A Yale-led research team identified a protein that plays an important role in the buildup of LDL cholesterol in blood vessels. The finding could lead to an additional strategy to block LDL accumulation, which could help prevent or slow the clogging of arteries that leads to heart disease, the researchers said.
The study was published by Nature Communications.
Arteries become clogged with fats and cholesterol when certain proteins in the body, known as lipoproteins, combine with and transport fats in the blood to cells. Scientists have long believed that the LDL receptor molecule was responsible for the transport of LDL within cells. But given that some individuals lacking the LDL receptor still have high levels of LDL, questions remained about the mechanism.
To identify the mechanism, the research team screened more than 18,000 genes from the endothelium – the inner layer of human blood vessels. They examined the transfer of LDL into endothelial cells and then focused on possible genes involved in the process.
The researchers found that a protein called ALK1 facilitated LDL’s pathway into cells. “We confirmed that ALK1 directly binds to LDL,” said William C. Sessa, senior author and the Alfred Gilman Professor of Pharmacology and professor of medicine (cardiology). The team also determined that the “LDL-ALK1 pathway” aided the transport of LDL from blood into tissue.
The role of ALK1 in LDL accumulation was not previously known, said Sessa.
“The discovery of ALK1 as an LDL-binding protein implies that it might initiate the early phases of atherosclerosis,” he noted. “If we can find a way of blocking ALK1 using small molecules or antibodies, it might be used in combination with lipid-lowering strategies.”
Current lipid-lowering strategies include statins, which target LDL cholesterol levels in the blood.
A therapeutic that blocks ALK1 “would be a unique strategy for reducing the burden of atherosclerosis and be synergistic with lipid- lowering therapies,” Sessa noted.
Heart disease caused by damage to blood vessels is the leading cause of death worldwide.
Other study authors include Jan R. Kraehling, John H. Chidlow, Chitra Rajagopal, Michael G. Sugiyama, Joseph W. Fowler, Monica Y. Lee, Xinbo Zhang, Cristina M. Ramírez, Eon Joo Park, Bo Tao, Keyang Chen, Leena Kuruvilla, Bruno Larrivee, Ewa Folta-Stogniew, Roxana Ola, Noemi Rotllan, Wenping Zhou, Michael W. Nagle, Joachim Herz, Kevin Jon Williams, Anne Eichmann, Warren L. Lee, and Carlos Fernández-Hernando.
Nagle is an employee of Pfizer Worldwide Research and Development, but the company had no infuence in study design, data collection, and analyses. Other authors declare no competing financial interests.
The study was supported in part by the Yale Center for Molecular Discovery, the National Institutes of Health, and the American Heart Association’s Innovative Research Grant and MERIT Grant.
Article: Genome-wide RNAi screen reveals ALK1 mediates LDL uptake and transcytosis in endothelial cells, William C. Sessa, Nature Communications, doi:10.1038/ncomms13516, published online 21 November 2016.