A novel assay uncovers an unexpected role for SR-BI in LDL transcytosis

Armstrong, Susan; Sugiyama, Michael G.; Fung, Karen; Gao, Yizhuo; Wang, Changsen; Levy, Andrew; Azizi, Paymon; Roufaiel, Mark; Zhu, Shudong; Neculai, Dante; Yin, Charles; Bolz, Steffen‐Sebastian; Seidah, Nabil G.; Cybulsky, Myron I.; Heit, Bryan; Lee, Warren L.

doi:10.1093/cvr/cvv218

Cited by 130 publications

(156 citation statements)

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“…Recently, a novel method to assess LDL transcytosis using total internal reflectance microscopy (TIRF) was developed18 where the docking, fusion and transcytosis of LDL could be easily quantified in human coronary arterial endothelial cells (HCAEC) treated with PCSK9 to remove LDLR from the surface (see Supplementary Fig. 7).…”

Section: Resultsmentioning

confidence: 99%

“…Interestingly, ALK1 has been localized to caveolae and may also contribute to reduced LDL uptake in Cav1 -knockout mice32. Most recently, the lipoprotein scavenger receptor for HDL, SR-B1, has been identified as a new candidate mediating the uptake and transcytosis of LDL in endothelial cells18. However, the loss of SR-B1 enhances atherogenesis, possibly by reducing hepatic HDL clearance33.…”

Section: Discussionmentioning

confidence: 99%

“…LDL transcytosis by confluent primary human coronary artery endothelial cells was measured by total internal reflection fluorescence (TIRF) microscopy1861. Briefly, confluent HCAECs seeded on 18 mm coverslips were placed in a cell chamber and treated with 40 μg ml −1 DiI-LDL and 5 μl NucBlue in cold RPMI 1640 media with HEPES at 4 °C for 10 min to allow the DiI-LDL to bind to the apical cell membrane without internalization.…”

Section: Methodsmentioning

confidence: 99%

“…Cross-section imaging ( x / y -axes) was performed following previous published work18 with a few modifications. In brief, EA.hy926 were either transfected with control siRNA or ACVRL1 siRNA or infected with adenovirus encoding GFP or ALK1-GFP on coverslips.…”

Section: Methodsmentioning

confidence: 99%

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Genome-wide RNAi screen reveals ALK1 mediates LDL uptake and transcytosis in endothelial cells

et al. 2016

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In humans and animals lacking functional LDL receptor (LDLR), LDL from plasma still readily traverses the endothelium. To identify the pathways of LDL uptake, a genome-wide RNAi screen was performed in endothelial cells and cross-referenced with GWAS-data sets. Here we show that the activin-like kinase 1 (ALK1) mediates LDL uptake into endothelial cells. ALK1 binds LDL with lower affinity than LDLR and saturates only at hypercholesterolemic concentrations. ALK1 mediates uptake of LDL into endothelial cells via an unusual endocytic pathway that diverts the ligand from lysosomal degradation and promotes LDL transcytosis. The endothelium-specific genetic ablation of Alk1 in Ldlr-KO animals leads to less LDL uptake into the aortic endothelium, showing its physiological role in endothelial lipoprotein metabolism. In summary, identification of pathways mediating LDLR-independent uptake of LDL may provide unique opportunities to block the initiation of LDL accumulation in the vessel wall or augment hepatic LDLR-dependent clearance of LDL.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Genome-wide RNAi screen reveals ALK1 mediates LDL uptake and transcytosis in endothelial cells

et al. 2016

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“…The transport of LDL across endothelial cells has previously not attracted much attention, but recent studies have shown that SR-BI 8 and possibly caveolin-1 9 mediate LDL transcytosis and that this process is responsive to LDL levels in the blood. 10 The retention of LDL is mediated by positively charged amino acids in apolipoprotein B (the main protein moiety on LDL) that interact with negatively charged artery wall proteoglycans.…”

Section: See Accompanying Article On Page 49mentioning

confidence: 99%

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Fogelstrand

Borén

2016

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Modeling cholesterol metabolism and atherosclerosis

Auley

2021

WIREs Mechanisms of Disease

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Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of morbidity and mortality among Western populations. Many risk factors have been identified for ASCVD; however, elevated low‐density lipoprotein cholesterol (LDL‐C) remains the gold standard. Cholesterol metabolism at the cellular and whole‐body level is maintained by an array of interacting components. These regulatory mechanisms have complex behavior. Likewise, the mechanisms which underpin atherogenesis are nontrivial and multifaceted. To help overcome the challenge of investigating these processes mathematical modeling, which is a core constituent of the systems biology paradigm has played a pivotal role in deciphering their dynamics. In so doing models have revealed new insights about the key drivers of ASCVD. The aim of this review is fourfold; to provide an overview of cholesterol metabolism and atherosclerosis, to briefly introduce mathematical approaches used in this field, to critically discuss models of cholesterol metabolism and atherosclerosis, and to highlight areas where mathematical modeling could help to investigate in the future. This article is categorized under: Cardiovascular Diseases > Computational Models

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A novel assay uncovers an unexpected role for SR-BI in LDL transcytosis

Abstract: We developed an assay to quantify LDL transcytosis across endothelial cells and discovered an unexpected role for SR-BI. Elucidating the mechanisms of LDL transcytosis may identify novel targets for the prevention or therapy of atherosclerosis.

Cited by 130 publications

References 49 publications

Genome-wide RNAi screen reveals ALK1 mediates LDL uptake and transcytosis in endothelial cells

Genome-wide RNAi screen reveals ALK1 mediates LDL uptake and transcytosis in endothelial cells

Catch and Release

Modeling cholesterol metabolism and atherosclerosis

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