Targeting ALK1 to lower LDL-c is a potential new therapeutic strategy

Kraehling JR, Chidlow JH, Rajagopal C, et al.
Nat comm 2016;7:13516

Researchers discovered a new pathway of LDL-c uptake into the cells that also has a physiological role in the lipoprotein metabolism. This research was recently published in Nature Communications. As the uptake, transfer and retention of LDL particles in the endothelial layer of blood vessels is considered a primary mechanism to initiate atherogenesis, this discovery may provide unique opportunities to treat atherosclerosis by blocking the initiation of LDL-c accumulation in the vessel wall or augment hepatic LDL receptor (LDLR)-dependent clearance of LDL-c. The pathway involves the activin-like kinase 1 (ALK1) protein that can bind LDL-c and mediates uptake into endothelial cells.

The importance of ALK1 in this process was initially revealed using a genome-wide RNAi screen in endothelial cells, in which 18,119 genes were examined for their capacity to transport LDL-c into the cell. Fifty-five positive hits were validated using secondary screens to assess broad effects on endocytosis, leaving 35 genes. Using detailed database analyses, 14 genes were interesting to follow-up, of which 3 (ACVRL1, ANGPT4 and GPR182) fulfilled all criteria for further research. Further experiments demonstrated that genetic silencing of the TGFbѐta receptor ACVRL1 (ALK1) in Ldlr-negative animals led to less LDL-c uptake into endothelial cells but did not affect sterol sensing. This was mediated by direct LDL-binding to ALK1 and this formation did also participate in transcytosis of LDL-c across the endothelium. Mouse models confirmed reduced LDL-c uptake in the aortic endothelium in the absence of ALK1.

This work defines new pathways for LDL uptake into endothelial cells and provides a molecular basis to begin unravelling LDL uptake, transcytosis and retention in the vessel wall. Although lipid lowering therapy is the mainstay for the prevention and treatment of atherosclerotic vascular disease, additional therapeutic approaches targeting the early events of atherogenesis in the vessel wall such as LDL transport, retention or endothelial cell dysfunction are interesting and feasible. Additionally, these mechanisms may also explain why some LDLR-negative individuals still have high levels of LDL-c.

Find this article online at Nat comm