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Principal Investigator: Ira J Goldberg
Organization: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
Fiscal Year: 2024
Award: $811,326
Funding agency: National Heart Lung and Blood Institute
ABSTRACT
The first steps in atherosclerosis are the transendothelial movement and subendothelial accumulation of
lipoprotein lipid. Endothelial cell (EC) transcytosis of LDL involves two receptors, scavenger receptor-BI (SR-BI)
and activin-like kinase 1 (ALK1). We showed that ECs also internalize undigested chylomicrons via SR-BI and
process them in lysosomes, leading to storage of some lipid as lipid droplets and the release of small extracellular
vesicles (sEVs) that cause lipid accumulation in macrophages. While many have considered chylomicrons as
non-atherogenic and too large to cross the EC barrier, this concept is now outdated with the understanding that
lipoprotein entry into the artery is a receptor-mediated process. The overall goal of this project is to determine
how EC chylomicron uptake affects EC biology, delivers lipids to the artery, and accelerates atherosclerosis. In
Aim 1, we propose to determine how triglyceride-rich lipoproteins affect lipid transfer across the vascular
endothelium. We provide preliminary data suggesting that N-terminal apoB18 has separate ligand binding
regions for ALK1 and SR-BI. We will determine whether lipoprotein size or apoB length determines exposure of
these two different regions. We also will determine how sEVs from chylomicron-conditioned ECs cause lipid
accumulation in macrophages and determine the differences between sEVs released from control and
chylomicron-treated ECs. In Aim 2, we propose in vivo studies to determine the role of the EC-chylomicron
uptake pathway in tissue lipid delivery and atherosclerosis. We provide preliminary data suggesting that
chylomicrons that accumulate in lipoprotein lipase (LpL) deficient mice increase atherosclerosis. We will use
genetically modified mice and knockdown strategies to assess the uptake of LDL and chylomicron lipids into
arteries and will assess whether more extensive atherosclerosis in mice with combined deficiency of LpL and
the LDL receptor is due to hyperchylomicronemia. Finally, we will determine whether AAV-mediated
overexpression of apoB18 reduces EC uptake of apoB lipoproteins in vivo and alters atherosclerosis. Completion
of the proposed studies promises to alter our view of the relationship of chylomicrons to vascular disease, define
a novel pathway for arterial accumulation of atherogenic lipids, and illustrate a possible approach to prevent
these lipids from entering the artery.
Terms: <Acceleration><Activins><Affect><Albumins><Apo-B><ApoB><Apolipoproteins B><Arterial Fatty Streak><Arterial Fatty Streaks><Arteries><Atheroma><Atheromatous><Atheromatous degeneration><Atheromatous plaque><Atherosclerosis><Atherosclerotic Cardiovascular Disease><Binding Sites><Biological><Biology><Blood Vessels><Blood leukocyte><Body Tissues><Body part><CD36 Antigens><CD36 Fatty Acid Transporter><CD36 protein><Cardiovascular Diseases><Cell Body><Cells><Cellular biology><Cholesterol><Cholesterol Esters><Cholesteryl Esters><Chylomicrons><Combining Site><DAG lipase><Data><Deposit><Deposition><Diacylglycerol Lipase><Dietary Fats><Diglyceride Lipase><Endothelial Cells><Endothelium><Event><FSH-Releasing Protein><Fats><Fatty acid glycerol esters><Filtration><Filtration Fractionation><Free Fatty Acids><GPIV Platelet Glycoprotein><Gene Expression><Gene Modified><Goals><Heart><Heparin-Clearing Factor><Hyperglyceridemia><Hypertriglyceridemia><In Vitro><Inflammation><Intestinal><Intestines><Investigators><Kinases><LDL><LDL Cholesterol><LDL Cholesterol Lipoproteins><LDL Lipoproteins><LDL Receptors><Label><Leanness><Length><Leukocytes><Leukocytes Reticuloendothelial System><Ligand Binding><Link><Lipemia-Clearing Factor><Lipids><Lipoprotein LDL Receptors><Lipoproteins><Low Density Lipoprotein Cholesterol><Low Density Lipoprotein Receptor><Low-Density Lipoproteins><Lysosomes><Macrophage><Marrow leukocyte><Mediating><Mice><Mice Mammals><Movement><Murine><Mus><Mφ><N-terminal><NH2-terminal><Non-Polyadenylated RNA><Nonesterified Fatty Acids><Pathway interactions><Peptide Fragments><Phenotype><Phosphotransferase Gene><Phosphotransferases><Post-Heparin Lipase><Postheparin Lipase><Postheparin Lipoprotein Lipase><Process><Production><Proteins><RNA><RNA Gene Products><Raised TG><Raised triglycerides><Reactive Site><Receptor Protein><Reporting><Research Personnel><Researchers><Ribonucleic Acid><Role><SR-BI receptor><Side><Site><Source><Specificity><Surface><Testing><Thinness><Thrombospondin Receptors><Tissues><Transphosphorylases><Travel><Triacylglycero-protein acylhydrolase><Triacylglycerol><Triglycerides><Vascular Diseases><Vascular Disorder><Vascular Endothelium><White Blood Cells><White Cell><Work><apo B-48><apoB-48><apoB48><apolipoprotein B-48><apolipoprotein B48><apoprotein B-48><atherogenesis><atheromatosis><atherosclerosis plaque><atherosclerotic disease><atherosclerotic lesions><atherosclerotic plaque><atherosclerotic vascular disease><beta-Lipoprotein Cholesterol><beta-Lipoproteins><biologic><blood vessel disorder><body movement><bowel><cardiovascular disorder><cell biology><clearing factor lipase><dietary lipid><elevated tg><elevated triglyceride><endothelial cell scavenger receptor><extracellular vesicles><gene modification><genetically modified><high triglycerides><impression><in vivo><increased triglycerides><knock-down><knockdown><lipoprotein lipase><new approaches><novel><novel approaches><novel strategies><novel strategy><overexpress><overexpression><pathway><prevent><preventing><receptor><scavenger receptor B type I><scavenger receptor B1><scavenger receptor BI><scavenger receptor class B type I><scavenger receptors, class B, type I><social role><transcytosis><triacylglycerol protein acylhydrolase><uptake><vascular><vascular dysfunction><vasculopathy><vesicle release><vesicular release><vulnerable plaque><white blood cell><white blood corpuscle>