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Optimum lipid testing for diabetic patients to enhance clinical care.
Devaraj, S, Jialal, I
Diabetes & metabolic syndrome. 2021;(1):461-464
Abstract
BACKGROUND AND AIMS Dyslipidemia is a common problem in diabetic patients that predisposes to premature ASCVD. Dyslipidemia in Type 2 diabetes (T2DM) is very common and is characterized by hypertriglyceridemia (HTG) with decreased levels of high-density lipoprotein (HDL)-cholesterol. METHODS Recommendations for lipid testing in diabetics from the Canadian, European and American guidelines will be discussed in this mini-review. RESULTS It is crucial to obtain appropriate lipid testing in patients with TG > 2.3 mmol/L and or LDL-C< 1.8 mmol/L. We also discuss the utility of the different measures of calculated LDL-C and their pitfalls. CONCLUSION In conclusion, we propose obtaining a non-HDL-C (preferred) or direct -LDL-C or apo B level to manage diabetic patients with dyslipidemia and optimize care. Also in some patients with a strong FH of premature ASCVD and have few or no risk factors, Lp (a) can be assayed to optimize statin therapy.
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Advancing Beyond Failed High-density Lipoprotein Clinical Trials to Pharmacogenetic Studies of ADCY9 and Cholesterol Ester Transfer Protein Inhibition.
Black, DM, Miller, M, Heinonen, TM, Zhang, G
Journal of cardiovascular pharmacology. 2021;(4):496-500
Abstract
Atherosclerosis has been effectively avoided with many therapies that lower low-density lipoprotein cholesterol. However, significant cardiovascular burden remains. The effect of raising high-density lipoprotein (HDL) has been confounded by other factors (such as lowering triglycerides or LDL) and unsuccessful when attempting to solely increase HDL. Reviewing the available data, the failures of previous strategies may reflect the complexity of HDL in human metabolism and the heterogeneity of human genetics. dal-GenE (NCT02525939) represents the first large cardiovascular outcomes study to use a selective genomic test to identify the target population most likely to receive therapeutic benefit and uses a cholesterol ester transfer protein inhibitor, dalcetrapib. Both the cholesterol ester transfer protein target and the ADCY9 polymorphism identified by the diagnostic test are based on inheritance and an evolving understanding of inborn risk. Selective treatment of subpopulations may be the key to the conundrum of HDL as an actionable risk factor.
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Role of Paraoxonase1 in the Regulation of High-Density Lipoprotein Functionality and in Cardiovascular Protection.
Khalil, A, Fulop, T, Berrougui, H
Antioxidants & redox signaling. 2021;(3):191-200
Abstract
Significance: Human paraoxonase (PON) is a member of the gene family that includes paraoxonase 1 (PON1), PON2, and PON3. PON is known for its capacity to hydrolyze a wide range of substrates, including organophosphorus compounds, nerve gases, and aromatic carboxylic acid esters. Recent Advances: Several studies have highlighted the involvement of PON, particularly PON1, in the modulation of the capacity of high-density lipoprotein (HDL) to protect against the atherosclerosis process and its clinical manifestations. PON1 exhibits antioxidant and anti-inflammatory activities and may be involved in the regulation of the principal antiatherogenic activity of HDL, that is, the regulation of the reverse cholesterol transport process. Critical Issues: Although epidemiological studies have shown that there is an inverse relationship between HDL levels and cardiovascular risk, several studies have emphasized the importance of HDL functionality in protecting against cardiovascular diseases (CVD). Given that PON1 is involved in several atheroprotective functions of HDL, the aim of this article is to review the existing literature on PON1 and to discuss the principal mechanisms by which PON1 may exert its different activities. Future Directions: The elucidation of the mechanisms by which PON1 modulates the functionality of HDL as well as the identification of the interventions that stimulate PON1 activity and/or increase its plasma concentration would make it possible to propose new strategies to prevent CVD. Antioxid. Redox Signal. 34, 191-200.
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Sphingolipids in HDL - Potential markers for adaptation to pregnancy?
Patanapirunhakit, P, Karlsson, H, Mulder, M, Ljunggren, S, Graham, D, Freeman, D
Biochimica et biophysica acta. Molecular and cell biology of lipids. 2021;(8):158955
Abstract
Plasma high density lipoprotein (HDL) exhibits many functions that render it an effective endothelial protective agent and may underlie its potential role in protecting the maternal vascular endothelium during pregnancy. In non-pregnant individuals, the HDL lipidome is altered in metabolic disease compared to healthy individuals and is linked to reduced cholesterol efflux, an effect that can be reversed by lifestyle management. Specific sphingolipids such as sphingosine-1-phosphate (S1P) have been shown to mediate the vaso-dilatory effects of plasma HDL via interaction with the endothelial nitric oxide synthase pathway. This review describes the relationship between plasma HDL and vascular function during healthy pregnancy and details how this is lost in pre-eclampsia, a disorder of pregnancy associated with widespread endothelial dysfunction. Evidence of a role for HDL sphingolipids, in particular S1P and ceramide, in cardiovascular disease and in healthy pregnancy and pre-eclampsia is discussed. Available data suggest that HDL-S1P and HDL-ceramide can mediate vascular protection in healthy pregnancy but not in preeclampsia. HDL sphingolipids thus are of potential importance in the healthy maternal adaptation to pregnancy.
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The Alcohol-High-Density Lipoprotein Athero-Protective Axis.
Rosales, C, Gillard, BK, Gotto, AM, Pownall, HJ
Biomolecules. 2020;(7)
Abstract
Ingestion of alcohol is associated with numerous changes in human energy metabolism, especially that of plasma lipids and lipoproteins. Regular moderate alcohol consumption is associated with reduced atherosclerotic cardiovascular disease (ASCVD), an effect that has been attributed to the concurrent elevations of plasma high-density lipoprotein-cholesterol (HDL-C) concentrations. More recent evidence has accrued against the hypothesis that raising plasma HDL concentrations prevents ASCVD so that other metabolic processes associated with alcohol consumption have been considered. This review explored the roles of other metabolites induced by alcohol consumption-triglyceride-rich lipoproteins, non-esterified free fatty acids, and acetate, the terminal alcohol metabolite in athero-protection: Current evidence suggests that acetate has a key role in athero-protection but additional studies are needed.
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High-Density Lipoproteins and Apolipoprotein A1.
van der Vorst, EPC
Sub-cellular biochemistry. 2020;:399-420
Abstract
High-density lipoprotein (HDL) and its main protein component apolipoprotein (apo)A-I, play an important role in cholesterol homeostasis. It has been demonstrated that HDLs comprise of a very heterogeneous group of particles, not only regarding size but also composition. HDL's best described function is its role in the reverse cholesterol transport, where lipid-free apoA-I or small HDLs can accept and take up cholesterol from peripheral cells and subsequently transport this to the liver for excretion. However, several other functions have also been described, like anti-oxidant, anti-inflammatory and anti-thrombotic effects. In this article, the general features, synthesis and metabolism of apoA-I and HDLs will be discussed. Additionally, an overview of HDL functions will be given, especially in the context of some major pathologies like cardiovascular disease, cancer and diabetes mellitus. Finally, the therapeutic potential of raising HDL will be discussed, focussing on the difficulties of the past and the promises of the future.
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Τhe Antioxidant Function of HDL in Atherosclerosis.
Xepapadaki, E, Zvintzou, E, Kalogeropoulou, C, Filou, S, Kypreos, KE
Angiology. 2020;(2):112-121
Abstract
Atherosclerosis is a multistep process that progresses over a long period of time and displays a broad range of severity. In its final form, it manifests as a lesion of the intimal layer of the arterial wall. There is strong evidence supporting that oxidative stress contributes to coronary heart disease morbidity and mortality and antioxidant high-density lipoprotein (HDL) could have a beneficial role in the prevention and prognosis of the disease. Indeed, certain subspecies of HDL may act as natural antioxidants preventing oxidation of lipids on low-density lipoprotein (LDL) and biological membranes. The antioxidant function may be attributed to inhibition of synthesis or neutralization of free radicals and reactive oxygen species by HDL lipids and associated enzymes or transfer of oxidation prone lipids from LDL and biological membranes to HDL for catabolism. A limited number of clinical trials suggest that the increased antioxidant potential of HDL correlates with decreased risk for atherosclerosis. Some nutritional interventions to increase HDL antioxidant activity have been proposed with limited success so far. The limitations in measuring and understanding HDL antioxidant function in vivo are also discussed.
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High-Density Lipoprotein in Lupus: Disease Biomarkers and Potential Therapeutic Strategy.
Kim, SY, Yu, M, Morin, EE, Kang, J, Kaplan, MJ, Schwendeman, A
Arthritis & rheumatology (Hoboken, N.J.). 2020;(1):20-30
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Abstract
Systemic lupus erythematosus (SLE) patients exhibit accelerated development of atherosclerosis and increased incidents of cardiovascular disease (CVD) that cannot be explained by traditional risk factors alone. Accumulating evidence suggests that reduced levels of high-density lipoproteins (HDLs), along with altered HDL composition and function, may contribute to the accelerated atherosclerosis in SLE patients. Normally, HDLs play various atheroprotective roles through facilitating cholesterol efflux, inhibiting vascular inflammation, and scavenging oxidative species. However, systemic inflammation, oxidative stress, and autoimmunity in SLE patients induce changes in HDL size distribution and proteomic and lipidomic signatures. These compositional changes in HDLs result in the formation of proinflammatory, dysfunctional HDL. These lupus-altered HDLs have impaired antiatherogenic function with reduced cholesterol efflux capacities, impaired antioxidation abilities, and diminished antiinflammatory properties. In fact, dysfunctional HDL may promote atherogenesis by inducing inflammation. Thus, dysfunctional HDLs could be an important biomarker of accelerated atherosclerosis in lupus. Additionally, HDL-targeted therapies, especially infusion of reconstituted HDLs, may serve as a potential therapeutic intervention for SLE patients with CVD.
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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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High-Density Lipoprotein Components and Functionality in Cancer: State-of-the-Art.
Ganjali, S, Ricciuti, B, Pirro, M, Butler, AE, Atkin, SL, Banach, M, Sahebkar, A
Trends in endocrinology and metabolism: TEM. 2019;(1):12-24
Abstract
Cancer is the second leading cause of death in western countries, and thus represents a major global public health issue. Whilst it is well-recognized that diet, obesity, and smoking are risk factors for cancer, the role of low levels of high-density lipoprotein cholesterol (HDL-C) in cancer is less well appreciated. Conflicting evidence suggests that serum HDL-C levels may be either positively or negatively associated with cancer incidence and mortality. Such disparate associations are supported in part by the multitude of high-density lipoprotein (HDL) functions that can all have an impact on cancer cell biology. The aim of this review is to provide a comprehensive overview of the crosstalk between HDLs and cancer, focusing on the molecular mechanisms underlying this association.