Extracellular microRNAs (miRNAs) are uniquely stable in plasma, and the levels of specific circulating miRNAs can differ with disease. Extracellular miRNAs are associated with lipid-based carriers ...and lipid-free proteins. miRNAs can be transferred from cell-to-cell by lipid-based carriers and affect gene expression. This review summarizes recent studies that demonstrate the transfer of miRNA between cells and their potential role in intercellular communication.
Microvesicles, exosomes, apoptotic bodies, lipoproteins, and large microparticles contain miRNAs. Recent studies have demonstrated that miRNAs are transferred between dendritic cells, hepatocellular carcinoma cells, and adipocytes in lipid-based carriers. miRNAs are also transferred from T cells to antigen-presenting cells, from stem cells to endothelial cells and fibroblasts, from macrophages to breast cancer cells, and from epithelial cells to hepatocytes in lipid-based carriers. The cellular export of miRNAs in lipid-based carriers is regulated by the ceramide pathway, and the delivery of lipid-associated miRNAs to recipient cells is achieved by various routes, including endocytotic uptake, membrane-fusion, and scavenger receptors.
Cellular miRNAs are exported in and to lipid-based carriers (vesicles and lipoprotein particles) and transferred to recipient cells with gene expression changes as intercellular communication.
Abstract
Background
Increased small dense low-density lipoprotein-cholesterol (sdLDL-C) is a risk factor for atherosclerotic cardiovascular disease (ASCVD) but typically requires advanced lipid ...testing. We describe two new equations, first one for calculating large buoyant LDL-C (lbLDL-C), based only upon results from the standard lipid panel, and the second one for sdLDL-C.
Methods
Equations for sdLDL-C and lbLDL-C were generated with least-squares regression analysis using the direct Denka sdLDL-C assay as reference (n = 20 171). sdLDL-C was assessed as a risk-enhancer test in the National Heart and Nutrition Examination Survey (NHANES), and for its association with ASCVD in the Multi-Ethnic Study of Atherosclerosis (MESA).
Results
The newly derived equations depend on two terms, namely LDL-C as determined by the Sampson equation, and an interaction term between LDL-C and the natural log of triglycerides (TG). The lbLDL-C equation (lbLDLC=1.43 × LDLC-0.14 ×(ln(TG)× LDLC)- 8.99) was more accurate (R2 = 0.933, slope = 0.94) than the sdLDL-C equation (sdLDLC=LDLC- lbLDLC; R2 = 0.745, slope = 0.73). Using the 80th percentile (46 mg/dL) as a cut-point, sdLDL-C identified in NHANES additional high-risk patients not identified by other risk-enhancer tests based on TG, LDL-C, apolipoprotein B, and nonHDL-C. By univariate survival-curve analysis, estimated sdLDL-C was superior to other risk-enhancer tests in predicting ASCVD events in MESA. After multivariate adjustment for other known ASCVD risk factors, estimated sdLDL-C had the strongest association with ASCVD compared to other lipid parameters, including measured sdLDL-C.
Conclusions
Estimated sdLDL-C could potentially be calculated on all patients tested with a standard lipid panel to improve ASCVD risk stratification.
The European Atherosclerosis Society-European Federation of Clinical Chemistry and Laboratory Medicine Consensus Panel aims to provide recommendations to optimize atherogenic lipoprotein ...quantification for cardiovascular risk management.
We critically examined LDL cholesterol, non-HDL cholesterol, apolipoprotein B (apoB), and LDL particle number assays based on key criteria for medical application of biomarkers. (
) Analytical performance: Discordant LDL cholesterol quantification occurs when LDL cholesterol is measured or calculated with different assays, especially in patients with hypertriglyceridemia >175 mg/dL (2 mmol/L) and low LDL cholesterol concentrations <70 mg/dL (1.8 mmol/L). Increased lipoprotein(a) should be excluded in patients not achieving LDL cholesterol goals with treatment. Non-HDL cholesterol includes the atherogenic risk component of remnant cholesterol and can be calculated in a standard nonfasting lipid panel without additional expense. ApoB more accurately reflects LDL particle number. (
) Clinical performance: LDL cholesterol, non-HDL cholesterol, and apoB are comparable predictors of cardiovascular events in prospective population studies and clinical trials; however, discordance analysis of the markers improves risk prediction by adding remnant cholesterol (included in non-HDL cholesterol) and LDL particle number (with apoB) risk components to LDL cholesterol testing. (
) Clinical and cost-effectiveness: There is no consistent evidence yet that non-HDL cholesterol-, apoB-, or LDL particle-targeted treatment reduces the number of cardiovascular events and healthcare-related costs than treatment targeted to LDL cholesterol.
Follow-up of pre- and on-treatment (measured or calculated) LDL cholesterol concentration in a patient should ideally be performed with the same documented test method. Non-HDL cholesterol (or apoB) should be the secondary treatment target in patients with mild to moderate hypertriglyceridemia, in whom LDL cholesterol measurement or calculation is less accurate and often less predictive of cardiovascular risk. Laboratories should report non-HDL cholesterol in all standard lipid panels.
Circulating microRNAs (miRNA) are relatively stable in plasma and are a new class of disease biomarkers. Here we present evidence that high-density lipoprotein (HDL) transports endogenous miRNAs and ...delivers them to recipient cells with functional targeting capabilities. Cellular export of miRNAs to HDL was demonstrated to be regulated by neutral sphingomyelinase. Reconstituted HDL injected into mice retrieved distinct miRNA profiles from normal and atherogenic models. HDL delivery of both exogenous and endogenous miRNAs resulted in the direct targeting of messenger RNA reporters. Furthermore, HDL-mediated delivery of miRNAs to recipient cells was demonstrated to be dependent on scavenger receptor class B type I. The human HDL-miRNA profile of normal subjects is significantly different from that of familial hypercholesterolemia subjects. Notably, HDL-miRNA from atherosclerotic subjects induced differential gene expression, with significant loss of conserved mRNA targets in cultured hepatocytes. Collectively, these observations indicate that HDL participates in a mechanism of intercellular communication involving the transport and delivery of miRNAs.
Pathophysiological, epidemiological, and genetic studies provide strong evidence that lipoprotein(a) Lp(a) is a causal mediator of cardiovascular disease (CVD) and calcific aortic valve disease ...(CAVD). Specific therapies to address Lp(a)-mediated CVD and CAVD are in clinical development. Due to knowledge gaps, the National Heart, Lung, and Blood Institute organized a working group that identified challenges in fully understanding the role of Lp(a) in CVD/CAVD. These included the lack of research funding, inadequate experimental models, lack of globally standardized Lp(a) assays, and inadequate understanding of the mechanisms underlying current drug therapies on Lp(a) levels. Specific recommendations were provided to facilitate basic, mechanistic, preclinical, and clinical research on Lp(a); foster collaborative research and resource sharing; leverage expertise of different groups and centers with complementary skills; and use existing National Heart, Lung, and Blood Institute resources. Concerted efforts to understand Lp(a) pathophysiology, together with diagnostic and therapeutic advances, are required to reduce Lp(a)-mediated risk of CVD and CAVD.
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Cholesterol on low-density lipoproteins (LDL-C) is one of the main drivers of atherosclerotic cardiovascular disease (ASCVD) and hence its measurement is critical in the management of patients at ...risk. Although LDL-C has routinely been either calculated by the Friedewald equation or measured with direct assays, these methods have limitations, particularly for patients with dyslipidaemias, low LDL-C, and hypertriglyceridemia. The focus of this review will be recent advances in the measurement of LDL for ASCVD risk management.
We first describe the recent recommendations on how LDL-C is used in ASCVD risk assessment and management. We then review the current approaches to the measurement of LDL-C and recent developments on new more accurate equations for calculating LDL-C. Finally, we present new and emerging LDL assays that may be superior to LDL-C for risk assessment, such as LDL particle number and small dense LDL-C, and several LDL-based lipid tests in early development.
LDL-C is valuable in ASCVD risk management but recent improvements in its measurement and the development of other LDL-related tests may further improve its value.
Drug repurposing is potentially the fastest available option in the race to identify safe and efficacious drugs that can be used to prevent and/or treat COVID‐19. By describing the life cycle of the ...newly emergent coronavirus, SARS‐CoV‐2, in light of emerging data on the therapeutic efficacy of various repurposed antimicrobials undergoing testing against the virus, we highlight in this review a possible mechanistic convergence between some of these tested compounds. Specifically, we propose that the lysosomotropic effects of hydroxychloroquine and several other drugs undergoing testing may be responsible for their demonstrated in vitro antiviral activities against COVID‐19. Moreover, we propose that Niemann‐Pick disease type C (NPC), a lysosomal storage disorder, may provide new insights into potential future therapeutic targets for SARS‐CoV‐2, by highlighting key established features of the disorder that together result in an “unfavorable” host cellular environment that may interfere with viral propagation. Our reasoning evolves from previous biochemical and cell biology findings related to NPC, coupled with the rapidly evolving data on COVID‐19. Our overall aim is to suggest that pharmacological interventions targeting lysosomal function in general, and those particularly capable of reversibly inducing transient NPC‐like cellular and biochemical phenotypes, constitute plausible mechanisms that could be used to therapeutically target COVID‐19.
Apolipoprotein C-II (apoC-II) is a small exchangeable apolipoprotein found on triglyceride-rich lipoproteins (TRL), such as chylomicrons (CM) and very low-density lipoproteins (VLDL), and on ...high-density lipoproteins (HDL), particularly during fasting. ApoC-II plays a critical role in TRL metabolism by acting as a cofactor of lipoprotein lipase (LPL), the main enzyme that hydrolyses plasma triglycerides (TG) on TRL. Here, we present an overview of the role of apoC-II in TG metabolism, emphasizing recent novel findings regarding its transcriptional regulation and biochemistry. We also review the 24 genetic mutations in the APOC2 gene reported to date that cause hypertriglyceridemia (HTG). Finally, we describe the clinical presentation of apoC-II deficiency and assess the current therapeutic approaches, as well as potential novel emerging therapies.
•ApoC-II is a cofactor for LPL and thus promotes hydrolysis of TG on TRL.•It is part of the APOE/C1/C4/C2 gene cluster and undergoes complex regulation.•ApoC-II prevents displacement of LPL from TRL during lipolysis.•We summarize 24 novel mutations reported to cause apoC-II deficiency.•Low-fat diet is the primary treatment but new therapies are under development.
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