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Article: Expanding the Molecular Disturbances of Lipoproteins in Cardiometabolic Diseases: Lessons from Lipidomics.

Kostara, Christina E

2023 Volume 13, Issue 4

Abstract: The increasing global burden of cardiometabolic diseases highlights the urgent clinical need for better personalized prediction and intervention strategies. Early diagnosis and prevention could greatly reduce the enormous socio-economic burden posed by ... ...

Abstract	The increasing global burden of cardiometabolic diseases highlights the urgent clinical need for better personalized prediction and intervention strategies. Early diagnosis and prevention could greatly reduce the enormous socio-economic burden posed by these states. Plasma lipids including total cholesterol, triglycerides, HDL-C, and LDL-C have been at the center stage of the prediction and prevention strategies for cardiovascular disease; however, the bulk of cardiovascular disease events cannot be explained sufficiently by these lipid parameters. The shift from traditional serum lipid measurements that are poorly descriptive of the total serum lipidomic profile to comprehensive lipid profiling is an urgent need, since a wealth of metabolic information is currently underutilized in the clinical setting. The tremendous advances in the field of lipidomics in the last two decades has facilitated the research efforts to unravel the lipid dysregulation in cardiometabolic diseases, enabling the understanding of the underlying pathophysiological mechanisms and identification of predictive biomarkers beyond traditional lipids. This review presents an overview of the application of lipidomics in the study of serum lipoproteins in cardiometabolic diseases. Integrating the emerging multiomics with lipidomics holds great potential in moving toward this goal.
Language	English
Publishing date	2023-02-15
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2662336-5
ISSN	2075-4418
ISSN	2075-4418
DOI	10.3390/diagnostics13040721
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Article ; Online: Effect of Clinical and Laboratory Parameters on HDL Particle Composition.

Kostara, Christina E / Bairaktari, Eleni T / Tsimihodimos, Vasilis

International journal of molecular sciences

2023 Volume 24, Issue 3

Abstract: The functional status of High-Density Lipoprotein (HDLs) is not dependent on the cholesterol content but is closely related to structural and compositional characteristics. We reported the analysis of HDL lipidome in the healthy population and the ... ...

Abstract	The functional status of High-Density Lipoprotein (HDLs) is not dependent on the cholesterol content but is closely related to structural and compositional characteristics. We reported the analysis of HDL lipidome in the healthy population and the influence of serum lipids, age, gender and menopausal status on its composition. Our sample comprised 90 healthy subjects aged between 30 and 77 years. HDL lipidome was investigated by Nuclear Magnetic Resonance (NMR) spectroscopy. Among serum lipids, triglycerides, apoAI, apoB and the ratio HDL-C/apoAI had a significant influence on HDL lipid composition. Aging was associated with significant aberrations, including an increase in triglyceride content, lysophosphatidylcholine, free cholesterol, and a decrease in esterified cholesterol, phospholipids, and sphingomyelin that may contribute to increased cardiovascular risk. Aging was also associated with an atherogenic fatty acid pattern. Changes occurring in the HDL lipidome between the two genders were more pronounced in the decade from 30 to 39 years of age and over 60 years. The postmenopausal group displayed significant pro-atherogenic changes in HDLs compared to the premenopausal group. The influence of serum lipids and intrinsic factors on HDL lipidome could improve our understanding of the remodeling capacity of HDLs directly related to its functionality and antiatherogenic properties, and also in appropriate clinical research study protocol design. These data demonstrate that NMR analysis can easily follow the subtle alterations of lipoprotein composition due to serum lipid parameters.
MeSH term(s)	Humans ; Male ; Female ; Adult ; Middle Aged ; Aged ; Lipoproteins, HDL ; Triglycerides ; Cholesterol ; Phospholipids ; Lipoproteins ; Cholesterol, HDL
Chemical Substances	Lipoproteins, HDL ; Triglycerides ; Cholesterol (97C5T2UQ7J) ; Phospholipids ; Lipoproteins ; Cholesterol, HDL
Language	English
Publishing date	2023-01-19
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms24031995
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Article: The effect of rosuvastatin alone or in combination with fenofibrate or omega-3 fatty acids on lipoprotein(a) levels in patients with mixed hyperlipidemia.

Agouridis, Aris P / Filippatos, Theodosios D / Kostapanos, Michael / Kostara, Christina / Tsimihodimos, Vasilis

Archives of medical sciences. Atherosclerotic diseases

2024 Volume 9, Page(s) e26–e32

Abstract: Introduction: Lipoprotein(a) [Lp(a)] is a strong, genetically determined, pathogenetic factor of atherosclerotic cardiovascular disease (ASCVD). The aim of this post-hoc analysis was to compare the effect of hypolipidemic treatment on Lp(a) levels of ... ...

Abstract	Introduction: Lipoprotein(a) [Lp(a)] is a strong, genetically determined, pathogenetic factor of atherosclerotic cardiovascular disease (ASCVD). The aim of this post-hoc analysis was to compare the effect of hypolipidemic treatment on Lp(a) levels of patients with mixed hyperlipidemia. Material and methods: We previously randomized patients with mixed hyperlipidemia (low-density lipoprotein [LDL-C] > 160 mg/dl and triglycerides > 200 mg/dl) to rosuvastatin monotherapy 40 mg/day (R group, Results: Significant reductions in total cholesterol, LDL-C, non-high-density lipoprotein-cholesterol (non-HDL-C) and triglyceride levels were observed in all groups. A significant increase in Lp(a) levels was noted in the R ( Conclusions: Rosuvastatin and/or fenofibrate treatment increases Lp(a) levels in patients with mixed hyperlipidemia. Novel therapies should target Lp(a) level reduction to decrease the residual ASCVD risk in patients with mixed hyperlipidemia.
Language	English
Publishing date	2024-02-19
Publishing country	Poland
Document type	Journal Article
ISSN	2451-0629
ISSN	2451-0629
DOI	10.5114/amsad/178441
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Article ; Online: Effect of fixed-dose combination of insulin degludec and liraglutide on apoB-containing lipoprotein subclasses and HDL lipidome in type 2 diabetes.

Pappa, Eleni / Kostara, Christina / Bairaktari, Eleni / Arvaniti, Eleni / Tsimihodimos, Vasilis

Journal of diabetes and its complications

2022 Volume 36, Issue 10, Page(s) 108286

Abstract: Aims: Administration of insulin degludec and liraglutide (IDegLira) correlates to fasting lipid profile changes of diabetic patients, while data concerning apoB-containing lipoprotein subclasses and HDL lipidome are scarce. We evaluated its effect on ... ...

Abstract	Aims: Administration of insulin degludec and liraglutide (IDegLira) correlates to fasting lipid profile changes of diabetic patients, while data concerning apoB-containing lipoprotein subclasses and HDL lipidome are scarce. We evaluated its effect on fasting lipid parameters, apolipoproteins, apoB-containing lipoprotein subclasses and HDL lipidome in patients with type 2 diabetes. Methods: Sixty three patients with HbA1c > 7 % on oral glucose-lowering drugs received either IDegLira or insulin degludec for 3 months. Lipoprotein subfraction profile was determined through Lipoprint method, whereas HDL lipid composition via Results: Compared to insulin degludec, IDegLira administration resulted in significantly greater reduction of total and LDL-cholesterol. On the other hand, the effect of the two drugs on apolipoprotein-B-containing lipoprotein subfractions concentration was minimal and did not differ between the 2 interventions. IDegLira, but not insulin degludec, induced an atheroprotective shift in HDL's fatty acid composition and particle core depletion in triglycerides. Conclusions: IDegLira administration is accompanied by total and LDL-cholesterol reduction, while sdLDL concentration only reduced in patients experiencing triglyceride reduction. IDegLira induced compositional changes of HDL particles. These changes may contribute to the cardioprotective properties of liraglutide.
MeSH term(s)	Apolipoproteins B ; Blood Glucose ; Cholesterol, LDL ; Diabetes Mellitus, Type 2/drug therapy ; Fatty Acids ; Glucose ; Glycated Hemoglobin A/analysis ; Humans ; Hypoglycemic Agents/therapeutic use ; Insulin, Long-Acting ; Lipidomics ; Lipoproteins ; Liraglutide/adverse effects ; Triglycerides
Chemical Substances	Apolipoproteins B ; Blood Glucose ; Cholesterol, LDL ; Fatty Acids ; Glycated Hemoglobin A ; Hypoglycemic Agents ; Insulin, Long-Acting ; Lipoproteins ; Triglycerides ; insulin degludec (54Q18076QB) ; Liraglutide (839I73S42A) ; Glucose (IY9XDZ35W2)
Language	English
Publishing date	2022-08-18
Publishing country	United States
Document type	Journal Article
ZDB-ID	1105840-7
ISSN	1873-460X ; 1056-8727
ISSN (online)	1873-460X
ISSN	1056-8727
DOI	10.1016/j.jdiacomp.2022.108286
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Article ; Online: NMR-based metabolomic signature: An important tool for the diagnosis and study of pathogenesis of autoimmune hepatitis.

Dimou, Aikaterini / Zachou, Kalliopi / Kostara, Christina / Azariadis, Kalliopi / Giannoulis, George / Lyberopoulou, Aggeliki / Bairaktari, Eleni / Dalekos, George N

Hepatology (Baltimore, Md.)

2024

Abstract: Background and aims: Metabolomics is used to predict, diagnose, and monitor metabolic disorders but altered metabolomic signatures have also been reported in diverse diseases, including autoimmune disorders. However, the metabolomic profile in ... ...

Abstract	Background and aims: Metabolomics is used to predict, diagnose, and monitor metabolic disorders but altered metabolomic signatures have also been reported in diverse diseases, including autoimmune disorders. However, the metabolomic profile in autoimmune hepatitis (AIH) has not been investigated in depth. Therefore, we investigated the metabolomic signature of AIH and its significance as a diagnostic and pathogenetic tool. Approach and results: Metabolites in plasma samples from 50 patients with AIH at diagnosis, 43 healthy controls, 72 patients with primary biliary cholangitis (PBC), 26 patients with metabolic dysfunction-associated liver disease, and 101 patients with chronic viral hepatitis were determined by 1 H NMR (nuclear magnetic resonance) spectroscopy. Fifty-two metabolites were quantified, and metabolic pathway analysis was performed. Multivariate analysis revealed that AIH could be differentiated from healthy controls and each of the disease controls ( p <0.001). Fifteen metabolites differentiated AIH from disease controls (PBC+chronic viral hepatitis+metabolic dysfunction-associated liver disease) (95% sensitivity and 92% specificity). Ten distinct metabolic pathways were altered in AIH compared to disease controls. The metabolic pathway of branched-chain amino acids (lower valine, leucine, and isoleucine levels and their catabolic intermediates in PBC), methionine (lower methionine, 2-aminobutyrate, and 2-hydroxybutyrate levels in PBC), alanine-aspartate-glutamate (lower metabolites in PBC), and that of metabolites associated with gut microbiota (lower choline, betaine, and dimethylamine levels in PBC) were significantly different between AIH and PBC ( p <0.01). Conclusions: 1 H NMR spectroscopy could be a promising novel tool to diagnose and study AIH pathogenesis as there is no need for much sample handling, is highly reproducible with high sensitivity and specificity, and low cost.
Language	English
Publishing date	2024-02-05
Publishing country	United States
Document type	Journal Article
ZDB-ID	604603-4
ISSN	1527-3350 ; 0270-9139
ISSN (online)	1527-3350
ISSN	0270-9139
DOI	10.1097/HEP.0000000000000767
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Article ; Online: Insulin resistance and cardiovascular disease.

Kosmas, Constantine E / Bousvarou, Maria D / Kostara, Christina E / Papakonstantinou, Evangelia J / Salamou, Evdokia / Guzman, Eliscer

The Journal of international medical research

2023 Volume 51, Issue 3, Page(s) 3000605231164548

Abstract: Insulin resistance (IR) and cardiovascular disease (CVD) represent two universal public health hazards, especially in today's Western societies. A causal-effect relationship has been established that links IR with CVD. The mediating mechanisms are ... ...

Abstract	Insulin resistance (IR) and cardiovascular disease (CVD) represent two universal public health hazards, especially in today's Western societies. A causal-effect relationship has been established that links IR with CVD. The mediating mechanisms are perplexing, under ongoing, rigorous investigation and remain to be fully elucidated. IR is a condition encompassing hyperglycemia and compensatory hyperinsulinemia. It occurs when insulin is not capable of exerting its maximum effects on target tissues, including skeletal muscles, liver and adipose tissue. This alteration of insulin signaling pathways results in the development of cardiometabolic disorders, including obesity, dyslipidemia, low-grade inflammation, endothelial dysfunction and hypertension, all of which are predisposing factors for atherosclerosis and CVD. The management of IR can be achieved through dietary modifications, the inclusion of regular exercise routines in everyday life, pharmacological agents and other interventions tailored to each individual patient's needs. It is important to underline though that, although various antidiabetic drugs that may improve IR are available, no medications are as yet specifically approved for the treatment of IR. This narrative review will focus on the current scientific and clinical evidence pertaining to IR, the mechanisms connecting IR with CVD, as well as plausible strategies for a holistic, personalized approach for IR management.
MeSH term(s)	Humans ; Insulin Resistance/physiology ; Cardiovascular Diseases ; Obesity/drug therapy ; Hypertension ; Insulin/therapeutic use
Chemical Substances	Insulin
Language	English
Publishing date	2023-03-30
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	184023-x
ISSN	1473-2300 ; 0300-0605 ; 0142-2596
ISSN (online)	1473-2300
ISSN	0300-0605 ; 0142-2596
DOI	10.1177/03000605231164548
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Article ; Online: Environmental Factors Modifying HDL Functionality.

Kosmas, Constantine E / Sourlas, Andreas / Guzman, Eliscer / Kostara, Christina E

Current medicinal chemistry

2021 Volume 29, Issue 10, Page(s) 1687–1701

Abstract: Background: Currently, it has been recognized that High-Density Lipoprotein (HDL) functionality plays a much more essential role in protection from atherosclerosis than circulating HDLcholesterol (HDL-C) levels per se. Cholesterol efflux capacity (CEC) ... ...

Abstract	Background: Currently, it has been recognized that High-Density Lipoprotein (HDL) functionality plays a much more essential role in protection from atherosclerosis than circulating HDLcholesterol (HDL-C) levels per se. Cholesterol efflux capacity (CEC) from macrophages to HDL has been shown to be a key metric of HDL functionality. Thus, quantitative assessment of CEC may be an important tool for the evaluation of HDL functionality, as improvement of HDL function may lead to a reduction of the risk for Cardiovascular disease (CVD). Introduction: Although the cardioprotective action of HDLs is exerted mainly through their involvement in the reverse cholesterol transport (RCT) pathway, HDLs have also important anti-inflammatory, antioxidant, antiaggregatory and anticoagulant properties that contribute to their favorable cardiovascular effects. Certain genetic, pathophysiologic, disease states and environmental conditions may influence the cardioprotective effects of HDL either by inducing modifications in lipidome and/or protein composition, or in the enzymes responsible for HDL metabolism. On the other hand, certain healthy habits or pharmacologic interventions may actually favorably affect HDL functionality. Methods: The present review discusses the effects of environmental factors, including obesity, smoking, alcohol consumption, dietary habits, various pharmacologic interventions, as well as aerobic exercise, on HDL functionality. Results: Experimental and clinical studies or pharmacological interventions support the impact of these environmental factors in the modification of HDL functionality, although the involved mechanisms are not fully understood. Conclusion: Further research should be conducted to identify the underlying mechanisms of these environmental factors and to identify new pharmacologic interventions capable of enhancing CEC, improving HDL functionality and potentially improving cardiovascular risk.
MeSH term(s)	Atherosclerosis/metabolism ; Cardiovascular Diseases/metabolism ; Cholesterol, HDL/metabolism ; Humans ; Lipoproteins, HDL/metabolism ; Macrophages/metabolism
Chemical Substances	Cholesterol, HDL ; Lipoproteins, HDL
Language	English
Publishing date	2021-07-16
Publishing country	United Arab Emirates
Document type	Journal Article ; Review
ZDB-ID	1319315-6
ISSN	1875-533X ; 0929-8673
ISSN (online)	1875-533X
ISSN	0929-8673
DOI	10.2174/0929867328666210714155422
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Article ; Online: Altered RBC membrane lipidome: A possible etiopathogenic link for the microvascular impairment in Type 2 diabetes.

Kostara, Christina E / Tsiafoulis, Constantinos G / Bairaktari, Eleni T / Tsimihodimos, Vasilis

Journal of diabetes and its complications

2021 Volume 35, Issue 10, Page(s) 107998

Abstract: Aims: Disturbances in red blood cells' (RBCs) membrane structure, that result in altered rheological properties, have been implicated in the pathogenesis of microvascular complications of diabetes mellitus(T2DM). However, the compositional alterations ... ...

Abstract	Aims: Disturbances in red blood cells' (RBCs) membrane structure, that result in altered rheological properties, have been implicated in the pathogenesis of microvascular complications of diabetes mellitus(T2DM). However, the compositional alterations in RBCs membranes of T2DM patients have not been characterized in detail. Methods: NMR-based lipidomic approach used for the global investigation of the lipidome of RBCs membrane in 20 newly diagnosed T2DM patients. Twenty healthy individuals served as controls. Results: In the lipidomic analysis, the discrimination power among the two groups was of high significance. T2DM patients characterized by an increased content of cholesterol, total sphingolipids, sphingomyelin and glycolipids, and decreased total phospholipids, mainly due to phosphatidylethanolamine, total ether glycerolipids and plasmalogen-phospholipids, and higher cholesterol-to-phospholipids molecular ratio compared to controls. In T2DM, lipids were esterified with saturated rather than unsaturated fatty acids, an atherogenic pattern that may be involved in the impairment of membrane fluidity and rigidity. Conclusions: NMR-based lipidomic analysis of RBCs can provide insights into molecular lipid features of membrane microenvironment that influence their vital function and rheological behavior in microvascular network in T2DM.Early identification of these disturbances, even before the onset of diabetes, could critically help to the development of novel preventative and curative therapies for reducing the risk of microvascular dysfunction.
MeSH term(s)	Cell Membrane/chemistry ; Cholesterol/chemistry ; Diabetes Mellitus, Type 2/complications ; Erythrocytes/chemistry ; Humans ; Lipidomics ; Phospholipids/chemistry
Chemical Substances	Phospholipids ; Cholesterol (97C5T2UQ7J)
Language	English
Publishing date	2021-07-28
Publishing country	United States
Document type	Journal Article
ZDB-ID	1105840-7
ISSN	1873-460X ; 1056-8727
ISSN (online)	1873-460X
ISSN	1056-8727
DOI	10.1016/j.jdiacomp.2021.107998
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Article: Progressive, Qualitative, and Quantitative Alterations in HDL Lipidome from Healthy Subjects to Patients with Prediabetes and Type 2 Diabetes.

Kostara, Christina E / Karakitsou, Kiriaki S / Florentin, Matilda / Bairaktari, Eleni T / Tsimihodimos, Vasilis

Metabolites

2022 Volume 12, Issue 8

Abstract: Prediabetes is a clinically silent, insulin-resistant state with increased risk for the development of type 2 diabetes (T2D) and cardiovascular disease (CVD). Since glucose homeostasis and lipid metabolism are highly intersected and interrelated, an in- ... ...

Abstract	Prediabetes is a clinically silent, insulin-resistant state with increased risk for the development of type 2 diabetes (T2D) and cardiovascular disease (CVD). Since glucose homeostasis and lipid metabolism are highly intersected and interrelated, an in-depth characterization of qualitative and quantitative abnormalities in lipoproteins could unravel the metabolic pathways underlying the progression of prediabetes to T2D and also the proneness of these patients to developing premature atherosclerosis. We investigated the HDL lipidome in 40 patients with prediabetes and compared it to that of 40 normoglycemic individuals and 40 patients with established T2D using Nuclear Magnetic Resonance (NMR) spectroscopy. Patients with prediabetes presented significant qualitative and quantitative alterations, potentially atherogenic, in HDL lipidome compared to normoglycemic characterized by higher percentages of free cholesterol and triglycerides, whereas phospholipids were lower. Glycerophospholipids and ether glycerolipids were significantly lower in prediabetic compared to normoglycemic individuals, whereas sphingolipids were significantly higher. In prediabetes, lipids were esterified with saturated rather than unsaturated fatty acids. These changes are qualitatively similar, but quantitatively milder, than those found in patients with T2D. We conclude that the detailed characterization of the HDL lipid profile bears a potential to identify patients with subtle (but still proatherogenic) abnormalities who are at high risk for development of T2D and CVD.
Language	English
Publishing date	2022-07-25
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2662251-8
ISSN	2218-1989
ISSN	2218-1989
DOI	10.3390/metabo12080683
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Article: A Study of the Metabolic Pathways Affected by Gestational Diabetes Mellitus: Comparison with Type 2 Diabetes.

Spanou, Loukia / Dimou, Aikaterini / Kostara, Christina E / Bairaktari, Eleni / Anastasiou, Eleni / Tsimihodimos, Vasilis

Diagnostics (Basel, Switzerland)

2022 Volume 12, Issue 11

Abstract: Background: Gestational diabetes mellitus (GDM) remains incompletely understood and increases the risk of developing Diabetes mellitus type 2 (DM2). Metabolomics provides insights etiology and pathogenesis of disease and discovery biomarkers for ... ...

Abstract	Background: Gestational diabetes mellitus (GDM) remains incompletely understood and increases the risk of developing Diabetes mellitus type 2 (DM2). Metabolomics provides insights etiology and pathogenesis of disease and discovery biomarkers for accurate detection. Nuclear magnetic resonance (NMR) spectroscopy is a key platform defining metabolic signatures in intact serum/plasma. In the present study, we used NMR-based analysis of macromolecules free-serum to accurately characterize the altered metabolic pathways of GDM and assessing their similarities to DM2. Our findings could contribute to the understanding of the pathophysiology of GDM and help in the identification of metabolomic markers of the disease. Methods: Sixty-two women with GDM matched with seventy-seven women without GDM (control group). Results: We identified 55 metabolites in both groups, 25 of which were significantly altered in the GDM group. GDM group showed elevated levels of ketone bodies, 2-hydroxybutyrate and of some metabolic intermediates of branched-chain amino acids (BCAAs) and significantly lower levels of metabolites of one-carbon metabolism, energy production, purine metabolism, certain amino acids, 3-methyl-2-oxovalerate, ornithine, 2-aminobutyrate, taurine and trimethylamine N-oxide. Conclusion: Metabolic pathways affected in GDM were beta-oxidation, ketone bodies metabolism, one-carbon metabolism, arginine and ornithine metabolism likewise in DM2, whereas BCAAs catabolism and aromatic amino acids metabolism were affected, but otherwise than in DM2.
Language	English
Publishing date	2022-11-21
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2662336-5
ISSN	2075-4418
ISSN	2075-4418
DOI	10.3390/diagnostics12112881
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