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Experiment

Endothelial-specific Het of ALK1 in a global LDLR-KO background

Summary

Data Summary

Investigator	Lee, Monica
Description	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. Applicable research area(s): Cardiovascular
Status	Completed
Public Release	11/11/2017
Data Collected?	Data will not be collected for this catalog item
Animal Age	Measured In: week(s) post-natal (w)
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Data Analysis

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Type	Count
Animals	71
Experimental Conditions	1
Catalog Items	2
Curation Info (# flags)	2
Phenotype Assays	2
Phenotype Measurements	139
Histology Images	0
Publications	0

Animals

Strain Name	Common Name	Females	Males	Unknown
C57BL/6J ^+/+	C57BL/6J ^+/+	0	33	0
C57BL/6-Ldlr^tm1Her Acvrl1^tm2Spo Tg(Cdh5-cre/ERT2)1Rha	endothelial specific het ALK1 on global LDLR KO	0	38	0

Animals/Strains

Experimental Factors

	Categorical Values
	Name / Abbreviation	Description
	Experimental Factor: Experimental Group
	Control	This animal belongs to the control group for the experiment.
	Experiment	This animal belongs to experimental group that is homozygous for gene manipulations.

Experimental Factor (Units)
Experimental Group

Experimental Factor Values

Phenotype Assays Add / Edit

Name	Abbreviation
cholesterol	cholesterol
triglycerides	TG

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