• atherosclerosis
• mitochondrial dysfunction
• mitochondrion
• noncommunicable diseases

• Cord blood
• Dry-AMD
• Platelet-rich plasma
• Proteomics
• Retinal degeneration

• TREM-1
• TREM-2
• antagonists & inhibitors
• clinical trial failure
• drug discovery & development
• inflammation
• ligand-independent inhibition
• multiligand receptors

• Animals
• Humans
• Membrane Glycoproteins/metabolism
• Molecular Targeted Therapy
• Receptors, Immunologic/metabolism
• Triggering Receptor Expressed on Myeloid Cells-1/metabolism

• R43 GM128369 NIGMS NIH HHS
• R43 HL165734 NHLBI NIH HHS
• R44 CA217400 NCI NIH HHS
• R44 EY034015 NEI NIH HHS

• HDL
• SR-BI
• adrenal stress response
• glucocorticoid
• precision medicine
• scavenger receptor BI
• sepsis

• Sepsis/metabolism
• Humans
• Animals
• Scavenger Receptors, Class B/metabolism
• Lipopolysaccharides
• Signal Transduction
• Macrophages/metabolism
• Liver/metabolism
• Liver/pathology
• Lipoproteins, HDL/metabolism
• Cholesterol/metabolism

• 1I01BX006408 The U.S. Department of Veterans Affairs
• I01 BX004639 BLRD VA
• 1I01BX004639 The U.S. Department of Veterans Affairs
• I01 BX006408 BLRD VA
• 1R35GM141478 NIH HHS
• R35 GM141478 NIGMS NIH HHS

• OxLDL
• aging
• atherosclerosis
• immunology
• inflammation
• metabolism
• senescence

• Lipoproteins, LDL/metabolism
• Lipoproteins, LDL/immunology
• Humans
• Atherosclerosis/metabolism
• Atherosclerosis/immunology
• Animals
• Inflammation/metabolism
• Inflammation/immunology
• Aging/immunology
• Aging/metabolism

• 19TPA34910132 American Heart Association

• Apoptosis
• Atherosclerosis
• Mitochondrial dysfunction
• Oxidative stress
• ROS

• Humans
• Atherosclerosis/metabolism
• Atherosclerosis/pathology
• Mitochondria/metabolism
• Mitochondria/pathology
• Animals
• Oxidative Stress/physiology
• Reactive Oxygen Species/metabolism
• Risk Factors
• Inflammation/metabolism
• Inflammation/pathology
• Macrophages/metabolism
• Endothelial Cells/metabolism
• Endothelial Cells/pathology
• Muscle, Smooth, Vascular/metabolism
• Muscle, Smooth, Vascular/pathology

• atherosclerosis
• atherosclerotic cardiovascular diseases
• high-density lipoprotein subfractions
• remodeling
• reverse cholesterol transport

• Humans
• Cardiovascular Diseases/prevention & control
• Lipoproteins, HDL
• Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use
• Cholesterol
• Cholesterol, HDL
• Atherosclerosis/drug therapy
• Atherosclerosis/prevention & control

• Cellular and tissue localization
• Multiligand membrane receptor
• Portunus trituberculatus
• Scavenger receptor class B

• Humans
• Animals
• CD36 Antigens/genetics
• Brachyura/genetics
• Amino Acid Sequence
• Base Sequence
• Phylogeny
• HEK293 Cells
• Drosophila/metabolism

• Autophagy
• Inflammation
• Lipoprotein
• Liposome
• Macrophage
• PEG
• Phagocytosis

• Humans
• Animals
• Mice
• Endothelial Cells
• Lipopolysaccharides
• Micelles
• Macrophages
• Immunologic Factors
• Phagocytosis
• Lipoproteins
• Mammals

• R15 GM116037 NIGMS NIH HHS
• R25 ES028976 NIEHS NIH HHS
• T32 GM142621 NIGMS NIH HHS

• Absorption
• Advanced glycation end-products
• Inhibition strategy

• Humans
• Maillard Reaction
• Glycation End Products, Advanced/metabolism
• Diabetes Mellitus
• Oxidative Stress
• Digestion
• Receptor for Advanced Glycation End Products/metabolism

• molecular biology
• physiology
• endocrine system and metabolic diseases

• Male
• Animals
• Mice
• Humans
• Chylomicrons
• Resveratrol/pharmacology
• Caco-2 Cells
• Polyphenols
• Receptors, Scavenger

• R01 HL131597 NHLBI NIH HHS
• PJT159735 CIHR
• Gouvernement du Canada | Canadian Institutes of Health Research (Instituts de Recherche en Santé du Canada)
• Foundation for the National Institutes of Health (Foundation for the National Institutes of Health, Inc.)
• National Natural Science Foundation of China (National Science Foundation of China)

The effect of genetic polymorphisms on fasting blood lipid levels have been widely studied but the effects of these within the context of a high-fat meal challenge remain less characterized. The current study aimed to investigate the association of SNPs in lipoprotein-related genes with blood lipid profiles in healthy adults in the U.S.

Subjects (n = 393) between 18–66 years of age with BMIs ranging from 18.5–45 kg/m² were enrolled the cross-sectional Nutritional Phenotyping Study. Among them, 349 subjects (men: 48%; women: 52%) gave consent for genotyping. SNPs in APOA5, APOB, APOC3, APOE, and LDLR were assessed. The association between lipid markers and genotypes was tested separately for each SNP with analysis of variance (ANOVA), adjusted for sex, age, and BMI. We also examined two-factor interactions between SNPs and sex, age, or BMI.

Women carrying the C allele of rs3135506 in APOA5 or men carrying the C allele of rs429358 in APOE had reduced HDL-cholesterol levels during fasting and postprandially. The C allele in APOE was also correlated to increased LDL-C levels. The TT genotype of rs2854116 in APOC3 was associated with elevated total cholesterol. Additive effect of the risk alleles of APOA5 and APOE or APOC3 and APOE was detected. Nevertheless, the tested SNPs had little impact on the postprandial triglyceride responses to the high-fat challenge meal. We found no significant effects of SNPs in APOB (rs1042034) or LDLR (rs2228671) on triglycerides, cholesterol, or free fatty acid levels.

In healthy adults, fasting and postprandial cholesterol levels are strongly correlated with the tested APOA5, APOE, and APOC3 genotypes. Sex contributes to the genetic impact of the tested SNPs on lipid profiles.

ClinicalTrials.gov, NCT02367287. Registered February 20, 2015, https://clinicaltrials.gov/ct2/show/NCT02367287.

The online version contains supplementary material available at 10.1186/s40795-022-00592-x.

• Apolipoproteins
• Cholesterol
• Dietary challenge
• HDL-C
• Healthy adults
• LDL receptor
• LDL-C
• Lipid profile
• NEFA
• Triglycerides

As opposed to adults, high-density lipoprotein (HDL) is the main cholesterol carrying lipoprotein in fetal circulation. The major HDL receptor, scavenger receptor class B type I (SR-BI), contributes to local cholesterol homeostasis. Arterial endothelial cells (ECA) from human placenta are enriched with cholesterol compared to venous endothelial cells (ECV). Moreover, umbilical venous and arterial plasma cholesterol levels differ markedly. We tested the hypothesis that the uptake of HDL-cholesteryl esters differs between ECA and ECV because of the differential expression of SR-BI. We aimed to identify the key regulators underlying these differences and the functional consequences. Immunohistochemistry was used for visualization of SR-BI in situ. ECA and ECV were isolated from the chorionic plate of human placenta and used for RT-qPCR, Western Blot, and HDL uptake assays with ³H- and ¹²⁵I-labeled HDL. DNA was extracted for the methylation profiling of the SR-BI promoter. SR-BI regulation was studied by exposing ECA and ECV to differential oxygen concentrations or shear stress. Our results show elevated SR-BI expression and protein abundance in ECA compared to ECV in situ and in vitro. Immunohistochemistry demonstrated that SR-BI is mainly expressed on the apical side of placental endothelial cells in situ, allowing interaction with mature HDL circulating in the fetal blood. This was functionally linked to a higher increase of selective cholesterol ester uptake from fetal HDL in ECA than in ECV, and resulted in increased cholesterol availability in ECA. SR-BI expression on ECV tended to decrease with shear stress, which, together with heterogeneous immunostaining, suggests that SR-BI expression is locally regulated in the placental vasculature. In addition, hypomethylation of several CpG sites within the SR-BI promoter region might contribute to differential expression of SR-BI between chorionic arteries and veins. Therefore, SR-BI contributes to a local cholesterol homeostasis in ECA and ECV of the human feto-placental vasculature.

• HDL
• SR-BI
• arterial-venous difference
• endothelium
• human placenta

• Arteries/metabolism
• CD36 Antigens/genetics
• CD36 Antigens/metabolism
• Cholesterol/metabolism
• Endothelial Cells/metabolism
• Female
• Homeostasis
• Humans
• Lipoproteins, HDL/metabolism
• Placenta/metabolism
• Pregnancy
• Receptors, Immunologic/metabolism
• Receptors, Lipoprotein
• Scavenger Receptors, Class B/genetics
• Scavenger Receptors, Class B/metabolism

• LRP5
• PCSK9
• cholesterol uptake
• hepatic stellate cells
• liver

Cholesterol is the main sterol in mammals that is essential for healthy cell functionining. It plays a key role in metabolic regulation and signaling, it is a precursor molecule of bile acids, oxysterols, and all steroid hormones. It also contributes to the structural makeup of the membranes. Its homeostasis is tightly controlled since it can harm the body if it is allowed to reach abnormal blood concentrations. One of the diseases associated with elevated cholesterol levels being the major cause of morbidities and mortalities worldwide, is atherosclerosis. In this study, we have developed a model of the cholesterol metabolism taking into account local inflammation and oxidative stress. The aim was to investigate the impact of the interplay of those processes and cholesterol metabolism disturbances on the atherosclerosis development and progression. We have also analyzed the effect of combining different classes of drugs targeting selected components of cholesterol metabolism.

Cholesterol is an essential component of mammalian cells and is involved in many fundamental physiological processes; hence, its homeostasis in the body is tightly controlled, and any disturbance has serious consequences. Disruption of the cellular metabolism of cholesterol, accompanied by inflammation and oxidative stress, promotes the formation of atherosclerotic plaques and, consequently, is one of the leading causes of death in the Western world. Therefore, new drugs to regulate disturbed cholesterol metabolism are used and developed, which help to control cholesterol homeostasis but still do not entirely cure atherosclerosis. In this study, a Petri net-based model of human cholesterol metabolism affected by a local inflammation and oxidative stress, has been created and analyzed. The use of knockout of selected pathways allowed us to observe and study the effect of various combinations of commonly used drugs on atherosclerosis. The analysis results led to the conclusion that combination therapy, targeting multiple pathways, may be a fundamental concept in the development of more effective strategies for the treatment and prevention of atherosclerosis.

• Arterial atherosclerosis
• CD36
• Macrophage
• intermediate-conductance Ca(2+)-activated K(+) channel
• ox-LDL

• Animals
• Apolipoproteins E/genetics
• Apolipoproteins E/metabolism
• Atherosclerosis/genetics
• Atherosclerosis/metabolism
• Atherosclerosis/prevention & control
• CD36 Antigens/genetics
• CD36 Antigens/metabolism
• Diabetes Mellitus
• Humans
• Lipoproteins, LDL
• Mice
• Mice, Knockout
• Plaque, Atherosclerotic/etiology
• STAT3 Transcription Factor/metabolism

• GnRH
• feeding
• grass carp
• pituitary
• reproduction

• Animals
• Gonadotropin-Releasing Hormone/metabolism
• Pituitary Gland/metabolism
• Reproduction/physiology
• Hypothalamus/metabolism
• Pituitary Hormones
• Carps/metabolism
• RNA, Messenger/genetics

Macrophages are key players in the development of atherosclerosis: they scavenge lipid, transform into foam cells, and produce proinflammatory mediators. At the same time, the arterial wall undergoes profound changes in its mechanical properties. We recently showed that macrophage morphology and proinflammatory potential are regulated by the linear stiffness of the growth surface. Here we asked whether linear stiffness also regulates lipid uptake by macrophages. We cultured murine bone marrow-derived macrophages (BMMs) on polyacrylamide gels modeling stiffness of healthy (1kPa) and diseased (10-150kPa) blood vessels. In unprimed BMMs, increased linear stiffness increased uptake of oxidized (oxLDL) and acetylated (acLDL) low density lipoproteins and generation of reactive oxygen species, but did not alter phagocytosis of bacteria or silica particles. Macrophages adapted to stiff growth surfaces had increased mRNA and protein expression of two key lipoprotein receptors: CD36 and scavenger receptor b1. Regulation of the lipoprotein receptor, lectin-like receptor for ox-LDL, was more complex: mRNA expression decreased but surface protein expression increased with increased stiffness. Focal adhesion kinase was required for maximal uptake of oxLDL, but not of acLDL. Uptake of oxLDL and acLDL was independent of rho-associated coiled coil kinase. Through pharmacologic inhibition and genetic deletion, we found that transient receptor potential vanilloid 4 (TRPV4), a mechanosensitive ion channel, plays an inhibitory role in the uptake of acLDL, but not oxLDL. Together, these results implicate mechanical signaling in the uptake of acLDL and oxLDL, opening up the possibility of new pharmacologic targets to modulate lipid uptake by macrophages in vivo.

• Animals
• Biological Transport
• Lipoproteins, LDL/metabolism
• Macrophages/metabolism
• Macrophages/pathology
• Male
• Mice
• Mice, Inbred C57BL
• Reactive Oxygen Species/metabolism
• Surface Properties
• TRPV Cation Channels/metabolism

• T32 OD011000 NIH HHS
• American Association of Immunologists
• NIH Office of the Director
• Center for Vertebrate Genomics, Cornell University

• Apoa1
• Bmal1
• Cholesterol transport
• Circadian clock
• Testosterone

• COVID-19
• HDL
• SARS-CoV-2
• SR-B1

• Animals
• COVID-19/blood
• COVID-19/diagnosis
• COVID-19/metabolism
• Cholesterol/blood
• Cholesterol/metabolism
• Host-Pathogen Interactions
• Humans
• Lipoproteins, HDL/blood
• Lipoproteins, HDL/metabolism
• Receptors, Lipoprotein/metabolism
• SARS-CoV-2/physiology
• Severity of Illness Index
• Spike Glycoprotein, Coronavirus/metabolism

• Cholesterol
• GRAM domain
• Membrane contact sites
• Non-vesicular lipid transport
• Phosphatidylserine
• StART-like domain

• Cholesterol/metabolism
• Endoplasmic Reticulum/metabolism
• Biological Transport
• Cell Membrane/metabolism
• Carrier Proteins/metabolism
• Humans
• Animals
• Saccharomyces cerevisiae Proteins/metabolism
• Saccharomyces cerevisiae Proteins/genetics
• Saccharomyces cerevisiae/metabolism

• Endocrinology
• Lipoproteins
• Metabolism

• Animals
• Aorta/metabolism
• Aorta/pathology
• Chylomicrons/genetics
• Chylomicrons/metabolism
• Coculture Techniques
• Disease Models, Animal
• Human Umbilical Vein Endothelial Cells/metabolism
• Human Umbilical Vein Endothelial Cells/pathology
• Humans
• Lipid Droplets/metabolism
• Lipid Droplets/pathology
• Lipoprotein Lipase/deficiency
• Lipoprotein Lipase/metabolism
• Macrophages/metabolism
• Macrophages/pathology
• Mice
• Triglycerides/genetics
• Triglycerides/metabolism
• Xanthomatosis/genetics
• Xanthomatosis/metabolism
• Xanthomatosis/pathology

• R01 DK060022 NIDDK NIH HHS
• P30 CA016087 NCI NIH HHS
• R01 HL045095 NHLBI NIH HHS
• P30 DK056341 NIDDK NIH HHS
• K08 DK117064 NIDDK NIH HHS
• R37 HL045095 NHLBI NIH HHS
• R01 DK111175 NIDDK NIH HHS
• P01 HL092969 NHLBI NIH HHS
• R01 HL073029 NHLBI NIH HHS
• P01 HL151328 NHLBI NIH HHS

• cardiomyopathy
• chylomicrons
• fatty acids
• lipoprotein
• triglyceride

• Atherosclerosis
• Endothelium
• Scavenger receptor type B class I
• Transcytosis

Amyloid-β (Aβ) accumulation in the brain is a hallmark of Alzheimer’s disease (AD) pathology. However, the molecular mechanism controlling microglial Aβ phagocytosis is poorly understood. Here we found that the E3 ubiquitin ligase Pellino 1 (Peli1) is induced in the microglia of AD-like five familial AD (5×FAD) mice, whose phagocytic efficiency for Aβ was then impaired, and therefore Peli1 depletion suppressed the Aβ deposition in the brains of 5×FAD mice. Mechanistic characterizations indicated that Peli1 directly targeted CCAAT/enhancer-binding protein (C/EBP)β, a major transcription factor responsible for the transcription of scavenger receptor CD36. Peli1 functioned as a direct E3 ubiquitin ligase of C/EBPβ and mediated its ubiquitination-induced degradation. Consequently, loss of Peli1 increased the protein levels of C/EBPβ and the expression of CD36 and thus, promoted the phagocytic ability in microglial cells. Together, our findings established Peli1 as a critical regulator of microglial phagocytosis and highlighted the therapeutic potential by targeting Peli1 for the treatment of microglia-mediated neurological diseases.

This study identifies Peli1, an E3 ubiqitin ligase enriched in microglia, as a restraining factor that curtails microglial phagocytosis of the amyloid Aβ. Correspondingly, deletion of Peli1 enhances Aβ phagocytosis and clearance in Alzheimer’s disease, implicating Peli1 as a therapeutic target with significant potential for the treatment of microglia-mediated neurological disease.

• atherosclerosis
• lipidomics
• liquid chromatography mass spectrometry (LC‐MS)
• metabolomics
• scavenger receptor class B type I

• 2016YFA0500302 National Key Research and Development Program of China
• 81430056 National Natural Science Foundation of China
• 31420103905 National Natural Science Foundation of China
• 81621063 National Natural Science Foundation of China
• 7161007 Beijing Natural Science Foundation

• Acat1
• Dicer1
• Hmgcs2
• Olr1
• lipid metabolism
• microRNA
• organoids
• small intestine

• antioxidants
• atherosclerosis
• endothelial cells
• inflammation
• mitochondrial dysfunction
• mtDNA damage
• oxidative stress

• 19-15-00297 Russian Science Foundation

It is widely reported how betaine addition regulates lipid metabolism but how betaine affects cholesterol metabolism is still unknown. This study aimed to investigate the role of betaine in hepatic cholesterol metabolism of Sprague-Dawley rats. Rats were randomly allocated to four groups and fed with a basal diet or a high-fat diet with or without 1% betaine. The experiment lasted 28 days. The results showed that dietary betaine supplementation reduced the feed intake of rats with final weight unchanged. Serum low-density-lipoprotein cholesterol was increased with the high-fat diet. The high-fat diet promoted cholesterol synthesis and excretion by enhancing the HMG-CoA reductase and ABCG5/G8, respectively, which lead to a balance of hepatic cholesterol. Rats in betaine groups showed a higher level of hepatic total cholesterol. Dietary betaine addition enhanced cholesterol synthesis as well as conversion of bile acid from cholesterol by increasing the levels of HMGCR and CYP7A1. The high-fat diet decreased the level of bile salt export pump, while dietary betaine addition inhibited this decrease and promoted bile acid efflux and increased total bile acid levels in the intestine. In summary, dietary betaine addition promoted hepatic cholesterol metabolism, including cholesterol synthesis, conversion of bile acids, and bile acid export.

• betaine
• bile acids efflux
• cholesterol metabolism
• cholesterol synthesis
• cholesterol transport

• ATP Binding Cassette Transporter, Subfamily G, Member 5/metabolism
• Animals
• Betaine/pharmacology
• Bile Acids and Salts/metabolism
• Cholesterol/metabolism
• Cholesterol 7-alpha-Hydroxylase/metabolism
• Diet, High-Fat/adverse effects
• Dietary Supplements
• Hydroxymethylglutaryl CoA Reductases/metabolism
• Lipoproteins/metabolism
• Lipoproteins, LDL/blood
• Liver/metabolism
• Models, Animal
• Rats
• Rats, Sprague-Dawley

Background: The oxidative stress, induced by both environmental and intrinsic stimuli, underlies the onset and persistency of chronic rhinosinusitis (CRS). Scavenger receptors (SRs) are a broad family of transmembrane receptors involved in a dysfunctional host–environment interaction through a reaction with reactive oxygen species (ROS) production. Objective: We hypothesized possible roles of two major SRs in CRS pathology that can translate to clinical phenotypes or histological subtypes: lectin-like oxidized low-density lipoproteins (LDL) receptor-1 (LOX-1) and scavenger receptor class B type 1 (SR-B1). Patients and Methods: We collected ethmoid sinus mucosa specimens and blood samples from patients with CRS with nasal polyps (CRSwNP; n = 31) or CRS without NP (CRSsNP; n = 13) and 19 control subjects. We performed an RT-PCR analysis, ELISA assay, and immunostaining to determine the expressions and distributions of LOX-1 and SR-B1. Results: The CRSwNP group showed a significant increase in LOX-1 mRNA expression compared to the control group. There was no significant difference in SR-B1 mRNA levels among the three groups. The LOX-1 mRNA levels were positively correlated with the sinus computed tomography (CT) scores. Sinus tissue, but not serum samples, showed elevated concentrations of LOX-1 protein in the CRSwNP group versus the control group. The LOX-1 protein distribution was localized in inflammatory cells and vascular endothelial cells. Conclusion: LOX-1 is a major receptor for oxidized low-density lipoprotein produced by oxidative stress. This is the first study to report alterations in LOX-1 expression and production triggered by persistent inflammatory processes in CRSwNP patients. Our findings reveal complex but important roles for SRs that may contribute to the onset of different CRS phenotypes.

• CRSwNP
• LOX-1
• ROS
• SR-B1
• chronic rhinosinusitis with nasal polyps
• lectin-like oxidized LDL receptor-1
• oxidative stress
• reactive oxygen species
• scavenger receptor class B type 1
• scavenger receptors

The presence of antiendothelial cell antibodies (AECAs) has been documented in Takayasu arteritis (TAK), a chronic granulomatous vasculitis. Here, we identify cell-surface autoantigens using an expression cloning system. A cDNA library of endothelial cells is retrovirally transfected into a rat myeloma cell line from which AECA-positive clones are sorted with flow cytometry. Four distinct AECA-positive clones are isolated, and endothelial protein C receptor (EPCR) and scavenger receptor class B type 1 (SR-BI) are identified as endothelial autoantigens. Autoantibodies against EPCR and SR-BI are detected in 34.6% and 36.5% of cases, respectively, with minimal overlap (3.8%). Autoantibodies against EPCR are also detected in ulcerative colitis, the frequent comorbidity of TAK. In mechanistic studies, EPCR and SR-BI function as negative regulators of endothelial activation. EPCR has also an effect on human T cells and impair Th17 differentiation. Autoantibodies against EPCR and SR-BI block the functions of their targets, thereby promoting pro-inflammatory phenotype.

Autoantibodies against endothelium have been recognized in Takayasu arteritis (TAK). Here the authors identify endothelial protein C receptor and scavenger receptor class B type 1 as major autoantigens in TAK, and find autoantibodies inhibit the negative regulation of endothelial activation.

• atherosclerosis
• capillary
• endothelial cells
• pericyte
• rAAV

• Cholesteryl esters
• Epidermis
• Free fatty acids
• High-density lipoprotein
• Hypercholesterolemia
• Hyperlipidemia
• Skin lipid metabolism

• Administration, Intravenous
• Animals
• Antibodies, Monoclonal/administration & dosage
• Antibodies, Monoclonal/pharmacokinetics
• Chronic Pain/drug therapy
• Cryopreservation
• Drug Evaluation, Preclinical/methods
• Hepatocytes
• Histocompatibility Antigens Class I/genetics
• Histocompatibility Antigens Class I/metabolism
• Immunoconjugates/administration & dosage
• Immunoconjugates/pharmacokinetics
• Macaca fascicularis
• Male
• Metabolic Clearance Rate
• Mice
• Mice, Knockout
• NAV1.7 Voltage-Gated Sodium Channel/metabolism
• Peptides/administration & dosage
• Peptides/pharmacokinetics
• Receptors, Fc/genetics
• Receptors, Fc/metabolism
• Tissue Distribution
• Voltage-Gated Sodium Channel Blockers/administration & dosage
• Voltage-Gated Sodium Channel Blockers/pharmacokinetics

Apolipoprotein E3 (apoE3) plays a critical role in the metabolism of lipoproteins and lowers plasma lipid levels by serving as a ligand for the low-density lipoprotein receptor (LDLr) family of proteins and by promoting macrophage cholesterol efflux. The current study examines the effect of acrolein (an endogenously generated metabolite and an environmental pollutant) modification on the structure and function of apoE3. Acrolein modification was confirmed in Western blots by reactivity with acrolein–lysine-specific antibody and by the presence of oligomeric species due to cross-linking. LC-MS/MS analysis revealed modification of 10 out of 12 lysines in apoE3, with N^ε-(3-methylpyridinium)-lysine being the predominant form of modification, and Lys75 being a ‘hot spot’ in terms of susceptibility to oxidation. Circular dichroism spectroscopy showed no major change in overall secondary structure compared to unmodified apoE3. Reconstituted high density lipoprotein (HDL) bearing acrolein modified apoE3 showed loss of binding to soluble LDLr; however, incubation with mouse endothelioma bEnd.3 cells showed that it was internalized. Incubation with excess LDL did not abolish cellular uptake of acrolein modified apoE3, suggesting alternative mechanism(s) not involving LDLr. Incubation with anti-CD36 antibody did not show a decrease in internalization while incubation with anti- lectin-like oxidized LDL receptor 1 (LOX1) showed partial internalization. However, incubation with anti-scavenger receptor class B type I (SRB1) antibody abolished internalization of acrolein modified apoE3. Taken together, our studies suggest that acrolein modification of apoE3 at lysine residues leads to increase in net negative charge, and as a consequence, results in clearance by LOX1 and SRB1 on endothelial cells. Overall, oxidative modification of apoE3 likely impairs its role in regulating plasma cholesterol homeostasis, eventually leading to lipid disorders.

• LOX1
• SRB1
• acrolein
• apolipoprotein E3
• endothelial cells
• lipoproteins

• Acrolein/metabolism
• Apolipoprotein E3/metabolism
• Biomarkers
• Cerebral Cortex/metabolism
• Endothelial Cells/metabolism
• Humans
• Lipoproteins/metabolism
• Mass Spectrometry
• Oxidation-Reduction
• Protein Binding
• Protein Transport

• SC3 GM105561 NIGMS NIH HHS
• GM105561 NIH HHS

• adrenal glands
• bone marrow cells
• bone marrow transplantation
• lymph nodes
• regeneration

• Androgens/metabolism
• Animals
• Apoptosis
• Biomarkers, Tumor/genetics
• Biomarkers, Tumor/metabolism
• Bone Neoplasms/metabolism
• Bone Neoplasms/secondary
• Bone Neoplasms/surgery
• Cell Proliferation
• Cholesterol/metabolism
• Gene Expression Regulation, Neoplastic
• Humans
• Liver Neoplasms/metabolism
• Liver Neoplasms/secondary
• Liver Neoplasms/surgery
• Lung Neoplasms/metabolism
• Lung Neoplasms/secondary
• Lung Neoplasms/surgery
• Male
• Mice
• Mice, Nude
• Orchiectomy
• Prognosis
• Prostatic Neoplasms, Castration-Resistant/metabolism
• Prostatic Neoplasms, Castration-Resistant/pathology
• Prostatic Neoplasms, Castration-Resistant/surgery
• Receptors, Androgen/genetics
• Receptors, Androgen/metabolism
• Scavenger Receptors, Class B/genetics
• Scavenger Receptors, Class B/metabolism
• Tumor Cells, Cultured
• Xenograft Model Antitumor Assays

• P01 CA163227 NCI NIH HHS
• P50 CA097186 NCI NIH HHS

• antioxidant
• atherosclerosis
• dyslipidemia
• high-density lipoprotein
• nutritional interventions

• High-density lipoproteins
• Inflammation-induced atherosclerosis
• Polymorphonuclear neutrophils
• microRNAs export

Atherosclerosis, which underlies life-threatening cardiovascular disorders including myocardial infarction and stroke¹, is initiated by low density lipoprotein cholesterol (LDL) passage into the artery wall and engulfment by macrophages, leading to foam cell formation and lesion development^{2, 2, 3, 3}. How circulating LDL enters the artery wall to instigate atherosclerosis is unknown. Here we show in mice that scavenger receptor, class B type 1 (SR-B1) in endothelial cells mediates LDL delivery into arteries and its accumulation by artery wall macrophages, thereby promoting atherosclerosis. LDL particles are colocalized with SR-B1 in endothelial cell intracellular vesicles in vivo, and LDL transcytosis across endothelial monolayers requires its direct binding to SR-B1 and an 8 amino acid cytoplasmic domain of the receptor that recruits the guanine nucleotide exchange factor dedicator of cytokinesis 4 (DOCK4)⁴. DOCK4 promotes SR-B1 internalization and LDL transport by coupling LDL binding to SR-B1 with Rac1 activation. SR-B1 and DOCK4 expression are increased in atherosclerosis-prone regions of the mouse aorta prior to lesion formation, and in human atherosclerotic versus normal arteries. These findings challenge the long-held concept that atherogenesis involves passive LDL movement across a compromised endothelial barrier. Interventions inhibiting endothelial delivery of LDL into the artery wall may represent a new therapeutic category in the battle against cardiovascular disease.