The Gram-negative outer membrane is a potent permeability barrier against antibiotics, limiting clinical options amid mounting rates of resistance. The Lol transport pathway delivers lipoproteins to the OM. All the OM assembly machines require one or more OM lipoprotein to function, making the Lol pathway central for all aspects of OM biogenesis. The Lol pathways of many medically important species clearly deviate from the Escherichia coli paradigm, perhaps with implications for efforts to develop novel antibiotics. Moreover, recent work reveals (...) the existence of an undiscovered alternate route for bringing lipoproteins to the OM. Here, lipoprotein transport mechanisms, and the quality control systems that underpin them, is re-examined in context of their diversity. All essential outer membrane assembly machines require lipoproteins to function. Hence, the transport mechanisms supplying these lipoproteins are critical for maintaining the integrity of the outer membrane barrier against antibiotics. Lipoprotein transport strategies of diverse Gram-negative bacteria will be reviewed in the context of recent discoveries. (shrink)

Lower plasma levels of high-density lipoproteins in adolescents with type 2 diabetes have been associated with a higher pulse wave velocity, a marker of arterial stiffness. Evidence suggests that HDL proteins or particle subspecies are altered in T2D and these may drive these relationships. In this work, we set out to reveal any specific proteins and subspecies that are related to arterial stiffness in youth with T2D from proteomics data. Plasma and PWV measurements were previously acquired from lean and T2D (...) adolescents. Each plasma sample was separated into 18 fractions and evaluated by mass spectrometry. Then, we applied a validated network-based computational approach to reveal HDL subspecies associated with PWV. Among 68 detected phospholipid-associated proteins, we found that seven were negatively correlated with PWV, indicating that they may be atheroprotective. Conversely, nine proteins show positive correlation with PWV, suggesting that they may be related to arterial stiffness. Intriguingly, our results demonstrate that apoA-I and histidine-rich glycoprotein may reverse their protective roles and become antagonistic in the setting of T2D. Furthermore, we revealed two arterial stiffness-associated HDL subspecies, each of which contains multiple PWV-related proteins. Correlation and disease association analyses suggest that these HDL subspecies might link T2D to its cardiovascular-related complications. (shrink)

The concentration of low‐density lipoprotein (LDL) cholesterol (C) in plasma is a key determinant of cardiovascular disease risk and human genetic studies have long endeavoured to elucidate the pathways that regulate LDL metabolism. Massive genome‐wide association studies (GWASs) of common genetic variation associated with LDL‐C in the population have implicated SORT1 in LDL metabolism. Using experimental paradigms and standards appropriate for understanding the mechanisms by which common variants alter phenotypic expression, three recent publications have presented divergent and even contradictory (...) findings. Interestingly, although these reports each linked SORT1 to LDL metabolism, they did not agree on a mechanism to explain the association. Here, we review recent mechanistic studies of SORT1 – the first gene identified by GWAS as a determinant of plasma LDL‐C to be evaluated mechanistically. (shrink)

Atherosclerosis is the major cause of death in the industrialised world. Though much work on the pathogenesis of atherosclerosis points to 'oxidised' low density lipoprotein (LDL) as a key aetiological feature in the generation of the atherosclerotic plaque, the nature of this 'oxidised' LDL in vivo remains an enigma. We argue here that glycated LDL shows many of the characteristics attributed to 'oxidised LDL' and may be the source of the latter in vivo. These include the increased uptake and (...) impaired degradation of glycated LDL by macrophages and the stimulation of transendothelial chemotaxis of monocytes, cytokine secretion and platelet aggregation. We hypothesise that the covalent binding of glycated LDL to the endothelial cell wall may result in the formation of the early atherosclerotic lesion of the fatty streak and that apolipoprotein E may mediate the physiological clearance of glycated moieties. The proposed role of glycation in the pathogenesis of atherosclerosis would explain its high incidence among diabetics and the contentious epidemiological and experimental correlations between dietary sugar and atherosclerosis. (shrink)

Despite recent advances in the research related to air pollution and associated adverse cardiovascular events, the combined effects of air pollution, climate change, and SARS‐CoV‐2 infection on cardiovascular health need to be researched further. This Commentary addresses their impacts on cardiovascular health in the approximately 25 million people with a severe form of inherited hypercholesterolemia, called familial hypercholesterolemia (FH). The arterial endothelium in these individuals is potentially under multiple attacks caused by particles of both endogenous and exogenous origin. Thus, they (...) have a lifelong highly elevated level of circulating low density lipoprotein (LDL) cholesterol which drives premature atherosclerosis. The high levels of LDL particles, often associated with an elevated level of circulating lipoprotein(a) particles, are both capable of inducing and maintaining endothelial dysfunction. Such pre‐existing endothelial dysfunction can be exacerbated by exposure to SARS‐CoV‐2 viral particles, by exposure to fine particulate matter generated by climate change‐associated wildfires, and by dehydration during deadly heatwaves linked to the globally rising temperatures. The external factors can severely worsen the pre‐existing endothelial dysfunction, and thereby significantly increase the risk of a cardiovascular event in the exposed FH patients. (shrink)

All insects appear to have a transport lipoprotein in the hemolymph (blood) that is responsible for moving hydrophobic materials through aqueous compartments. This has been called lipophorin because it is believed to be a reversible transport shuttle. Since most insects undergo some degree of metamorphosis from larval stages to the adult, the need to transport hydrophobic materials or the nature of these materials may change in the course of the life span. This is especially marked in the case of (...) the holometabolous insects – those which undergo drastic change of form, e.g. caterpillar‐pupa‐adult moth. We have found that lipophorin undergoes a molecular metamorphosis paralleling that of the insect. (shrink)

Previous studies have found that serum lipid levels independently associate with mental health problems in adulthood. However, little is known about the association between serum lipid levels and positive aspects of mental health such as resilience and self-esteem, which develop in adolescence. The aim of this study is to examine the association between serum lipid levels and resilience and self-esteem in Japanese adolescents. Data were pooled data from the Adachi Child Health Impact of Living Difficulty study in 2016 and 2018, (...) a school-based, cross-sectional study in Adachi City, Tokyo, Japan. Resilience of the child was assessed by caregivers, and self-esteem was self-identified via questionnaires. Serum lipid levels [total cholesterol, low-density lipoproteins, and high-density lipoproteins ] were assessed in school health checkup, in addition to height and weight measurements. Multiple linear regression was applied to investigate the association between standardized serum lipid levels and resilience and self-esteem. LDL showed inverse association with resilience [β = −1.26, 95% confidence interval = −2.39 to −0.14] after adjusting for child’s BMI, month of birth, sex, absence of parent, household income, caregiver’s mental health, and lifestyle. We also found an inverse association of total cholesterol and higher LDL cholesterol with self-esteem. HDL cholesterol was not associated with resilience and self-esteem. Among Japanese adolescent, total and LDL cholesterol may be biomarkers of resilience and self-esteem. (shrink)

To investigate the effects of two different modes of physical activity on body composition, physical fitness, cardiometabolic risk, and psychological responses in female adolescents participating in a multi-disciplinary program. The 12-week randomized intervention included 25-adolescents with overweight divided into two groups: sports practice-SPG and functional training-FTG. The SPG intervention was divided into three sports: basketball, handball, and futsal. SPG participants performed one sport 3-times/week, over the course of 1 month. The FTG performed concurrent exercises 3-times/week. This study was registered in (...) Clinical Trials Registry Platform under number: RBR-45ywtg and registered in Local Ethics Committee number: 2,505.200/2018. The intensity of physical exercises-PE was matched between groups by the rating of perceived exertion. The primary outcome was body composition, and secondary outcomes were physical fitness, cardiometabolic risk, and psychological responses. There was a significant time-effect for body mass, body mass index, and low-density lipoprotein, all being reduced. There were increases over time for musculoskeletal mass, aerobic fitness, and high-density lipoprotein. There was a group time interaction with body fat percentage being lower post-intervention in the SPG. No significant differences were observed for the other variables. Both physical activity models were effective in improving a subset of obesity-related health parameters. The findings should be extended by further investigation using more sophisticated measures of energy expenditure.Clinical Trial Registration:https://ensaiosclinicos.gov.br/, identifier: RBR-45ywtg. (shrink)

The developing vertebrate oocyte autonomously makes most of the components of the machinery for DNA and protein synthesis, as well as ‘maternal’ mRNAs, needed immediately after fertilization. However, specialized egg constituents such as yolk proteins, egg white, cholesterol, lipoproteins and egg coat substances, are formed in the liver, oviduct and perhaps in follicle cells. The assembly of the developing egg is therefore a fascinating example of division of labor among oocytes and extra‐oocyte tissues, the coordination of activities of the latter (...) being achieved by hormones. (shrink)

Causal models have proven extremely useful in offering formal representations of causal relationships between a set of variables. Yet in many situations, there are non-causal relationships among variables. For example, we may want variables LDL, HDL, and TOT that represent the level of low-density lipoprotein cholesterol, the level of lipoprotein high-density lipoprotein cholesterol, and total cholesterol level, with the relation LDL+HDL=TOT. This cannot be done in standard causal models, because we can intervene simultaneously on all three variables. (...) The goal of this paper is to extend standard causal models to allow for constraints on settings of variables. Although the extension is relatively straightforward, to make it useful we have to define a new intervention operation that disconnects a variable from a causal equation. We give examples showing the usefulness of this extension, and provide a sound and complete axiomatization for causal models with constraints. (shrink)

Brain function depends on the cooperation between highly specialized cells. Neurons generate electrical signals and glial cells provide structural and metabolic support. Here, I propose a new kind of job‐sharing between neurons and astrocytes. Recent studies on primary cultures of highly purified neurons from the rodent central nervous system (CNS) suggest that, during development, neurons reduce or even abandon cholesterol synthesis to save energy and import cholesterol from astrocytes via lipoproteins. The cholesterol shuttle may be restricted to compartments distant from (...) the soma including synapses and may be regulated by electrical activity. Testing these hypotheses will help to improve our still insufficient understanding of brain cholesterol metabolism and its role in neurodegeneration. BioEssays 25:72–78, 2003. © 2002 Wiley Periodicals, Inc. (shrink)

The close link between signaling by the developmental regulators of the Hedgehog family and cholesterol biochemistry has been known for some time. The morphogen is covalently attached to cholesterol in a peculiar autocatalytic reaction and embryonal disruption of cholesterol synthesis leads to malformations that mimic Hh signaling defects. Recently, it was furthermore shown that secreted Hh could hitchhike on lipoprotein particles to establish its morphogenic gradient in the developing embryo. Additionally, there is new evidence that the Hh‐receptor Patched transmits (...) the Hh signal by modulating the secretion of an inhibitory sterol molecule from the receiving cells. Here we present some of the most recent discoveries on the Hh–sterol link and discuss their implications from a systems design perspective. We predict that a robust functioning of the Hh pathway will require the involvement of more sterol metabolites, and these should be the subject of future research. BioEssays 29:1085–1094, 2007. © 2007 Wiley Periodicals, Inc. (shrink)