Search

Background/objectiveYouth with obesity have an altered high-density lipoprotein (HDL) subspecies profile characterized by depletion of large apoE-rich HDL particles and an enrichment of small HDL particles. The goal of this study was to test the hypothesis that this atherogenic HDL profile is reversible and that HDL function would improve with metabolic surgery.MethodsSerum samples from adolescent males with severe obesity mean±s.d. age of 17.4±1.6 years were studied at baseline and 1 year following vertical sleeve gastrectomy (VSG). HDL subspecies and HDL function were evaluated pre and post VSG using paired t-tests. A lean group of adolescents was included as a reference group.ResultsAfter VSG, body mass index decreased by 32% and insulin resistance as estimated by homeostatic model assessment of insulin resistance decreased by 75% (both P

This paper argues that the issues facing effective prevention programs when they embark on dissemination, implementation, and routinization have been largely ignored by the field. Through the example of the Adolescent Diversion Program, these issues are illustrated and discussed. Four sequential longitudinal experimental studies are summarized as a context for the discussion of dissemination issues. In each case, the alternative preventive program is demonstrated to be more effective than traditional approaches. Challenges to widespread implementation of effective prevention programs are then discussed with a call for the field to add such issues to its scientific agenda. [ABSTRACT FROM AUTHOR]

The Adolescent Diversion Project (ADP) is an ecological program that seeks to promote family and community support and divert youth from further potentially labeling contact with the juvenile justice system. This manuscript reviews results from three phases of research that test program efficacy, compare intervention components, and examine staffing models. The model involves trained paraprofessionals who utilize behavioral contracting and community advocacy to help families of delinquent youth. Results are then presented from the fourth phase, the current study that replicates the model and presents an empirical test of the underlying conceptual framework derived from social-interactionist/ labeling theory. Again, ADP is found to result in less official delinquency than the 'warn and release' or juvenile justice processing conditions. Perceived negative labeling is related to increased delinquency while perceived awareness of youth activities without labeling is related to reduced delinquency. The results highlight the importance of the family, community, and juvenile justice contexts and their reactions to juvenile delinquency. [ABSTRACT FROM AUTHOR]

Women's (N = 205) IPV experiences were assessed during their pregnancies, in the year before their pregnancies, and with their previous partners. The study explored whether psychosocial indicators and severity of violence could be predicted from a woman's continuity and history of IPV. Two 4-group classifications-partner (IPV experiences across partners) and time (history of IPV experiences)-and one 2-group classification (IPV or no IPV in the past 6 months) were compared. Both four-group classifications accounted for more variance than did the two-group. Within the four-group classifications, most of the significant differences on psychosocial out-comes and severity of IPV were between the no IPV and chronic IPV groups (IPV experiences with two partners and across three different time periods). However, the groups that also fared poorly were those who experienced recent IPV and continuity of IPV across time with their current partners. [ABSTRACT FROM AUTHOR]

We assessed the incidence of sexual violence, physical violence, physical health symptoms, gynecological symptoms, and risk behaviors for contracting an STD or HIV infection in women who had used a shelter for women with abusive partners. In addition, we investigated the relationships between sexual violence and the frequency of physical health symptoms, including specific gynecological symptoms. Results indicated that one fourth of the women interviewed had experienced sexual violence and nearly two thirds of the women had experienced physical violence in the past 6 months. The incidence of physical health symptoms, gynecological symptoms, and risk behaviors for exposure to STDs and HIV infection are presented. The correlations among sexual violence, physical violence, and experiences of physical health symptoms are also reported. This study is particularly valuable because previous research has not documented the relationship between sexual violence and physical health symptoms. [ABSTRACT FROM AUTHOR]

Bardet-Biedl Syndrome (BBS) is an autosomal recessive, multisystem, genetically heterogeneous, ciliopathic condition caused by mutations in multiple genes. Here we sought to determine if inheritance of a single BBS mutation increased the risks of frequent disorders of this syndrome such as obesity, hypertension, and diabetes. Various metabolic and renal diseases in a cohort of 46 patients with BBS, prospectively followed for up to 28 years, were compared to recent assessments of these factors in 96 relatives with a heterozygote mutation (carriers) and 37 relatives without a contributing mutation (non-carriers). Ten mutations in 6 genes causing this syndrome were identified in 21 families from whom DNA was obtained. The body mass index or the incidences of hypertension, diabetes, or stage 3 chronic kidney diseases were found to be similar between carriers and non-carriers but were all significantly less than those of family members with BBS. Similarly, the median age of onset of hypertension or diagnosis of stage 3 kidney disease, or the diagnosis of diabetes by age 70 were all significantly lower in those with BBS than in gene carriers or non-carriers. While our study shows that metabolic and renal events occurred frequently and at an early age in BBS, the heterozygous inheritance of any of the 10 described BBS mutations did not predispose family members to obesity, diabetes, hypertension, or renal impairment. [ABSTRACT FROM AUTHOR]

Purpose of Review: Doubts about whether high-density lipoprotein-cholesterol (HDL-C) levels are causally related to atherosclerotic cardiovascular disease (CVD) risk have stimulated research on identifying HDL-related metrics that might better reflect its cardioprotective functions. HDL is made up of different types of particles that vary in size, protein and lipid composition, and function. This review focuses on recent findings on the specific roles of HDL subpopulations defined by size in CVD., Recent Findings: Small HDL particles are more effective than larger particles at promoting cellular cholesterol efflux because apolipoprotein A-I on their surface better engages ABCA1 (ATP binding cassette subfamily A member 1). In contrast, large HDL particles bind more effectively to scavenger receptor class B type 1 on endothelial cells, which helps prevent LDL from moving into the artery wall. The specific role of medium-sized HDL particles, the most abundant subpopulation, is still unclear., Summary: HDL is made up of subpopulations of different sizes of particles, with selective functional roles for small and large HDLs. The function of HDL may depend more on the size and composition of its subpopulations than on HDL-C levels. Further research is required to understand how these different HDL subpopulations influence the development of CVD., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Transmission of vector-borne diseases can be slowed by symbionts within the secondary hosts that spread disease. Snails spread schistosomiasis, and the snail symbiont Capsaspora owczarzaki kills schistosome larvae. In studying how Capsaspora colonizes its host snail, we discovered that Capsaspora responded to its host by forming multicellular aggregates. We elucidated the chemical cue for aggregation: hemolymph phosphatidylcholines (PCs). Furthermore, we uncovered that Capsaspora cells aggregate to different degrees in sera from different host snails-and these responses correlate with serum concentrations of PCs. Therefore, Capsaspora senses a host factor that can indicate the identity and physiological state of its host. Since cellular aggregation controls microbial motility, feeding, and immune evasion, this response within host tissue may be important for colonization. If so, snail serum PC and Capsaspora aggregation will be molecular and cellular markers to discern which conditions will favor the colonization of snails (and potential exclusion of schistosomes) by Capsaspora ., Competing Interests: The authors declare no competing interests., (© 2024 The Author(s).)

Background: The cholesterol efflux capacity of high density lipoprotein (HDL) is negatively associated with cardiovascular risk. Small HDL particles account almost quantitatively for cholesterol efflux capacity, perhaps mediated through efflux of cholesterol and outer leaflet plasma membrane phospholipids by ABCA1 (ATP binding cassette subfamily A member 1). People with type 1 diabetes are at increased coronary artery disease (CAD) risk despite normal HDL-cholesterol concentrations. We therefore tested the hypothesis that small HDL particles (HDL-P)-rather than HDL-cholesterol-predict incident CAD in type 1 diabetes., Methods and Results: Incident CAD (CAD death, myocardial infarction, or coronary revascularization) was determined in 550 individuals with childhood-onset type 1 diabetes. HDL-P was quantified by calibrated ion mobility analysis and cholesterol efflux capacity was quantified with validated assays. During a median follow-up of 26 years, 36.5% of the participants developed incident CAD, for an incidence density of 181.3 per 10 000 person-years. In multivariable Cox models, neither HDL-cholesterol nor apolipoprotein A1 concentration was significantly associated with CAD risk. In contrast, higher extra-small HDL-P concentrations were significantly associated with decreased CAD risk (hazard ratio [HR], 0.26 [95% CI, 0.14-0.50]). Weaker associations were observed for total HDL-P (HR, 0.88 [95% CI, 0.83-0.93]), small HDL (HR, 0.83 [95% CI, 0.68-1.02]), medium HDL (HR, 0.79 [95% CI, 0.71-0.89]), and large HDL (HR, 0.72 [95% CI, 0.59-0.89]). Although cholesterol efflux capacity was negatively associated with incident CAD, this association was no longer significant after adjustment for total HDL-P., Conclusions: Lower concentrations of total HDL-P and HDL subpopulations were positively associated with incident CAD independently of HDL-cholesterol, apolipoprotein A1, and other common CVD risk factors. Extra-small HDL was a much stronger predictor of risk than the other HDLs. Our data are consistent with the proposal that extra-small HDL plays a critical role in cardioprotection in type 1 diabetes, mediated by macrophage cholesterol efflux by the ABCA1 pathway.

Objective: Weight loss following vertical sleeve gastrectomy (VSG) in youth can range from 10% to 50%. We examined whether there are differences in demographic or metabolic parameters before VSG in youth who achieve above-average weight loss (AAWL) versus below-average weight loss (BAWL) at 1 year post VSG and if youth with BAWL still achieve metabolic health improvements at 1 year post VSG., Methods: Demographic, anthropometric, and clinical lab data were collected before VSG and at 1, 3, 6, and 12 months after VSG., Results: Forty-three youth with a mean age of 16.9 (SD 1.7) years before VSG were studied; 70% were female, 19% non-Hispanic Black, 58% non-Hispanic White, and 23% mixed/other race. Mean baseline BMI was 51.1 (SD 10.5) kg/m 2 . Average weight loss was 25.8%. The AAWL group lost 18.6 kg/m 2 (35.3%) versus the BAWL group, who lost 8.8 kg/m 2 (17.5%). BMI, age, race, sex, and socioeconomic status at baseline were similar between AAWL and BAWL groups; however, the BAWL group had a higher frequency of pre-VSG dysglycemia, steatotic liver disease, and dyslipidemia. At 1 year post VSG, fewer youth in the BAWL group achieved ideal health parameters, and they had less resolution of comorbidities., Conclusions: The presence of comorbidities before VSG is associated with less weight loss and reduced resolution of metabolic conditions at 1 year post VSG., (© 2024 The Authors. Obesity published by Wiley Periodicals LLC on behalf of The Obesity Society.)

Several studies in animal models and human cohorts have recently suggested that HDLs (high-density lipoproteins) not only modulate innate immune responses but also adaptative immune responses, particularly CD4+ T cells. CD4+ T cells are central effectors and regulators of the adaptive immune system, and any alterations in their homeostasis contribute to the pathogenesis of cardiovascular diseases, autoimmunity, and inflammatory diseases. In this review, we focus on how HDLs and their components affect CD4+ T-cell homeostasis by modulating cholesterol efflux, immune synapsis, proliferation, differentiation, oxidative stress, and apoptosis. While the effects of apoB-containing lipoproteins on T cells have been relatively well established, this review focuses specifically on new connections between HDL and CD4+ T cells. We present a model where HDL may modulate T cells through both direct and indirect mechanisms., Competing Interests: Disclosures None.

HDL particles vary in lipidome and proteome, which dictate their individual physicochemical properties, metabolism, and biological activities. HDL dysmetabolism in nondiabetic hypertriglyceridemia (HTG) involves subnormal HDL-cholesterol and apoAI levels. Metabolic anomalies may impact the qualitative features of both the HDL lipidome and proteome. Whether particle content of bioactive lipids and proteins may differentiate HDL subclasses (HDL2b, 2a, 3a, 3b, and 3c) in HTG is unknown. Moreover, little is known of the effect of statin treatment on the proteolipidome of hypertriglyceridemic HDL and its subclasses. Nondiabetic, obese, HTG males (n = 12) received pitavastatin calcium (4 mg/day) for 180 days in a single-phase, unblinded study. ApoB-containing lipoproteins were normalized poststatin. Individual proteolipidomes of density-defined HDL subclasses were characterized prestatin and poststatin. At baseline, dense HDL3c was distinguished by marked protein diversity and peak abundance of surface lysophospholipids, amphipathic diacylglycerol and dihydroceramide, and core cholesteryl ester and triacylglycerol, (normalized to mol phosphatidylcholine), whereas light HDL2b showed peak abundance of free cholesterol, sphingomyelin, glycosphingolipids (monohexosylceramide, dihexosylceramide, trihexosylceramide, and anionic GM3), thereby arguing for differential lipid transport and metabolism between subclasses. Poststatin, bioactive lysophospholipid (lysophosphatidylcholine, lysoalkylphosphatidylcholine, lysophosphatidylethanolamine, and lysophosphatidylinositol) cargo was preferentially depleted in HDL3c. By contrast, baseline lipidomic profiles of ceramide, dihydroceramide and related glycosphingolipids, and GM3/phosphatidylcholine were maintained across particle subclasses. All subclasses were depleted in triacylglycerol and diacylglycerol/phosphatidylcholine. The abundance of apolipoproteins CI, CII, CIV, and M diminished in the HDL proteome. Statin treatment principally impacts metabolic remodeling of the abnormal lipidome of HDL particle subclasses in nondiabetic HTG, with lesser effects on the proteome., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The binding of low-density lipoprotein (LDL) to proteoglycans (PGs) in the extracellular matrix (ECM) of the arterial intima is a key initial step in the development of atherosclerosis. Although many techniques have been developed to assess this binding, most of the methods are labor-intensive and technically challenging to standardize across research laboratories. Thus, sensitive, and reproducible assay to detect LDL binding to PGs is needed to screen clinical populations for atherosclerosis risk., Objectives: The aim of this study was to develop a quantitative, and reproducible assay to evaluate the affinity of LDL towards PGs and to replicate previously published results on LDL-PG binding., Methods: Immunofluorescence microscopy was performed to visualize the binding of LDL to PGs using mouse vascular smooth muscle (MOVAS) cells. An in-cell ELISA (ICE) was also developed and optimized to quantitatively measure LDL-PG binding using fixed MOVAS cells cultured in a 96-well format., Results: We used the ICE assay to show that, despite equal APOB concentrations, LDL isolated from adults with cardiovascular disease bound to PG to a greater extent than LDL isolated from adults without cardiovascular disease (p<0.05)., Conclusion: We have developed an LDL-PG binding assay that is capable of detecting differences in PG binding affinities despite equal APOB concentrations. Future work will focus on candidate apolipoproteins that enhance or diminish this interaction., Competing Interests: The authors have declared that no competing interests exist., (Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.)

Purpose of Review: ATP-binding cassette transporter A1 (ABCA1) plays a key role in high-density lipoprotein (HDL) biogenesis and cholesterol export from artery wall cells. Recent evidence challenges the generally accepted model for lipid transport by ABCA1, termed the alternating access mechanism, which proposes that phospholipid moves from the inner leaflet to the outer leaflet of the plasma membrane., Recent Findings: In contrast to the standard model, our computer simulations of ABCA1 indicate that ABCA1 extracts phospholipid from the plasma membrane's outer leaflet. The lipid then diffuses into the interior of ABCA1 to contact a structure termed the 'gateway'. A conformational change opens the gateway and forces the lipid through a ring-shaped domain, the 'annulus orifice', into the base of an elongated hydrophobic tunnel in the transporter's extracellular domain. Engineered mutations in the gateway and annulus strongly inhibited lipid export by ABCA1 without affecting cell-surface expression levels of the transporter, strongly supporting the proposed model., Summary: Our demonstration that ABCA1 extracts lipid from the outer face of the plasma membrane and forces it into an elongated hydrophobic tunnel contrasts with the alternating access model, which flops phospholipid from the membrane's inner leaflet to its outer leaflet. These results suggest that ABCA1 is a phospholipid translocase that transports lipids by a mechanism distinct from that of other ABC transporters., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Type 1 diabetes (T1D) results from an autoimmune attack of the pancreatic β cells that progresses to dysglycemia and symptomatic hyperglycemia. Current biomarkers to track this evolution are limited, with development of islet autoantibodies marking the onset of autoimmunity and metabolic tests used to detect dysglycemia. Therefore, additional biomarkers are needed to better track disease initiation and progression. Multiple clinical studies have used proteomics to identify biomarker candidates. However, most of the studies were limited to the initial candidate identification, which needs to be further validated and have assays developed for clinical use. Here we curate these studies to help prioritize biomarker candidates for validation studies and to obtain a broader view of processes regulated during disease development., Methods: This systematic review was registered with Open Science Framework ( https://doi.org/10.17605/OSF.IO/N8TSA ). Using PRISMA guidelines, we conducted a systematic search of proteomics studies of T1D in the PubMed to identify putative protein biomarkers of the disease. Studies that performed mass spectrometry-based untargeted/targeted proteomic analysis of human serum/plasma of control, pre-seroconversion, post-seroconversion, and/or T1D-diagnosed subjects were included. For unbiased screening, 3 reviewers screened all the articles independently using the pre-determined criteria., Results: A total of 13 studies met our inclusion criteria, resulting in the identification of 266 unique proteins, with 31 (11.6%) being identified across 3 or more studies. The circulating protein biomarkers were found to be enriched in complement, lipid metabolism, and immune response pathways, all of which are found to be dysregulated in different phases of T1D development. We found 2 subsets: 17 proteins (C3, C1R, C8G, C4B, IBP2, IBP3, ITIH1, ITIH2, BTD, APOE, TETN, C1S, C6A3, SAA4, ALS, SEPP1 and PI16) and 3 proteins (C3, CLUS and C4A) have consistent regulation in at least 2 independent studies at post-seroconversion and post-diagnosis compared to controls, respectively, making them strong candidates for clinical assay development., Conclusions: Biomarkers analyzed in this systematic review highlight alterations in specific biological processes in T1D, including complement, lipid metabolism, and immune response pathways, and may have potential for further use in the clinic as prognostic or diagnostic assays., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Plasma levels of HDL cholesterol are inversely associated with CVD progression. It is becoming increasingly clear that HDL plays important roles in immunity that go beyond its traditionally understood roles in lipid transport. We previously reported that HDL interaction with regulatory T cells (Treg) protected them from apoptosis, which could be a mechanism underlying the broad anti-inflammatory effect of HDL. Herein, we extend our work to show that HDL interacts mainly with memory Treg, particularly with the highly suppressive effector memory Treg, by limiting caspase-dependent apoptosis in an Akt-dependent manner. Reconstitution experiments identified the protein component of HDL as the primary driver of the effect, though the most abundant HDL protein, apolipoprotein A-I (APOA1), was inactive. In contrast, APOE-depleted HDL failed to rescue effector memory Treg, suggesting the critical role of APOE proteins. HDL particles reconstituted with APOE, and synthetic phospholipids blunted Treg apoptosis at physiological concentrations. The APOE3 and APOE4 isoforms were the most efficient. Similar results were obtained when lipid-free recombinant APOEs were tested. Binding experiments showed that lipid-free APOE3 bound to memory Treg but not to naive Treg. Overall, our results show that APOE interaction with Treg results in blunted caspase-dependent apoptosis and increased survival. As dysregulation of HDL-APOE levels has been reported in CVD and obesity, our data bring new insight on how this defect may contribute to these diseases., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Lipoproteins in cerebrospinal fluid (CSF) of the central nervous system (CNS) resemble plasma high-density lipoproteins (HDLs), which are a compositionally and structurally diverse spectrum of nanoparticles with pleiotropic functionality. Whether CSF lipoproteins (CSF-Lps) exhibit similar heterogeneity is poorly understood because they are present at 100-fold lower concentrations than plasma HDL. To investigate the diversity of CSF-Lps, we developed a sensitive fluorescent technology to characterize lipoprotein subspecies in small volumes of human CSF. We identified 10 distinctly sized populations of CSF-Lps, most of which were larger than plasma HDL. Mass spectrometric analysis identified 303 proteins across the populations, over half of which have not been reported in plasma HDL. Computational analysis revealed that CSF-Lps are enriched in proteins important for wound healing, inflammation, immune response, and both neuron generation and development. Network analysis indicated that different subpopulations of CSF-Lps contain unique combinations of these proteins. Our study demonstrates that CSF-Lp subspecies likely exist that contain compositional signatures related to CNS health.

Long-chain fatty acids induce apolipoprotein A4 (APOA4) production in the small intestine and activate brown adipose tissue (BAT) thermogenesis. The increase in BAT thermogenesis enhances triglyceride clearance and insulin sensitivity. Acute administration of recombinant APOA4 protein elevates BAT thermogenesis in chow-fed mice. However, the physiological role of continuous infusion of recombinant APOA4 protein in regulating sympathetic activity, thermogenesis, and lipid and glucose metabolism in low-fat-diet (LFD)-fed mice remained elusive. The hypothesis of this study was that continuous infusion of mouse APOA4 protein would increase sympathetic activity and thermogenesis in BAT and subcutaneous inguinal white adipose tissue (IWAT), attenuate plasma lipid levels, and improve glucose tolerance. To test this hypothesis, sympathetic activity, BAT temperature, energy expenditure, body weight, fat mass, caloric intake, glucose tolerance, and levels of BAT and IWAT thermogenic and lipolytic proteins, plasma lipids, and markers of fatty acid oxidation in the liver in mice with APOA4 or saline treatment were measured. Plasma APOA4 levels were elevated, BAT temperature and thermogenesis were upregulated, and plasma triglyceride (TG) levels were reduced, while body weight, fat mass, caloric intake, energy expenditure, and plasma cholesterol and leptin levels were comparable between APOA4- and saline-treated mice. Additionally, APOA4 infusion stimulated sympathetic activity in BAT and liver but not in IWAT. APOA4-treated mice had greater fatty acid oxidation but less TG content in the liver than saline-treated mice had. Plasma insulin in APOA4-treated mice was lower than that in saline-treated mice after a glucose challenge. In conclusion, continuous infusion of mouse APOA4 protein stimulated sympathetic activity in BAT and the liver, elevated BAT thermogenesis and hepatic fatty acid oxidation, and consequently attenuated levels of plasma and hepatic TG and plasma insulin without altering caloric intake, body weight gain and fat mass.

Regulated cellular aggregation is an essential process for development and healing in many animal tissues. In some animals and a few distantly related unicellular species, cellular aggregation is regulated by diffusible chemical cues. However, it is unclear whether regulated cellular aggregation was part of the life cycles of the first multicellular animals and/or their unicellular ancestors. To fill this gap, we investigated the triggers of cellular aggregation in one of animals' closest unicellular living relatives-the filasterean Capsaspora owczarzaki . We discovered that Capsaspora aggregation is induced by chemical cues, as observed in some of the earliest branching animals and other unicellular species. Specifically, we found that calcium ions and lipids present in lipoproteins function together to induce aggregation of viable Capsaspora cells. We also found that this multicellular stage is reversible as depletion of the cues triggers disaggregation, which can be overcome upon reinduction. Our finding demonstrates that chemically regulated aggregation is important across diverse members of the holozoan clade. Therefore, this phenotype was plausibly integral to the life cycles of the unicellular ancestors of animals.

Coho salmon (Oncorhynchus kisutch) are a culturally and economically important species that return from multiyear ocean migrations to spawn in rivers that flow to the Northern Pacific Ocean. Southern stocks of coho salmon in Canada and the United States have significantly declined over the past quarter century, and unfortunately, conservation efforts have not reversed this trend. To assist in stock management and conservation efforts, we generated a chromosome-level genome assembly. We also resequenced the genomes of 83 coho salmon across the North American range to identify nucleotide variants and understand the demographic histories of these salmon by modeling effective population size from genome-wide data. From demographic history modeling, we observed reductions in effective population sizes between 3,750 and 8,000 years ago for several northern sampling sites, which may correspond to bottleneck events during recolonization after glacial retreat., Competing Interests: Conflicts of interest statement The authors declare no conflict of interest., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Genetics Society of America.)

Cardiovascular disease (CVD) is a leading cause of enhanced morbidity and mortality in persons with HIV (PWH) in the era of highly active antiretroviral therapy (AART). However, the underlying mechanisms are not fully understood. Regulatory T cells (Treg), notably the highly suppressive memory subset, have been shown to limit CVD. Importantly, memory Treg cell numbers remain low in many treated PWH. High density lipoproteins (HDL) also protect from CVD, and we previously found that Treg-HDL interactions reduce oxidative stress in these cells. Here, we evaluated Treg-HDL interactions in PWH and whether they were operative in those higher CVD risk. To do that, we recruited a cohort of PWH with intermediate/high CVD risk (median ASCVD risk score of 13.2%, n=15) or low/borderline risk (median ASCVD risk score of 3.6%, n=14), as well as a group of statins treated PWH with intermediate/high CVD risk (median ASCVD risk score of 12.7%, n=14). We evaluated Treg frequency, phenotype and response to HDL. PWH with Int/High CVD risk had a significantly lower number of memory Treg, but memory Treg were more activated and displayed an inflammatory phenotype, versus those with Low/BL CVD risk. In untreated patients, Treg absolute numbers were negatively correlated with ASCVD score. Although HDL decreased oxidative stress in memory Treg in all subjects, memory Treg from PWH with Int/High CVD risk were significantly less responsive to HDL than those from PWH with Low/BL CVD risk. The level of oxidative stress in memory Treg positively correlated with ASCVD scores. In contrast, plasma HDL from PWH, regardless of CVD risk, retained their anti-oxidative properties, suggesting that the defect in memory Treg response to HDL is intrinsic. Statin treatment partially ameliorated the memory Treg defect. In conclusion, the defective HDL-Treg interactions may contribute to the inflammation-induced increased CVD risk observed in many AART-treated PWH., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Atehortua, Baig, Morris, Trentman, Davidson, Fichtenbaum and Chougnet.)

Background: Lipoprotein subfraction concentrations have been shown to change as gestation progresses in resource-rich settings. The objective of the current study was to evaluate the impact of pregnancy on different-sized lipoprotein particle concentrations and compositions in a resource-poor setting., Method: Samples were collected from pregnant women in rural Gambia at enrollment (8-20 weeks), 20 weeks, and 30 weeks of gestation. Concentrations of different-sized high-density, low-density, and triglyceride-rich lipoprotein particles (HDL, LDL, and TRL, respectively) were measured by nuclear magnetic resonance in 126 pooled plasma samples from a subset of women. HDL was isolated and the HDL proteome evaluated using mass spectroscopy. Subfraction concentrations from women in The Gambia were also compared to concentrations in women in the U.S. in mid gestation., Results: Total lipoprotein particles and all-sized TRL, LDL, and HDL particle concentrations increased during gestation, with the exception of medium-sized LDL and HDL particles which decreased. Subfraction concentrations were not associated with infant birth weights, though relationships were found between some lipoprotein subfraction concentrations in women with normal versus low birth weight infants (< 2500 kg). HDL's proteome also changed during gestation, showing enrichment in proteins associated with metal ion binding, hemostasis, lipid metabolism, protease inhibitors, proteolysis, and complement activation. Compared to women in the U.S., Gambian women had lower large- and small-sized LDL and HDL concentrations, but similar medium-sized LDL and HDL concentrations., Conclusions: Most lipoprotein subfraction concentrations increase throughout pregnancy in Gambian women and are lower in Gambian vs U.S. women, the exception being medium-sized LDL and HDL particle concentrations which decrease during gestation and are similar in both cohorts of women. The proteomes of HDL also change in ways to support gestation. These changes warrant further study to determine how a lack of change or different changes could impact negative pregnancy outcomes., (© 2023. The Author(s).)

Production of high density lipoprotein (HDL) requires ATP-binding cassette transporter A1 (ABCA1) to drive phospholipid (PL) from the plasma membrane into extracellular apolipoprotein A-I. Here, we use simulations to show that domains of ABCA1 within the plasma membrane remove PL from the membrane's outer leaflet. In our simulations, after the lipid diffuses into the interior of ABCA1's outward-open cavity, PL extracted by the gateway passes through a ring-shaped domain, the annulus orifice, which forms the base of an elongated hydrophobic tunnel in the transporter's extracellular domain. Engineered mutations in the gateway and annulus strongly inhibit lipid export by ABCA1 without affecting cell-surface expression levels. Our finding that ABCA1 extracts lipid from the outer face of the plasma membrane and forces it through its gateway and annulus into an elongated hydrophobic tunnel contrasts with the alternating access model, which proposes that ABCA1 flops PL substrate from the inner leaflet to the outer leaflet of the membrane. Consistent with our model, ABCA1 lacks the charged amino acid residues in the transmembrane domain found in the floppase members of the ABC transporter family., (© 2022. The Author(s).)

Atherosclerotic CVD is the major cause of death in patients with type 1 diabetes mellitus (T1DM). Alterations in the HDL proteome have been shown to associate with prevalent CVD in T1DM. We therefore sought to determine which proteins carried by HDL might predict incident CVD in patients with T1DM. Using targeted MS/MS, we quantified 50 proteins in HDL from 181 T1DM subjects enrolled in the prospective Coronary Artery Calcification in Type 1 Diabetes study. We used Cox proportional regression analysis and a case-cohort design to test associations of HDL proteins with incident CVD (myocardial infarction, coronary artery bypass grafting, angioplasty, or death from coronary heart disease). We found that only one HDL protein-SFTPB (pulmonary surfactant protein B)-predicted incident CVD in all the models tested. In a fully adjusted model that controlled for lipids and other risk factors, the hazard ratio was 2.17 per SD increase of SFTPB (95% confidence interval, 1.12-4.21, P = 0.022). In addition, plasma fractionation demonstrated that SFTPB is nearly entirely bound to HDL. Although previous studies have shown that high plasma levels of SFTPB associate with prevalent atherosclerosis only in smokers, we found that SFTPB predicted incident CVD in T1DM independently of smoking status and a wide range of confounding factors, including HDL-C, LDL-C, and triglyceride levels. Because SFTPB is almost entirely bound to plasma HDL, our observations support the proposal that SFTPB carried by HDL is a marker-and perhaps mediator-of CVD risk in patients with T1DM., Competing Interests: Conflict of interest Jay Heinecke is named as a coinventor on patents for using oxidation and protein markers to predict the risk of CVD. All other authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Because of its critical role in HDL formation, significant efforts have been devoted to studying apolipoprotein A-I (APOA1) structural transitions in response to lipid binding. To assess the requirements for the conformational freedom of its termini during HDL particle formation, we generated three dimeric APOA1 molecules with their termini covalently joined in different combinations. The dimeric (d)-APOA1C-N mutant coupled the C-terminus of one APOA1 molecule to the N-terminus of a second with a short alanine linker, whereas the d-APOA1C-C and d-APOA1N-N mutants coupled the C-termini and the N-termini of two APOA1 molecules, respectively, using introduced cysteine residues to form disulfide linkages. We then tested the ability of these constructs to generate reconstituted HDL by detergent-assisted and spontaneous phospholipid microsolubilization methods. Using cholate dialysis, we demonstrate WT and all APOA1 mutants generated reconstituted HDL particles of similar sizes, morphologies, compositions, and abilities to activate lecithin:cholesterol acyltransferase. Unlike WT, however, the mutants were incapable of spontaneously solubilizing short chain phospholipids into discoidal particles. We found lipid-free d-APOA1C-N and d-APOA1N-N retained most of WT APOA1's ability to promote cholesterol efflux via the ATP binding cassette transporter A1, whereas d-APOA1C-C exhibited impaired cholesterol efflux. Our data support the double belt model for a lipid-bound APOA1 structure in nascent HDL particles and refute other postulated arrangements like the "double super helix." Furthermore, we conclude the conformational freedom of both the N- and C-termini of APOA1 is important in spontaneous microsolubilization of bulk phospholipid but is not critical for ABCA1-mediated cholesterol efflux., Competing Interests: Conflict of interest The authors state no conflict of interest., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose of Review: High density lipoproteins (HDL) are a heterogeneous family of particles that contain distinct complements of proteins that define their function. Thus, it is important to accurately and sensitively identify proteins associated with HDL. Here we highlight the HDL Proteome Watch Database which tracks proteomics studies from different laboratories across the world., Recent Findings: In 45 published reports, almost 1000 individual proteins have been detected in preparations of HDL. Of these, 251 have been identified in at least three different laboratories. The known functions of these consensus HDL proteins go well beyond traditionally recognized roles in lipid transport with many proteins pointing to HDL functions in innate immunity, inflammation, cell adhesion, hemostasis and protease regulation, and even vitamin and metal binding., Summary: The HDL proteome derived across multiple studies using various methodologies provides confidence in protein identifications that can offer interesting new insights into HDL function. We also point out significant issues that will require additional study going forward., (Copyright © 2021 Elsevier B.V. All rights reserved.)

High levels of circulating triglycerides (TGs), or hypertriglyceridemia, are key components of metabolic diseases, such as type 2 diabetes, metabolic syndrome, and CVD. As TGs are carried by lipoproteins in plasma, hypertriglyceridemia can result from overproduction or lack of clearance of TG-rich lipoproteins (TRLs) such as VLDLs. The primary driver of TRL clearance is TG hydrolysis mediated by LPL. LPL is regulated by numerous TRL protein components, including the cofactor apolipoprotein C-II, but it is not clear how their effects combine to impact TRL hydrolysis across individuals. Using a novel assay designed to mimic human plasma conditions in vitro, we tested the ability of VLDL from 15 normolipidemic donors to act as substrates for human LPL. We found a striking 10-fold difference in hydrolysis rates across individuals when the particles were compared on a protein or a TG basis. While VLDL TG contents moderately correlated with hydrolysis rate, we noticed substantial variations in non-apoB proteins within these particles by MS. The ability of LPL to hydrolyze VLDL TGs did not correlate with apolipoprotein C-II content, but it was strongly inversely correlated with apolipoprotein E (APOE) and, to a lesser extent, apolipoprotein A-II. Addition of exogenous APOE inhibited LPL lipolysis in a dose-dependent manner. The APOE3 and (particularly) APOE4 isoforms were effective at limiting LPL hydrolysis, whereas APOE2 was not. We conclude that APOE on VLDL modulates LPL activity and could be a relevant factor in the pathogenesis of metabolic disease., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

OBJECTIVE: Niacin therapy fails to reduce cardiovascular events in statin-treated subjects even though it increases plasma HDL-C (HDL [high-density lipoprotein] cholesterol) and decreases LDL-C (LDL [low-density lipoprotein] cholesterol) and triglyceride levels. To investigate potential mechanisms for this lack of cardioprotection, we quantified the HDL proteome of subjects in 2 niacin clinical trials: the CPC study (Carotid Plaque Composition) and the HDL Proteomics substudy of the AIM-HIGH trial (Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides). APPROACH AND RESULTS: Using targeted proteomics, we quantified levels of 31 HDL proteins from 124 CPC subjects and 120 AIM-HIGH subjects. The samples were obtained at baseline and after 1 year of statin monotherapy or niacin-statin combination therapy. Compared with statin monotherapy, niacin-statin combination therapy did not reduce HDL-associated apolipoproteins APOC1, APOC2, APOC3, and APOC4, despite significantly lowering triglycerides. In contrast, niacin markedly elevated HDL-associated PLTP (phospholipid transfer protein), CLU (clusterin), and HP/HPR (haptoglobin/haptoglobinrelated proteins; P≤0.0001 for each) in both the CPC and AIM-HIGH cohorts. CONCLUSIONS: The addition of niacin to statin therapy resulted in elevated levels of multiple HDL proteins linked to increased atherosclerotic risk, which might have compromised the cardioprotective effects associated with higher HDL-C levels and lower levels of LDL-C and triglycerides. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT00715273; NCT00880178; NCT00120289.

The biogenesis of high-density lipoprotein (HDL) requires apoA1 and the cholesterol transporter ABCA1. Although the liver generates most of the HDL in the blood, HDL synthesis also occurs in the small intestine. Here, we show that intestine-derived HDL traverses the portal vein in the HDL 3 subspecies form, in complex with lipopolysaccharide (LPS)-binding protein (LBP). HDL 3 , but not HDL 2 or low-density lipoprotein, prevented LPS binding to and inflammatory activation of liver macrophages and instead supported extracellular inactivation of LPS. In mouse models involving surgical, dietary, or alcoholic intestinal insult, loss of intestine-derived HDL worsened liver injury, whereas outcomes were improved by therapeutics that elevated and depended upon raising intestinal HDL. Thus, protection of the liver from injury in response to gut-derived LPS is a major function of intestinally synthesized HDL., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Apolipoprotein A4 (APOA4) is one of the most abundant and versatile apolipoproteins facilitating lipid transport and metabolism. APOA4 is synthesized in the small intestine, packaged onto chylomicrons, secreted into intestinal lymph and transported via circulation to several tissues, including adipose. Since its discovery nearly 4 decades ago, to date, only platelet integrin αIIbβ3 has been identified as APOA4 receptor in the plasma. Using co-immunoprecipitation coupled with mass spectrometry, we probed the APOA4 interactome in mouse gonadal fat tissue, where ApoA4 gene is not transcribed but APOA4 protein is abundant. We demonstrate that lipoprotein receptor-related protein 1 (LRP1) is the cognate receptor for APOA4 in adipose tissue. LRP1 colocalized with APOA4 in adipocytes; it interacted with APOA4 under fasting condition and their interaction was enhanced during lipid feeding concomitant with increased APOA4 levels in plasma. In 3T3-L1 mature adipocytes, APOA4 promoted glucose uptake both in absence and presence of insulin in a dose-dependent manner. Knockdown of LRP1 abrogated APOA4-induced glucose uptake as well as activation of phosphatidylinositol 3 kinase (PI3K)-mediated protein kinase B (AKT). Taken together, we identified LRP1 as a novel receptor for APOA4 in promoting glucose uptake. Considering both APOA4 and LRP1 are multifunctional players in lipid and glucose metabolism, our finding opens up a door to better understand the molecular mechanisms along APOA4-LRP1 axis, whose dysregulation leads to obesity, cardiovascular disease, and diabetes.

Purpose of Review: The term high density lipoproteins (HDL) refers to an eclectic collection of subparticles that play diverse roles in physiology. Here, we define the term "HDL subspecies" and review recent work on their molecular characterization and relation to disease, focusing on cardiovascular disease and diabetes., Recent Findings: The HDL family contains over 200 proteins and nearly 200 lipids that partition into different particles in plasma. Simple subfractionation of HDL based on a particular physicochemical property has not risen to the challenge of revealing the roles of specific particles in disease. However, by targeting minor protein or lipid components, a handful of compositionally defined HDL subspecies have been described and characterized. By combining targeted particle isolation techniques with the power of large human studies, progress is being made in understanding HDL subspecies functions and implications for disease. However, much work remains before these advancements can be translated into disease mitigation strategies.