Recent studies from Atsushi Kodan and colleagues shed light on the complex pathway of high-density lipoprotein (HDL) biogenesis. This process is key to the body’s ability to control cholesterol levels and promote heart health. By means of high speed atomic force microscopy, they described the crucial role of the ATP-dependent transporter ABCA1 in this process. Their findings, published in the journal Nano Letters, open the door to greater understanding of HDL biogenesis and its implications for health.
ABCA1 is a crucial protein because it is essential for the production of nascent HDL. This process is critical for moving cholesterol out of cells and into the liver, where it can be excreted. This study builds on work done in 1999. That research led to the discovery that genetic analysis of Tangier disease, characterized by low blood HDL levels, underscored the key role of ABCA1 in HDL production.
The Role of ABCA1 in HDL Production
Atsushi Kodan worked under the technical leads of Noriyuki Kodera and Kazumitsu Ueda. Collectively, they examined the ways by which ABCA1 promotes the biogenesis of nascent HDL. Ueda emphasized the importance of understanding the physiological roles of HDL and cholesterol, stating, “The physiological roles of HDL and cholesterol are often not fully understood.” Our primary goal in this research is to further define these roles and help inform a more comprehensive understanding of lipid transport and metabolism.
ABCA1 functions mainly as an ATP-dependent bidirectional sterol transporter. Its actions lead to the net movement of phospholipids and cholesterol from cells to lipid-poor apolipoproteins, which subsequently aggregate to form nascent HDL particles. As the study research team pointed out, very few teams around the world have the technical ability to conduct such complex in vivo experiments with ABCA1.
Kazumitsu Ueda remarked on the historical perspective of HDL function, noting, “It was historically believed that HDLs pull out excess cholesterol from cells through passive diffusion.” Yet the subsequent discovery that ABCA1 is absolutely required for HDL biogenesis has changed this picture dramatically.
High-Speed Atomic Force Microscopy in Action
To get an idea of what was happening on a molecular level, the researchers used high-speed atomic force microscopy (HS-AFM) to visualize ABCA1. With this new imaging technology, researchers were able to take never-before-seen side-view snapshots of membrane proteins. In doing so, they uncovered details on the HDL biogenesis machinery that we couldn’t otherwise see.
Ueda was very excited about the importance of this new methodology, as Ueda stressed its many possible uses. “This new methodology for efficient side-view imaging of human ABCA1 has the potential to be applied across a broad range of membrane protein systems, including the transport of lipids, drugs, and metabolic products,” he explained.
Kodans team also came up with a new visualization of how ABCA1 forms nascent HDL particles. Their work provides extremely valuable data with which to advance the field of lipid metabolism. The application of HS-AFM was a watershed for their studies, providing never-before-seen views that had the potential to spur new research directions.
Implications for Future Research
Collectively, these findings from this study provide significant implications regarding a better understanding of the cardiovascular health and diseases associated with cholesterol metabolism. In light of these issues, researchers are identifying the molecular pathways that induce HDL creation. This knowledge will further our understanding of conditions, such as Tangier disease, and other dyslipidemia disorders.
The knowledge obtained from this complex study could open new therapeutic horizons to affect cholesterol transport and metabolism. Learning how ABCA1 works reveals possibilities for novel approaches. These approaches can be used to positively modulate HDL levels in patients who are most at-risk for cardiovascular disease.