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Chronic kidney disease (CKD) is often associated with decreased activity of lecithin-cholesterol acyltransferase (LCAT), an enzyme essential for HDL maturation. This reduction in LCAT activity may potentially contribute to an increased risk of cardiovascular mortality in patients with CKD. The objective of this study was to investigate the association between LCAT activity in patients with CKD and the risk of adverse outcomes. We measured serum LCAT activity and characterized lipoprotein profiles using nuclear magnetic resonance spectroscopy in 453 non-dialysis CKD patients from the CARE FOR HOMe study. LCAT activity correlated directly with smaller HDL particle size, a type of HDL potentially linked to greater cardiovascular protection. Over a mean follow-up of 5.0 ± 2.2 years, baseline LCAT activity was inversely associated with risk of death (standardized HR 0.62, 95% CI 0.50–0.76; P

COVID-19, caused by the SARS-CoV-2 coronavirus, emerged as a global pandemic in late 2019, resulting in significant global public health challenges. The emerging evidence suggests that diminished high-density lipoprotein (HDL) cholesterol levels are associated with the severity of COVID-19, beyond inflammation and oxidative stress. Here, we used nuclear magnetic resonance spectroscopy to compare the lipoprotein and metabolic profiles of COVID-19-infected patients with non-COVID-19 pneumonia. We compared the control group and the COVID-19 group using inflammatory markers to ensure that the differences in lipoprotein levels were due to COVID-19 infection. Our analyses revealed supramolecular phospholipid composite (SPC), phenylalanine, and HDL-related parameters as key discriminators between COVID-19-positive and non-COVID-19 pneumonia patients. More specifically, the levels of HDL parameters, including apolipoprotein A-I (ApoA-I), ApoA-II, HDL cholesterol, and HDL phospholipids, were significantly different. These findings underscore the potential impact of HDL-related factors in patients with COVID-19. Significantly, among the HDL-related metrics, the cholesterol efflux capacity (CEC) displayed the strongest negative association with COVID-19 mortality. CEC is a measure of how well HDL removes cholesterol from cells, which may affect the way SARS-CoV-2 enters cells. In summary, this study validates previously established markers of COVID-19 infection and further highlights the potential significance of HDL functionality in the context of COVID-19 mortality.

The HDL proteome has been widely recognized as an important mediator of HDL function. While a variety of HDL isolation methods exist, their impact on the HDL proteome and its associated function remain largely unknown. Here, we compared three of the most common methods for HDL isolation, namely immunoaffinity (IA), density gradient ultracentrifugation (UC), and dextran-sulfate precipitation (DS), in terms of their effects on the HDL proteome and associated functionalities. We used state-of-the-art mass spectrometry to identify 171 proteins across all three isolation methods. IA-HDL contained higher levels of paraoxonase 1, apoB, clusterin, vitronectin, and fibronectin, while UC-HDL had higher levels of apoA2, apoC3, and α-1-antytrypsin. DS-HDL was enriched with apoA4 and complement proteins, while the apoA2 content was very low. Importantly, size-exclusion chromatography analysis showed that IA-HDL isolates contained subspecies in the size range above 12 nm, which were entirely absent in UC-HDL and DS-HDL isolates. Analysis of these subspecies indicated that they primarily consisted of apoA1, IGκC, apoC1, and clusterin. Functional analysis revealed that paraoxonase 1 activity was almost completely lost in IA-HDL, despite high paraoxonase content. We observed that the elution conditions, using 3M thiocyanate, during IA resulted in an almost complete loss of paraoxonase 1 activity. Notably, the cholesterol efflux capacity of UC-HDL and DS-HDL was significantly higher compared to IA-HDL. Together, our data clearly demonstrate that the isolation procedure has a substantial impact on the composition, subclass distribution, and functionality of HDL. In summary, our data show that the isolation procedure has a significant impact on the composition, subclass distribution and functionality of HDL. Our data can be helpful in the comparison, replication and analysis of proteomic datasets of HDL.

Summary: Adipose tissue inflammation drives obesity-related cardiometabolic diseases. Enhancing endogenous resolution mechanisms through administration of lipoxin A4, a specialized pro-resolving lipid mediator, was shown to reduce adipose inflammation and subsequently protects against obesity-induced systemic disease in mice. Here, we demonstrate that lipoxins reduce inflammation in 3D-cultured human adipocytes and adipose tissue explants from obese patients. Approximately 50% of patients responded particularly well to lipoxins by reducing inflammatory cytokines and promoting an anti-inflammatory M2 macrophage phenotype. Responding patients were characterized by elevated systemic levels of C-reactive protein, which causes inflammation in cultured human adipocytes. Responders appeared more prone to producing anti-inflammatory oxylipins and displayed elevated prostaglandin D2 levels, which has been interlinked with transcription of lipoxin-generating enzymes. Using explant cultures, this study provides the first proof-of-concept evidence supporting the therapeutic potential of lipoxins in reducing human adipose tissue inflammation. Our data further indicate that lipoxin treatment may require a tailored personalized-medicine approach.

High-density lipoproteins (HDL) are complex endogenous nanoparticles involved in important functions such as reverse cholesterol transport and immunomodulatory activities, ensuring metabolic homeostasis and vascular health. The ability of HDL to interact with a plethora of immune cells and structural cells places it in the center of numerous disease pathophysiologies. However, inflammatory dysregulation can lead to pathogenic remodeling and post-translational modification of HDL, rendering HDL dysfunctional or even pro-inflammatory. Monocytes and macrophages play a critical role in mediating vascular inflammation, such as in coronary artery disease (CAD). The fact that HDL nanoparticles have potent anti-inflammatory effects on mononuclear phagocytes has opened new avenues for the development of nanotherapeutics to restore vascular integrity. HDL infusion therapies are being developed to improve the physiological functions of HDL and to quantitatively restore or increase the native HDL pool. The components and design of HDL-based nanoparticles have evolved significantly since their initial introduction with highly anticipated results in an ongoing phase III clinical trial in subjects with acute coronary syndrome. The understanding of mechanisms involved in HDL-based synthetic nanotherapeutics is critical to their design, therapeutic potential and effectiveness. In this review, we provide a current update on HDL-ApoA-I mimetic nanotherapeutics, highlighting the scope of treating vascular diseases by targeting monocytes and macrophages.

Plasma membrane cholesterol is required for proper trafficking and localization of receptors that facilitate severe acute respiratory syndrome coronavirus 2 infection. High-density lipoproteins (HDL) mobilize plasma membrane cholesterol, and HDL-cholesterol levels are associated with the severity of COVID-19 disease and mortality. However, HDL-cholesterol levels poorly reflect the function of this complex family of particles, and a detailed assessment of COVID-19-associated changes in HDL functionality and its prognostic value is lacking. In the present study, we assessed HDL cholesterol efflux capacity, HDL anti-inflammatory and antioxidant properties, and changes in HDL composition and metabolism in COVID-19 (n = 48) and non-COVID pneumonia patients (n = 32). COVID-19 infection markedly reduced the activity of lecithin-cholesteryl-acyltransferase and functional parameters of HDL, such as the cholesterol efflux capacity, arylesterase activity of paraoxonase 1, and anti-oxidative capacity of apoB-depleted serum when compared to non-COVID pneumonia at baseline, paralleled by markedly reduced levels of HDL-cholesterol. Of particular interest, low HDL cholesterol efflux capacity was associated with increased mortality risk in COVID-19 patients, independent of HDL-C levels. Our results highlight profound effects of COVID-19 infection on HDL function, metabolism, and composition. Low HDL cholesterol efflux capacity indicates a fatal course of COVID-19, independent of HDL-cholesterol levels.

Anorexia nervosa (AN) is a severe eating disorder affecting primarily female adolescents and younger adults. The energy deprivation associated with AN has been shown to alter lipoprotein metabolism, which may affect cardiovascular risk. However, the mechanisms leading to alterations in the composition, structure, and function of lipoproteins in AN patients are not well-understood yet. Here, we investigated the lipid abnormalities associated with AN, particularly changes in the distribution, composition, metabolism, and function of lipoprotein subclasses. In this exploratory study, we analyzed serum samples of 18 women diagnosed with AN (BMI < 17.5 kg/m2) and 24 normal-weight women (BMI from 18.5–24.9 kg/m2). Using the Quantimetrix Lipoprint® system, we determined low-density lipoprotein (LDL) subclass distribution, including quantitative measurements of very low-density lipoprotein (VLDL), intermediate density lipoprotein (IDL) and high-density lipoprotein (HDL) subclass distribution. We quantified the most abundant apolipoproteins of HDL and assessed lecithin-cholesterol acyltransferase (LCAT) and cholesteryl-ester transfer protein (CETP) activities. In addition, anti-oxidative capacity of apoB-depleted serum and functional metrics of HDL, including cholesterol efflux capacity and paraoxonase activity were assessed. The atherogenic lipoprotein subclasses VLDL and small LDL particles were increased in AN. Levels of VLDL correlated significantly with CETP activity (rs = 0.432, p = 0.005). AN was accompanied by changes in the content of HDL-associated apolipoproteins involved in triglyceride catabolism, such as apolipoprotein C-II (+24%) and apoA-II (−27%), whereas HDL-associated cholesterol, phospholipids, and triglycerides were not altered. Moreover, AN did not affect HDL subclass distribution, cholesterol efflux capacity, and paraoxonase activity. We observed a shift to more atherogenic lipoprotein subclasses in AN patients, whereas HDL functionality and subclass distribution were not altered. This finding underpins potential detrimental effects of AN on lipid metabolism and the cardiovascular system by increasing atherosclerotic risk factors.