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High-density lipoprotein function is associated with atherosclerotic burden and cardiovascular outcomes in type 2 diabetes.
Heier, M, Ofstad, AP, Borja, MS, Brunborg, C, Endresen, K, Gullestad, L, Birkeland, KI, Johansen, OE, Oda, MN
Atherosclerosis. 2019;:183-187
Abstract
BACKGROUND AND AIMS Measures of HDL function are emerging tools for assessing cardiovascular disease (CVD) event risk. HDL-apoA-I exchange (HAE) reflects HDL capacity for reverse cholesterol transport. METHODS HAE was measured in 93 participants with type 2 diabetes (T2D) and at least one additional CVD risk factor in the Asker and Bærum Cardiovascular Diabetes study. At baseline and after seven years, the atherosclerotic burden was assessed by invasive coronary angiography. Major CVD events were registered throughout the study. RESULTS Linear regression analysis demonstrated a significant inverse association between HAE and atherosclerotic burden. Cox proportional hazard regression analysis showed a significant association between HAE and a composite of major CVD events when controlling for waist-hip ratio, HR = 0.89, 95% CI = 0.80-1.00 and p=0.040. CONCLUSIONS Despite the relatively small size of the study population and the limited number of CVD events, these findings suggest that HAE provides valuable information in determining CVD risk.
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Emerging roles for high-density lipoproteins in neurodegenerative disorders.
Bahrami, A, Barreto, GE, Lombardi, G, Pirro, M, Sahebkar, A
BioFactors (Oxford, England). 2019;(5):725-739
Abstract
Lipoproteins are the complexes of different lipids and proteins, which are devoted to the transport and clearance of lipids or lipid-related molecules in the circulation. Lipoproteins have been found to play a crucial role in brain function and may influence myelination process. Among lipoproteins, high-density lipoproteins (HDLs) and their major protein component, apoA-I, are directly involved in cholesterol efflux in the brain. It has been suggested that inadequate or dysfunctional brain HDLs may contribute to cerebrovascular dysfunctions, neurodegeneration, or neurovascular instability. HDL deficiency could also promote cognitive decline through impacting on atherosclerotic risk. The focus of this review is to discuss knowledge on HDL dysregulation in neurological disorders. A better understanding on how changes in cellular HDL and apolipoprotein homeostasis affect central nervous system function may provide promising novel avenues for the treatment of specific HDL-related neurological disorders.
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Low high-density lipoprotein and psychopathology: A review.
Douglas, J, Nasrallah, HA
Annals of clinical psychiatry : official journal of the American Academy of Clinical Psychiatrists. 2019;(3):209-213
Abstract
BACKGROUND An association between the level of total cholesterol and psychopathology has been the focus of numerous studies. Low total cholesterol has been found to be related to depression, personality disorders, and dissociative disorder. High cholesterol has been associated with schizophrenia, obsessive-compulsive disorder (OCD), panic disorder, generalized anxiety disorder, and posttraumatic stress disorder. However, no reviews of the psychiatric correlates of high-density lipoprotein (HDL) have been published. We reviewed the literature for studies reporting a significant association between low or high levels of HDL and psychopathology. METHODS A search of major databases (PubMed and CINAHL) was conducted using the following keywords: HDL, depression, anxiety, schizophrenia, OCD, and psychiatric disorders. RESULTS Eight studies met our search criteria. Six of the 8 studies reported significantly higher rates of depression, anxiety, suicide attempts, and violent behaviors in participants with low HDL. CONCLUSIONS Overall, a low HDL may not only be associated with risk for cardiac disease, but also with increased risk for serious psychiatric disorders. Further controlled studies are warranted.
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Humoral Immunity Against HDL Particle: A New Perspective in Cardiovascular Diseases?
Satta, N, Frias, MA, Vuilleumier, N, Pagano, S
Current pharmaceutical design. 2019;(29):3128-3146
Abstract
BACKGROUND Autoimmune diseases are closely associated with cardiovascular diseases (CVD). Over the last decades, the comprehension of atherosclerosis, the principal initiator of CVD, evolved from a lipidcentered disease to a predominant inflammatory and immune response-driven disease displaying features of autoimmunity against a broad range of auto-antigens, including lipoproteins. Among them, high density lipoproteins (HDL) are important actors of cholesterol transport and bear several anti-atherogenic properties, raising a growing interest as therapeutic targets to decrease atherosclerosis and CVD burden, with nevertheless rather disappointing results so far. Reflecting HDL composition complexity, autoimmune responses and autoantibodies against various HDL components have been reported. RESULTS In this review, we addressed the important complexity of humoral autoimmunity towards HDL and particularly how this autoimmune response could help improving our understanding of HDL biological implication in atherosclerosis and CVD. We also discussed several issues related to specific HDL autoantibody subclasses characteristics, including etiology, prognosis and pathological mechanisms according to Rose criteria. CONCLUSION Finally, we addressed the possible clinical value of using these antibodies not only as potential biomarkers of atherogenesis and CVD, but also as a factor potentially mitigating the benefit of HDL-raising therapies.
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The effects of cigarette smoking and smoking cessation on high-density lipoprotein functions: implications for coronary artery disease.
Chen, HY, Li, SC, Chen, LF, Wang, W, Wang, Y, Yan, XW
Annals of clinical biochemistry. 2019;(1):100-111
Abstract
BACKGROUND Smoking cessation was associated with improved prognosis of coronary artery disease. This study was designed to investigate the effect of smoking cessation on high-density lipoprotein functionality in coronary artery disease patients. METHODS In this prospective, randomized and parallel controlled study, coronary artery disease smokers ( n = 28) and healthy smokers ( n = 30) were divided into smoking cessation group and continuous smoking group, respectively. Blood samples were collected before and after three-month smoking cessation. Plasma high-density lipoprotein was isolated by density gradient centrifugation. The ability of high-density lipoprotein against copper-induced oxidation of lipoprotein was determined to evaluate the antioxidative property of high-density lipoprotein, and the macrophage migration inhibited by high-density lipoprotein was tested to identify the antichemotactic property of high-density lipoprotein. High-density lipoprotein-induced macrophage cholesterol efflux was measured by fluorescence spectrometry using NBD cholesterol analogue. Healthy non-smoking volunteers were enrolled as the baseline control. RESULTS The baseline antioxidative, antichemotactic ability of high-density lipoprotein and high-density lipoprotein-induced cellular cholesterol efflux in coronary artery disease smokers and healthy smokers were significantly attenuated when compared with those in healthy non-smokers. After three-month smoking cessation, both the antioxidative ability and antichemotactic ability of high-density lipoprotein were improved significantly in coronary artery disease smokers. However, high-density lipoprotein-induced cellular cholesterol efflux was not increased by smoking cessation. In in vitro experiments, carbon monoxide reduced the antioxidative ability and nicotine enhanced the antichemotactic ability of high-density lipoprotein. CONCLUSIONS Smoking cessation is an effective measure to improve high-density lipoprotein functions in coronary artery disease smokers. Our study re-emphasizes the importance of smoking cessation in the secondary prevention of coronary artery disease.
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Site-Specific Glycoprofiles of HDL-Associated ApoE are Correlated with HDL Functional Capacity and Unaffected by Short-Term Diet.
Zhu, C, Wong, M, Li, Q, Sawrey-Kubicek, L, Beals, E, Rhodes, CH, Sacchi, R, Lebrilla, CB, Zivkovic, AM
Journal of proteome research. 2019;(11):3977-3984
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Abstract
Since high-density lipoprotein (HDL) glycoprofiles are associated with HDL functional capacity, we set out to determine whether diet can alter the glycoprofiles of key HDL-associated proteins, including ApoE, a potent driver of chronic disease risk. Ten healthy subjects consumed a fast food (FF) and a Mediterranean (Med) diet for 4 days in randomized order, with a 4-day wash-out between treatments. A multiple reaction monitoring method was used to characterize the site-specific glycoprofiles of HDL proteins, and HDL functional capacity was analyzed. We describe for the first time that ApoE has 7 mucin-type O-glycosylation sites, which were not affected by short-term diet. The glycoprofiles of other HDL-associated proteins were also unaffected, except that a disialylated ApoC-III glycan was enriched after Med diet, and a nonsialylated ApoC-III glycan was enriched after FF diet. Twenty-five individual glycopeptides were significantly correlated with cholesterol efflux capacity and 21 glycopeptides were correlated with immunomodulatory capacity. Results from this study indicate that the glycoprofiles of HDL-associated proteins including ApoE are correlated with HDL functional capacity but generally unaffected by diet in the short term, except ApoC-III sialylation. These results suggest that HDL protein glycoprofiles are affected by both acute and long-term factors and may be useful for biomarker discovery.
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Dysfunctional HDL as a Therapeutic Target for Atherosclerosis Prevention.
Ossoli, A, Pavanello, C, Giorgio, E, Calabresi, L, Gomaraschi, M
Current medicinal chemistry. 2019;(9):1610-1630
Abstract
Hypercholesterolemia is one of the main risk factors for the development of atherosclerosis. Among the various lipoprotein classes, however, high density lipoproteins (HDL) are inversely associated with the incidence of atherosclerosis, since they are able to exert a series of atheroprotective functions. The central role of HDL within the reverse cholesterol transport, their antioxidant and anti-inflammatory properties and their ability to preserve endothelial homeostasis are likely responsible for HDL-mediated atheroprotection. However, drugs that effectively raise HDL-C failed to result in a decreased incidence of cardiovascular event, suggesting that plasma levels of HDL-C and HDL function are not always related. Several evidences are showing that different pathologic conditions, especially those associated with an inflammatory response, can cause dramatic alterations of HDL protein and lipid cargo resulting in HDL dysfunction. Established and investigational drugs designed to affect lipid metabolism and to increase HDL-C are only partly effective in correcting HDL dysfunction.
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Reduced plasma levels of small HDL particles transporting fibrinolytic proteins in pulmonary arterial hypertension.
Harbaum, L, Ghataorhe, P, Wharton, J, Jiménez, B, Howard, LSG, Gibbs, JSR, Nicholson, JK, Rhodes, CJ, Wilkins, MR
Thorax. 2019;(4):380-389
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Abstract
BACKGROUND Aberrant lipoprotein metabolism has been implicated in experimental pulmonary hypertension, but the relevance to patients with pulmonary arterial hypertension (PAH) is inconclusive. OBJECTIVE To investigate the relationship between circulating lipoprotein subclasses and survival in patients with PAH. METHODS Using nuclear magnetic resonance spectroscopy, 105 discrete lipoproteins were measured in plasma samples from two cohorts of patients with idiopathic or heritable PAH. Data from 1124 plasma proteins were used to identify proteins linked to lipoprotein subclasses. The physical presence of proteins was confirmed in plasma lipoprotein subfractions separated by ultracentrifugation. RESULTS Plasma levels of three lipoproteins from the small high-density lipoprotein (HDL) subclass, termed HDL-4, were inversely related to survival in both the discovery (n=127) and validation (n=77) cohorts, independent of exercise capacity, comorbidities, treatment, N-terminal probrain natriuretic peptide, C reactive protein and the principal lipoprotein classes. The small HDL subclass rich in apolipoprotein A-2 content (HDL-4-Apo A-2) exhibited the most significant association with survival. None of the other lipoprotein classes, including principal lipoprotein classes HDL and low-density lipoprotein cholesterol, were prognostic. Three out of nine proteins identified to associate with HDL-4-Apo A-2 are involved in the regulation of fibrinolysis, namely, the plasmin regulator, alpha-2-antiplasmin, and two major components of the kallikrein-kinin pathway (coagulation factor XI and prekallikrein), and their physical presence in the HDL-4 subfraction was confirmed. CONCLUSION Reduced plasma levels of small HDL particles transporting fibrinolytic proteins are associated with poor outcomes in patients with idiopathic and heritable PAH.
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Weight loss achieved by bariatric surgery modifies high-density lipoprotein subfractions and low-density lipoprotein oxidation towards atheroprotection.
Coimbra, S, Reis, F, Ferreira, C, Nunes, S, Viana, S, Catarino, A, Rocha-Pereira, P, Belo, L, Monteiro, L, Catarino, C, et al
Clinical biochemistry. 2019;:46-53
Abstract
OBJECTIVES Weight loss achieved by laparoscopic adjustable gastric banding (LAGB) induces an increase in high-density lipoprotein cholesterol (HDLc) but a small effect on low-density lipoprotein (LDL), although changes in their quality (size and composition) are uncertain. Our aim was to study the impact of weight loss, achieved 13-months after LAGB, on inflammation and dyslipidemia, focusing on HDL and LDL subfractions, and oxidized LDL (oxLDL). DESIGN & METHODS We evaluated standard lipid profile, HDL and LDL subfractions, oxLDL, interleukin (IL)-6 and C-reactive protein (CRP), in twenty obese patients, before (T0) and 13-months after LAGB (T1), and in seventeen healthy controls. RESULTS At T1, patients showed lower body weight (12% median weight loss) and anthropometric indices; reduction in TG, atherogenic indices, oxLDL, oxLDL/LDL ratio, CRP and IL-6, and enhancement in HDLc; an increase in large HDL and intermediate HDL subfractions, and a decrease in small HDL subfraction; LDL subfractions were not modified. Percentual change (%Δ) of oxLDL, from T0 to T1, correlated significantly and positively with %Δ of small HDL subfraction and with %Δ of body mass index. CONCLUSIONS Weight loss induced atheroprotective changes on inflammation, and lipid profile, enhancing larger HDL, the more atheroprotective subfraction, reducing the less protective subclass, small HDL, and reducing oxLDL and oxLDL/LDL ratio. Quality of lipoproteins appears useful cardiovascular risk biomarkers, deserving further studies.
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Large-scale plasma metabolome analysis reveals alterations in HDL metabolism in migraine.
Onderwater, GLJ, Ligthart, L, Bot, M, Demirkan, A, Fu, J, van der Kallen, CJH, Vijfhuizen, LS, Pool, R, Liu, J, Vanmolkot, FHM, et al
Neurology. 2019;(16):e1899-e1911
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Abstract
OBJECTIVE To identify a plasma metabolomic biomarker signature for migraine. METHODS Plasma samples from 8 Dutch cohorts (n = 10,153: 2,800 migraine patients and 7,353 controls) were profiled on a 1H-NMR-based metabolomics platform, to quantify 146 individual metabolites (e.g., lipids, fatty acids, and lipoproteins) and 79 metabolite ratios. Metabolite measures associated with migraine were obtained after single-metabolite logistic regression combined with a random-effects meta-analysis performed in a nonstratified and sex-stratified manner. Next, a global test analysis was performed to identify sets of related metabolites associated with migraine. The Holm procedure was applied to control the family-wise error rate at 5% in single-metabolite and global test analyses. RESULTS Decreases in the level of apolipoprotein A1 (β -0.10; 95% confidence interval [CI] -0.16, -0.05; adjusted p = 0.029) and free cholesterol to total lipid ratio present in small high-density lipoprotein subspecies (HDL) (β -0.10; 95% CI -0.15, -0.05; adjusted p = 0.029) were associated with migraine status. In addition, only in male participants, a decreased level of omega-3 fatty acids (β -0.24; 95% CI -0.36, -0.12; adjusted p = 0.033) was associated with migraine. Global test analysis further supported that HDL traits (but not other lipoproteins) were associated with migraine status. CONCLUSIONS Metabolic profiling of plasma yielded alterations in HDL metabolism in migraine patients and decreased omega-3 fatty acids only in male migraineurs.