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Is it time to reconcile HDL with cardiovascular diseases and beyond? An update on a paradigm shift.
Martinez, LO, Ingueneau, C, Genoux, A
Current opinion in lipidology. 2020;(5):302-304
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2.
[Challenges in Drug Development Targeting Anti-atherosclerotic Proteins].
Okuhira, K
Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan. 2020;(2):153-157
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Abstract
Atherosclerosis is a vascular disease responsible for acute heart attacks and stroke, which are leading causes of death not only in industrialized countries but also worldwide, and the number of patients afflicted by this disease has been increasing in Japan. High-density lipoprotein (HDL) is the plasma lipoprotein that carries what is often called your "good cholesterol" through the blood. This good cholesterol moniker is associated with HDL because higher circulating levels of this lipoprotein are associated with a well-known reduction in the risk of arteriosclerosis. Moreover, many protective mechanisms by which HDL could reduce atherosclerosis are described, including reverse cholesterol transport, along with anti-oxidant, anti-inflammatory and anti-thrombosis activities. However, HDL-modulating therapies to lower cardiovascular risk are not yet available. It has recently been proposed that apolipoprotein A-I (apoA-I) binding protein (AIBP) enhances HDL function by accelerating lipid release from cells and reducing associated inflammatory processes. In this context, our research is focused on the function of HDL-related proteins, such as proteins that regulate HDL production (ATP-binding cassette transporters), and HDL-binding proteins. We expect that these studies could eventually help in the development of HDL-related prognostic and therapeutic strategies to reduce the burden of cardiovascular disease in the future.
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High-Density Lipoprotein Cholesterol in Age-Related Ocular Diseases.
Betzler, BK, Rim, TH, Sabanayagam, C, Cheung, CMG, Cheng, CY
Biomolecules. 2020;(4)
Abstract
There is limited understanding of the specific role of high-density lipoprotein cholesterol (HDL-C) in the development of various age-related ocular diseases, despite it being a common measurable biomarker in lipid profiles. This literature review summarizes current knowledge of the role of HDL-C, if any, in pathogenesis and progression of four age-related ocular diseases, namely age-related macular degeneration (AMD), age-related cataract, glaucoma, and diabetic retinopathy (DR), and will primarily discuss epidemiological and genetic evidence.
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4.
Cannabis effects on lipoproteins.
Lazarte, J, Hegele, RA
Current opinion in lipidology. 2019;(2):140-146
Abstract
PURPOSE OF REVIEW The endocannabinoid system affects several physiological functions. A family of endocannabinoid receptors is susceptible to cannabis constituents. Cannabis is widely used in our society and following its recent legalization in Canada, we focus on how exposure to cannabis and pharmacologic cannabinoid receptor type 1 (CB1) inhibition affect lipoprotein levels. RECENT FINDINGS Several groups have reported that exposure to cannabis does not increase weight despite the marked increase in caloric intake. In observational studies, the effect of smoked cannabis exposure on plasma lipids is variable. Some studies in specific patient populations with longer exposure to cannabis seemed to identify slightly more favorable lipoprotein profiles in the exposed group. Several larger controlled clinical trials using orally administered rimonabant, a CB1 receptor antagonist, have consistently shown relative improvements in weight and plasma levels of triglyceride and high-density lipoprotein cholesterol among patients receiving the treatment. SUMMARY The widely variable findings on the relationship of cannabis in various forms with plasma lipids preclude any definitive conclusions. Cannabis has complex effects on the cardiovascular system and its effects on lipid profile must be considered in this overall context. Further properly controlled research is required to better understand this topic.
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5.
Rethinking good cholesterol: a clinicians' guide to understanding HDL.
Xiang, AS, Kingwell, BA
The lancet. Diabetes & endocrinology. 2019;(7):575-582
Abstract
Low HDL cholesterol dyslipidaemia affects about half of people with type 2 diabetes and represents a major independent risk factor for atherosclerotic cardiovascular disease. The "good cholesterol" label was coined decades ago on the basis of a presumed causal role of HDL cholesterol in atherosclerotic cardiovascular disease. However, this view has been challenged by the negative results of several studies of HDL cholesterol-raising drugs, creating a paradox for clinicians regarding the value of HDL cholesterol as a risk biomarker and therapeutic target, and seemingly contradicting decades of evidence substantiating an inverse relation between HDL cholesterol and cardiovascular disease risk. We seek to resolve this issue by revisiting the history of the HDL hypothesis, chronicling how this paradox is ultimately rooted in the progressive erroneous blurring of the distinction between HDL and HDL cholesterol. We describe the compositional complexity of HDL particles beyond their cholesterol cargo and focus on their role in lipid transport. We discuss the evidence regarding novel HDL functions, including effects on glucose metabolism, and speculate on the implications for type 2 diabetes. HDL cholesterol is an imperfect biomarker of a highly complex and multifunctional lipid transport system, and we should now consider how new HDL markers more causally linked to cardiovascular complications could be adapted for clinical use. In the absence of a superior alternative, HDL cholesterol generally has value as a component of primary cardiovascular disease risk prediction models, including in people with type 2 diabetes. However, to avoid prognostic overgeneralisations, it is high time that the good cholesterol label is dropped.
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Chylomicron retention disease: genetics, biochemistry, and clinical spectrum.
Levy, E, Poinsot, P, Spahis, S
Current opinion in lipidology. 2019;(2):134-139
Abstract
PURPOSE OF REVIEW Chylomicron retention disease (CRD) is an autosomic recessive disorder, in which intestinal fat malabsorption is the main cause of diverse severe manifestations. The specific molecular defect was identified in 2003 and consists of mutations in the SAR1B or SARA2 gene encoding for intracellular SAR1B GTPase protein. The aim of this review is first to provide an update of the recent biochemical, genetic and clinical findings, and second to discuss novel mechanisms related to hallmark symptoms. RECENT FINDINGS CRD patients present with SAR1B mutations, which disable the formation of coat protein complex II and thus blocks the transport of chylomicron cargo from the endoplasmic reticulum to the Golgi. Consequently, there is a total absence of chylomicron and apolipoprotein B-48 in the blood circulation following a fat meal, accompanied by a deficiency in liposoluble vitamins and essential fatty acids. The recent discovery of Transport and Golgi organization and Transport and Golgi organization-like proteins may explain the intriguing export of large chylomicron, exceeding coat protein complex II size. Hypocholesterolemia could be accounted for by a decrease in HDL cholesterol, likely a reflection of limited production of intestinal HDL in view of reduced ATP-binding cassette family A protein 1 and apolipoprotein A-I protein. In experimental studies, the paralog SAR1A compensates for the lack of the SAR1B GTPase protein. SUMMARY Molecular testing for CRD is recommended to distinguish the disease from other congenital fat malabsorptions, and to early define molecular aberrations, accelerate treatment, and prevent complications.
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Relationship Between HDL Functional Characteristics and Cardiovascular Health and Potential Impact of Dietary Patterns: A Narrative Review.
Bardagjy, AS, Steinberg, FM
Nutrients. 2019;(6)
Abstract
Cardiovascular disease is a leading cause of death around the world. Overall diet quality and dietary behaviors are core contributors to metabolic health. While therapeutic targets have traditionally focused on levels of lipoprotein cholesterol when evaluating cardiovascular risk, current perspectives on high-density lipoprotein (HDL) have shifted to evaluating the functionality of this lipoprotein particle. Effects of diet on cardiovascular health are mediated through multiple pathways, but the impact on HDL composition and function deserves greater attention. Potential areas of investigation involve changes in particle characteristics, distribution, microRNA cargo, and other functional changes such as improvements to cholesterol efflux capacity. Various dietary patterns like the Mediterranean diet and Dietary Approaches to Stop Hypertension (DASH) diet have beneficial effects on cardiovascular health and may prevent cardiovascular events. These healthful dietary patterns tend to be rich in plant-based foods, with cardiovascular benefits likely resulting from synergistic effects of the individual dietary components. The purpose of this review is to summarize current perspectives on selected functions of HDL particles and how various dietary patterns affect cardiovascular health biomarkers, with a focus on HDL functionality.
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8.
From HDL-cholesterol to HDL-function: cholesterol efflux capacity determinants.
Rhainds, D, Tardif, JC
Current opinion in lipidology. 2019;(2):101-107
Abstract
PURPOSE OF REVIEW The validity of HDL-cholesterol (HDL-C) elevation as a therapeutic target has been questioned, in comparison to enhancing HDL functionality. Cholesterol efflux capacity (CEC) is an in-vitro assay that measures the ability of an individual's HDL to promote cholesterol efflux from cholesterol donor cells such as macrophages. CEC of HDL is a predictor of cardiovascular risk independent of HDL-C levels. However, molecular determinants of CEC and the effects of diseases and therapeutic interventions on CEC have not been completely defined. RECENT FINDINGS We review here recent findings on elevated HDL-C and disease risk, as well as determinants of CEC, from genetics and proteomics to pathophysiology and therapeutic interventions that contribute to our understanding of CEC as a biomarker of HDL functionality. SUMMARY Elevated HDL-C levels are not always protective against cardiovascular disease and mortality. CEC is a heritable trait, and genetic polymorphisms in genes involved in HDL and triglycerides metabolism are associated with CEC. Multiple HDL proteins correlate positively with CEC levels and inversely with noncalcified plaque burden. Differences in CEC assays that make comparisons between studies difficult are also emphasized. CEC should be measured in clinical trials of lipid-modifying and anti-inflammatory therapies to determine whether increases are cardioprotective.
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Non-HDL-cholesterol and apolipoprotein B compared with LDL-cholesterol in atherosclerotic cardiovascular disease risk assessment.
Carr, SS, Hooper, AJ, Sullivan, DR, Burnett, JR
Pathology. 2019;(2):148-154
Abstract
Low density lipoprotein (LDL) is the predominant atherogenic lipoprotein particle in the circulation. Conventionally, a fasting lipid profile has been used for atherosclerotic cardiovascular disease (ASCVD) risk assessment. A non-fasting sample is now regarded as a suitable alternative to a fasting sample. In routine clinical practice, the Friedewald equation is used to estimate LDL-cholesterol, but it has limitations. Commercially available direct measures of LDL-cholesterol are not standardised. LDL-cholesterol is a well-established risk factor for ASCVD, being the primary therapeutic target in both primary and secondary prevention. Non-high-density lipoprotein (HDL)-cholesterol is a measure of the cholesterol content in the atherogenic lipoproteins, but it does not reflect the particle number. Non-HDL-cholesterol has the advantage over LDL-cholesterol of including remnant cholesterol and being independent of triglyceride variability, but it is compromised by the non-specificity bias of direct HDL-cholesterol methods used in the calculation. Apolipoprotein (apo) B, the major structural protein in very low-density lipoprotein, intermediate density lipoprotein, LDL and lipoprotein (a), is a measure of the number of atherogenic lipoproteins. ApoB methods are standardised, but the assay comes at an additional, albeit relatively low cost. Non-HDL-cholesterol and apoB are more accurate measures than LDL-cholesterol in hypertriglyceridaemic individuals, non-fasting samples, and in those with very-low LDL-cholesterol concentrations. Accumulating evidence suggests that non-HDL-cholesterol and apoB are superior to LDL-cholesterol in predicting ASCVD risk, and both have been designated as secondary targets in some treatment guidelines. We review the measurement, potential role, utility and current status of non-HDL-cholesterol and apoB when compared with LDL-cholesterol in ASCVD risk assessment.
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10.
HDL cholesterol and ASCVD risk stratification: A debate.
Barter, P, Genest, J
Atherosclerosis. 2019;:7-12
Abstract
This debate is designed to review the usefulness of the cholesterol mass within high-density lipoproteins (HDL-C) to predict the risk of atherosclerotic cardiovascular disease (ASCVD). PRO: There is much current confusion regarding the role of high density lipoproteins (HDLs) in atherosclerotic cardiovascular disease (ASCVD). While it is an established fact that the concentration of HDL cholesterol is a robust, independent, inverse predictor of the risk of having an ASCVD event, recent studies have questioned whether HDLs actually protect against ASCVD. But this in no way challenges that fact that the concentration of HDL cholesterol is a powerful tool to be used in risk stratification of ASCVD. CON: The measurement of HDL-C in the 1970 heralded a new area of promising and exciting research in cardiovascular disease. The measurement of HDL-C has been part of cardiovascular risk stratification for the past three decades. HDL have pleotropic beneficial effects on the arterial vasculature and promote the removal of excess cholesterol from lipid laden macrophages. These effects are only weakly correlated with HDL-C levels. While HDL-C is associated with atherosclerotic cardiovascular disease, the epidemiological relationship falters at the extremes of measurement. Mendelian randomization does not support a link of causality and to date, attempts to raise HDL-C pharmacologically have not yielded the expected outcomes. The time has come to consider abandoning HDL-C for cardiovascular risk prediction and clinical decision making and to double efforts to develop better biomarkers of HDL function.