Editors' ChoiceAtherosclerosis

LDL cholesterol hitches a ride

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Science Translational Medicine  07 Dec 2016:
Vol. 8, Issue 368, pp. 368ec196
DOI: 10.1126/scitranslmed.aal2805

The pinpointing of rare loss-of-function polymorphisms in the PCSK9 gene in people has ushered in a new era in the possible prevention of cardiovascular diseases through a new class of cholesterol-lowering medications. Now in clinical trials, PCSK9-targeted drugs show low-density lipoprotein (LDL) lowering to unprecedented levels. But despite our increased understanding of how and why too much LDL circulates in the blood, the process by which that LDL becomes trapped in the vessel wall to drive atherosclerosis has remained limited. Indeed, this “response to retention” hypothesis was coined more than 20 years ago; yet, a major question remains unanswered: How does LDL translocate across the endothelial layer to become trapped in the vessel wall? Now, Kraehling et al. attempt to provide mechanistic answers to this enigmatic question.

The authors undertook an unbiased siRNA library screen to search for new proteins that carry LDL particles into endothelial cells and transport them into the intimal space, the innermost layer of a blood vessel. This approach uncovered activin-like kinase 1 (ALK1), a type I transforming growth factor–β receptor that is highly expressed in human and mouse endothelial cells. The ALK1-LDL complex was internalized and translocated from the apical to the basolateral side of the endothelium, where LDL was released into the extracellular space. Classic receptor binding and kinetic studies confirmed that ALK1 bound directly to LDL in a distinct and noncompetitive manner, relative to LDL binding to the canonical LDL receptor (LDLR). Unlike LDL, this noncompetitive binding to LDLR was not down-regulated by sterols or the PCSK9 protein. These observations indicate that even when LDLR expression is down-regulated and circulating LDL levels are lowered by statins or PCSK9 inhibitors, LDL can still enter the subendothelial space via ALK1. The authors did not investigate the role of ALK1 in the development of atherosclerosis in vivo. However, the new results suggest the ALK1 axis as a new target for reducing cholesterol accumulation directly in the artery wall. Such therapies could offer a solution for millions of atherosclerosis sufferers that goes beyond lowering of LDL.

J. R. Kraehling et al., Genome-wide RNAi screen reveals ALK1 mediates LDL uptake and transcytosis in endothelial cells. Nat. Commun. 10.1038/ncomms13516 (2016). [Full Text]

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