthy controls (HCs). Immunoblot and a proteomic-based assay were used to validate previously identified fragments of apolipoprotein A-1 (ApoA1) and fibronectin (FBN) as CD biomarkers. Results. Correlation between seroreversion and absence of ApoA1 and FBN fragments by immunoblot was observed in 30/30 (100%) and 29/30 (96.6%) CD children, respectively. ApoA1 and FBN fragments were absent at the end of BZ treatment in 20/30 (66.6%) and 16/30 (53.3%) children, respectively. Absence of fragments in serum profiles was confirmed by mass spectrometry. Using intact protein analysis, a 28 109-Da protein identified as full-length ApoA1 by tandem mass spectrometry was detected in HC serum samples. Conclusions. These data confirm that ApoA1 and FBN fragments can discriminate between healthy and T. cruzi-infected samples. Correlation with seroreversion was shown for the first time; results suggest predictive capacity potentially superior to serology, making them potentially useful as surrogate biomarkers. Fil: Ruiz Lancheros, Elizabeth. National Reference Centre For Parasitology; Canadá Fil: Rasoolizadeh, Asieh. National Reference Centre For Parasitology; Canadá Fil: Chatelain, Eric. No especifíca; Fil: Garcia Bournissen, Facundo. Gobierno de la Ciudad de Buenos Aires. Instituto Multidisciplinario de Investigaciones en Patologías Pediátricas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto Multidisciplinario de Investigaciones en Patologías Pediátricas; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez". Servicio de Parasitología y Chagas; Argentina Fil: Moroni, Samanta. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez". Servicio de Parasitología y Chagas; Argentina Fil: Moscatelli, Guillermo. Gobierno de la Ciudad de Buenos Aires. Instituto Multidisciplinario de Investigaciones en Patologías Pediátricas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto Multidisciplinario de Investigaciones en Patologías Pediátricas; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez". Servicio de Parasitología y Chagas; Argentina Fil: Altcheh, Jaime Marcelo. Gobierno de la Ciudad de Buenos Aires. Instituto Multidisciplinario de Investigaciones en Patologías Pediátricas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto Multidisciplinario de Investigaciones en Patologías Pediátricas; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez". Servicio de Parasitología y Chagas; Argentina Fil: Ndao, Momar. National Reference Centre For Parasitology; Canadá

Background The aim of this study was to propose a prognostic scoring system based on preoperative serum apolipoprotein A-1 and C-reactive protein (ApoA-1 and CRP, AC score) levels and to evaluate the prognostic value of these markers in patients with hepatocellular carcinoma (HCC). Methods In all, 539 consecutive cases diagnosed with HCC from 2009 to 2012 at Sun Yat-sen University Cancer Center were analysed. The characteristics and levels of pretreatment lipids (ApoA-1, apolipoprotein B (Apo-B), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), triglycerides (TGs)) and CRP were reviewed and determined by univariate and multivariate Cox hazard models. Then, the AC score was proposed, which combines two independent risk factors (ApoA-1 and CRP). Results The optimal cut-off points in our study were determined according to established reference ranges. Patients with decreased ApoA-1 levels (

Rationale: Apolipoprotein A-1 (ApoA-1)-related amyloidosis is characterized by the deposition of ApoA-1 in various organs and can be either hereditary or nonhereditary. It is rare and easily misdiagnosed. Renal involvement is common in hereditary ApoA-1 amyloidosis, but rare in the nonhereditary form. Patient concerns: We reported two cases with ApoA-1 amyloidosis, a 64-year-old man suffering from nephrotic syndrome and a 40-year-old man with nephrotic syndrome and splenomegaly. Renal biopsies revealed glomerular, interstitial and vascular amyloid deposits and positive phospholipase A2 receptor staining in the glomerular capillary loop in case 1, and mesangial amyloid deposits in case 2. Diagnoses: After immunostaining failed to determine the specific amyloid protein, proteomic analysis of amyloid deposits by mass spectrometry was performed and demonstrated the ApoA-1 origin of the amyloid. Genetic testing revealed no mutation of the APOA1 gene in case 1 but a heterozygous mutation, Trp74Arg, in case 2. Case 1 was thus diagnosed as nonhereditary ApoA-1 associated renal amyloidosis with membranous nephropathy, and case 2 as hereditary ApoA-1 amyloidosis with multiorgan injuries (kidney and spleen) and a positive family history. Interventions: Case 1 was treated with glucocorticoid combined with cyclosporine. Case 2 was treated with calcitriol and angiotensin converting enzyme inhibitors. Outcomes: Two cases were followed up for 5 months and 2 years, respectively; and case 1 was found to have attenuated proteinuria while case 2 had an elevation of cholestasis indices along with renal insufficiency. Lessons: Proteomic analysis by mass spectrometry of the amyloid deposits combined with genetic analysis can provide accurate diagnosis of ApoA-1 amyloidosis. Besides, these 2 cases expand our knowledge of ApoA-1-related renal amyloidosis.

OBJECTIVE To investigate whether serum levels of high-density lipoprotein (HDL) and apolipoprotein A-1 (ApoA1), after the return of spontaneous circulation, can predict the neurologic outcome in patients with out-of-hospital cardiac arrest (OHCA). METHODS This was a retrospective observational study conducted in a single tertiary hospital intensive care unit. All adult OHCA survivors with admission lipid profiles were enrolled from March 2013 to December 2015. Good neurologic outcome was defined as discharge cerebral performance categories 1 and 2. RESULTS Among 59 patients enrolled, 13 (22.0%) had a good neurologic outcome. Serum levels of HDL (56.7 vs. 40 mg/dL) and ApoA1 (117 vs. 91.6 mg/dL) were significantly higher in patients with a good outcome. Areas under the HDL and ApoA1 receiver operating curves to predict good outcomes were 0.799 and 0.759, respectively. The proportion of good outcome was significantly higher in patients in higher tertiles of HDL and ApoA1 (test for trend, both P=0.003). HDL (P=0.018) was an independent predictor in the multivariate logistic regression model. CONCLUSION Admission levels of HDL and ApoA1 are associated with neurologic outcome in patients with OHCA. Prognostic and potential therapeutic values of HDL and ApoA1 merit further evaluation in the post-cardiac arrest state, as in other systemic inflammatory conditions such as sepsis.

Background/purpose:\ud One to three per cent of the world’s population has hepatitis C virus (HCV) infection, which is not only a major cause of liver disease and cancer but also associated with an increased risk of atherosclerosis, despite an ostensibly favourable lipid profile. Autoantibodies are frequent in HCV infection and emerging evidence shows that autoantibodies could be valuable for cardiovascular disease (CVD) risk stratification. This study investigated a novel independent biomarker of CVD, autoantibodies to apolipoprotein A-1 (anti-apoA-1 IgG) and lipids in patients with chronic HCV before, during and after direct-acting anti-viral (DAA) therapy.\ud \ud Methods:\ud Eighty-nine blinded serum samples from 27 patients with advanced chronic HCV were assayed for lipids and anti-apoA-1 IgG by ELISA.\ud \ud Results:\ud Pre-treatment HCV viral load correlated with high-density lipoprotein cholesterol (HDL-C, r = 0.417; p = 0.042) and negatively with apolipoprotein (apo)B (r = − 0.497; p = 0.013) and markers of CVD risk, the apoB/apoA-1 ratio (r = − 0.490; p = 0.015) and triglyceride level (TG)/HDL-C ratio (r = − 0.450; p = 0.031). Fourteen (52%) of 27 patients had detectable anti-apoA-1 IgG autoantibodies pre-treatment; only two became undetectable with virological cure. Autoantibody-positive sera had lower apoA-1 (p = 0.012), HDL-C (p = 0.009) and total cholesterol (p = 0.006) levels.\ud \ud Conclusions:\ud This is the first report of the presence of an emerging biomarker for atherosclerosis, anti-apoA-1 IgG, in some patients with HCV infection. It may be induced by apoA-1 on the surface of HCV lipoviral particles. The autoantibodies inversely correlate with apoA-1 and HDL levels and may render HDL dysfunctional. Whether these hypothesis-generating findings have clinical implications in HCV patients requires further study.

Transintestinal cholesterol efflux (TICE) has been proposed to represent a non-hepatobiliary route of cholesterol secretion directly “from blood to gut” and to play a physiologically significant role in excretion of neutral sterols, but so far little is known about the proteins involved in the process. We have previously observed that apolipoprotein A-1 (apoA-1) synthesized by enterocytes of the small intestine is mainly secreted apically into the gut lumen during fasting where its assembly into chylomicrons and basolateral discharge is at a minimal level. In the present work we showed, both by immunomicroscopy and subcellular fractionation, that a fraction of the apically secreted apoA-1 in porcine small intestine was not released from the cell surface but instead deposited in the brush border. Cholesterol was detected in immunoisolated microvillar apoA-1, and it was partially associated with detergent resistant membranes (DRMs), indicative of localization in lipid raft microdomains. The apolipoprotein was not readily released from microvillar vesicles by high salt or by incubation with phosphatidylcholine-specific phospholipase C or trypsin, indicating a relatively firm attachment to the membrane bilayer. However, whole bile or taurocholate efficiently released apoA-1 at low concentrations that did not solubilize the transmembrane microvillar protein aminopeptidase N. Based on these findings and the well known role played by apoA-1 in extrahepatic cellular cholesterol removal and reverse cholesterol transport (RCT), we propose that brush border-deposited apoA-1 in the small intestine acts in TICE by mediating cholesterol efflux into the gut lumen.

Background Idiopathic pulmonary fibrosis (IPF) is a progressive and lethal lung disease characterized by the accumulation of excessive fibroblasts and myofibroblasts in the extracellular matrix. The transforming growth factor β1 (TGF-β1)–induced epithelial-to-mesenchymal transition (EMT) is thought to be a possible source of fibroblasts/myofibroblasts in IPF lungs. We have previously reported that apolipoprotein A1 (ApoA1) has anti-fibrotic activity in experimental lung fibrosis. In this study, we determine whether ApoA1 modulates TGF-β1–induced EMT in experimental lung fibrosis and clarify its mechanism of action. Methods The A549 alveolar epithelial cell line was treated with TGF-β1 with or without ApoA1. Morphological changes and expression of EMT-related markers, including E-cadherin, N-cadherin, and α-smooth muscle actin were evaluated. Expressions of Smad and non-Smad mediators and TGF-β1 receptor type 1 (TβRI) and type 2 (TβRII) were measured. The silica-induced lung fibrosis model was established using ApoA1 overexpressing transgenic mice. Results TGF-β1–treated A549 cells were changed to the mesenchymal morphology with less E-cadherin and more N-cadherin expression. The addition of ApoA1 inhibited the TGF-β1–induced change of the EMT phenotype. ApoA1 inhibited the TGF-β1–induced increase in the phosphorylation of Smad2 and 3 as well as that of ERK and p38 mitogen-activated protein kinase mediators. In addition, ApoA1 reduced the TGF-β1–induced increase in TβRI and TβRII expression. In a mouse model of silica-induced lung fibrosis, ApoA1 overexpression reduced the silica-mediated effects, which were increased N-cadherin and decreased E-cadherin expression in the alveolar epithelium. Conclusion Our data demonstrate that ApoA1 inhibits TGF-β1–induced EMT in experimental lung fibrosis.

Identifying biomarkers that distinguish Parkinsons disease (PD) from normal control (NC) individuals has the potential to increase diagnostic sensitivity for the detection of early-stage PD. A previous proteomic study identified potential biomarkers in postmortem ventricular cerebrospinal fluid (V-CSF) from neuropathologically diagnosed PD subjects lacking Alzheimers disease (AD) neuropathology. In the present study, we assessed these biomarkers as well as p-tau(181), Aβ42, and S100B by ELISA in PD (n = 43) and NC (n = 49) cases. The p-tau(181)/Aβ42 ratio and ApoA-1 showed statistically significant differences between groups. Multiple regression analysis demonstrated that p-tau(181)/Aβ42 had a significant odds ratio: OR = 1.42 (95% confidence interval [CI], 1.12-1.84), P = 0.006. Among the molecules investigated, intriguing correlations were observed that require further investigation. Our results suggest coexistent AD CSF biomarkers within the PD group notwithstanding that it was selected to minimize AD neuropathological lesions.

The antioxidant property of plasma high-density lipoprotein (HDL) is thought to be involved in potential anti-atherogenic effects but the exact mechanism is not known. We aimed to reveal the contribution of HDL on the elimination of lipid hydroperoxides (LOOH) derived from oxidized low-density lipoprotein (LDL). Oxidized LDL prepared by copper ion-induced oxidation contained nonesterified fatty acid hydroperoxides (FFA-OOH) and lysophosphatidylcholine (lysoPtdCho), in addition to cholesteryl ester hydroperoxides (CE-OOH) and phosphatidylcholine hydroperoxides (PtdCho-OOH). A platelet-activating factor-acetylhydrolase (PAF-AH) inhibitor suppressed formation of FFA-OOH and lysoPtdCho in oxidized LDL. Among LOOH species, FFA-OOH was preferentially reduced by incubating oxidized LDL with HDL. HDL exhibited selective FFA-OOH reducing ability if it was mixed with a liposomal solution containing FFA-OOH, CE-OOH and PtdCho-OOH. Two-electron reduction of the hydroperoxy group to the hydroxy group was confirmed by the formation of 13-hydroxyoctadecadienoic acid from 13-hydroperoxyoctadecadienoic acid in HPLC analyses. This reducing effect was also found in apolipoprotein A-1 (apoA-1). FFA-OOH released from PtdCho-OOH due to PAF-AH activity in oxidized LDL undergo two-electron reduction by the reducing ability of apoA1 in HDL. This preferential reduction of FFA-OOH may participate in the mechanism of the antioxidant property of HDL.