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1.
J Lipid Res ; 64(6): 100381, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-37100172

RESUMO

Patients with chronic kidney disease (CKD) are at high risk for CVD. However, traditional CVD risk factors cannot completely explain the increased risk. Altered HDL proteome is linked with incident CVD in CKD patients, but it is unclear whether other HDL metrics are associated with incident CVD in this population. In the current study, we analyzed samples from two independent prospective case-control cohorts of CKD patients, the Clinical Phenotyping and Resource Biobank Core (CPROBE) and the Chronic Renal Insufficiency Cohort (CRIC). We measured HDL particle sizes and concentrations (HDL-P) by calibrated ion mobility analysis and HDL cholesterol efflux capacity (CEC) by cAMP-stimulated J774 macrophages in 92 subjects from the CPROBE cohort (46 CVD and 46 controls) and in 91 subjects from the CRIC cohort (34 CVD and 57 controls). We tested associations of HDL metrics with incident CVD using logistic regression analysis. No significant associations were found for HDL-C or HDL-CEC in either cohort. Total HDL-P was only negatively associated with incident CVD in the CRIC cohort in unadjusted analysis. Among the six sized HDL subspecies, only medium-sized HDL-P was significantly and negatively associated with incident CVD in both cohorts after adjusting for clinical confounders and lipid risk factors with odds ratios (per 1-SD) of 0.45 (0.22-0.93, P = 0.032) and 0.42 (0.20-0.87, P = 0.019) for CPROBE and CRIC cohorts, respectively. Our observations indicate that medium-sized HDL-P-but not other-sized HDL-P or total HDL-P, HDL-C, or HDL-CEC-may be a prognostic cardiovascular risk marker in CKD.


Assuntos
Doenças Cardiovasculares , Insuficiência Renal Crônica , Humanos , Insuficiência Renal Crônica/complicações , HDL-Colesterol , Fatores de Risco , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/etiologia
2.
J Lipid Res ; 62: 100135, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34634315

RESUMO

Patients with chronic kidney disease (CKD) are at high risk for CVD. However, traditional lipid risk factors, including low HDL levels, cannot completely explain the increased risk. Altered HDL proteome is linked with both CVD and CKD, but the role of HDL proteins in incident CVD events in patients with CKD is unknown. In this prospective case-control study, we used targeted proteomics to quantify 31 HDL proteins in 92 subjects (46 incident new CVD and 46 one-to-one matched controls) at various stages of CKD. We tested associations of HDL proteins with incident CVD using matched logistic regression analysis. In the model fully adjusted for clinical confounders, lipid levels, C-reactive protein, and proteinuria, no significant associations were found for HDL-C, but we observed inverse associations between levels of HDL proteins paraoxonase/arylesterase 1 (PON1), paraoxonase/arylesterase 3 (PON3), and LCAT and incident CVD. Odds ratios (per 1 SD) were 0.38 (0.18-0.97, P = 0.042), 0.42 (0.20-0.92, P = 0.031), and 0.30 (0.11-0.83, P = 0.020) for PON1, PON3, and LCAT, respectively. Apolipoprotein A-IV remained associated with incident CVD in CKD patients in models adjusted for clinical confounders and lipid levels but lost significance with the addition of C-reactive protein and proteinuria to the model. In conclusion, levels of four HDL proteins, PON1, PON3, LCAT, and apolipoprotein A-IV, were found to be inversely associated with incident CVD events in CKD patients. Our observations indicate that HDLs' protein cargo, but not HDL-C levels, can serve as a marker-and perhaps mediator-for elevated CVD risk in CKD patients.


Assuntos
Doenças Cardiovasculares/metabolismo , Lipoproteínas HDL/metabolismo , Insuficiência Renal Crônica/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Apolipoproteínas A/metabolismo , Arildialquilfosfatase/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fosfatidilcolina-Esterol O-Aciltransferase/metabolismo , Análise de Regressão
3.
J Lipid Res ; 62: 100099, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34324889

RESUMO

Human high-density lipoproteins (HDLs) are a complex mixture of structurally related nanoparticles that perform distinct physiological functions. We previously showed that human HDL containing apolipoprotein A-I (APOA1) but not apolipoprotein A-II (APOA2), designated LpA-I, is composed primarily of two discretely sized populations. Here, we isolated these particles directly from human plasma by antibody affinity chromatography, separated them by high-resolution size-exclusion chromatography and performed a deep molecular characterization of each species. The large and small LpA-I populations were spherical with mean diameters of 109 Å and 91 Å, respectively. Unexpectedly, isotope dilution MS/MS with [15N]-APOA1 in concert with quantitation of particle concentration by calibrated ion mobility analysis demonstrated that the large particles contained fewer APOA1 molecules than the small particles; the stoichiometries were 3.0 and 3.7 molecules of APOA1 per particle, respectively. MS/MS experiments showed that the protein cargo of large LpA-I particles was more diverse. Human HDL and isolated particles containing both APOA1 and APOA2 exhibit a much wider range and variation of particle sizes than LpA-I, indicating that APOA2 is likely the major contributor to HDL size heterogeneity. We propose a ratchet model based on the trefoil structure of APOA1 whereby the helical cage maintaining particle structure has two "settings"-large and small-that accounts for these findings. This understanding of the determinants of HDL particle size and protein cargo distribution serves as a basis for determining the roles of HDL subpopulations in metabolism and disease states.


Assuntos
Apolipoproteína A-II/química , Apolipoproteína A-I/química , HDL-Colesterol/química , Tamanho da Partícula
4.
J Clin Invest ; 131(22)2021 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-34491909

RESUMO

Loss-of-function mutations in the transcription factor CREB3L3 (CREBH) associate with severe hypertriglyceridemia in humans. CREBH is believed to lower plasma triglycerides by augmenting the activity of lipoprotein lipase (LPL). However, by using a mouse model of type 1 diabetes mellitus (T1DM), we found that greater liver expression of active CREBH normalized both elevated plasma triglycerides and cholesterol. Residual triglyceride-rich lipoprotein (TRL) remnants were enriched in apolipoprotein E (APOE) and impoverished in APOC3, an apolipoprotein composition indicative of increased hepatic clearance. The underlying mechanism was independent of LPL, as CREBH reduced both triglycerides and cholesterol in LPL-deficient mice. Instead, APOE was critical for CREBH's ability to lower circulating remnant lipoproteins because it failed to reduce TRL cholesterol in Apoe-/- mice. Importantly, individuals with CREB3L3 loss-of-function mutations exhibited increased levels of remnant lipoproteins that were deprived of APOE. Recent evidence suggests that impaired clearance of TRL remnants promotes cardiovascular disease in patients with T1DM. Consistently, we found that hepatic expression of CREBH prevented the progression of diabetes-accelerated atherosclerosis. Our results support the proposal that CREBH acts through an APOE-dependent pathway to increase hepatic clearance of remnant lipoproteins. They also implicate elevated levels of remnants in the pathogenesis of atherosclerosis in T1DM.


Assuntos
Aterosclerose/prevenção & controle , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/fisiologia , Diabetes Mellitus Tipo 1/complicações , Dislipidemias/prevenção & controle , Lipoproteínas/sangue , Triglicerídeos/sangue , Animais , Apolipoproteína C-III/sangue , Apolipoproteínas E/sangue , Aterosclerose/etiologia , Remanescentes de Quilomícrons/sangue , Dislipidemias/etiologia , Humanos , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL
5.
Mol Pharmacol ; 67(5): 1505-12, 2005 May.
Artigo em Inglês | MEDLINE | ID: mdl-15705743

RESUMO

Anthracycline therapy is associated with a life-threatening but poorly understood cardiotoxicity. Effects of treatment are consistent with drug-induced disruption of cardiac sarcoplasmic reticulum (SR) calcium homeostasis, including inhibition of calcium release by anthracyclines. This effect, which depends on luminal SR calcium concentration, is hypothesized to involve interactions of anthracyclines with the calcium binding protein calsequestrin (CSQ). This study was designed to test the hypothesis that an interaction between CSQ and anthracyclines could be related to alterations in SR calcium release and cardiac function. The effects of the anthracycline, daunorubicin, and its metabolite daunorubicinol were compared with those of a known CSQ inhibitor, trifluoperazine (TFP). Protein fluorescence quenching studies demonstrated that TFP, daunorubicin, and daunorubicinol bind to CSQ with apparent binding affinities in the low micromolar range. The presence of calcium decreases the drug-dependent fluorescence quenching, probably because of calcium-induced CSQ conformational changes. TFP also inhibited SR calcium release. Although the TFP IC50 value is somewhat larger than for anthracyclines, the TFP effect is also dependent on luminal SR calcium concentration. In a muscle preparation, micromolar TFP decreased cardiac contractility in a manner that implicates the involvement of SR calcium and resembles the effects of anthracyclines. These data are consistent with a mechanism in which TFP or anthracyclines impair SR calcium release and cardiac function through a mechanism involving disruption of CSQ function. Such a mechanism may contribute to anthracycline cardiotoxicity.


Assuntos
Calsequestrina/metabolismo , Daunorrubicina/análogos & derivados , Daunorrubicina/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Trifluoperazina/administração & dosagem , Animais , Antraciclinas/administração & dosagem , Antraciclinas/química , Antraciclinas/metabolismo , Daunorrubicina/química , Daunorrubicina/metabolismo , Cães , Relação Dose-Resposta a Droga , Contração Miocárdica/efeitos dos fármacos , Contração Miocárdica/fisiologia , Coelhos , Trifluoperazina/química , Trifluoperazina/metabolismo
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