A collaborative team led by researchers at the National Heart, Lung, and Blood Institute (NHLBI) has elucidated the precise molecular events needed to transport cholesterol from the surface of cells into their interior. This essential process, known as endocytosis, is disrupted in a genetic condition called familial hypercholesterolemia, which leads to high levels of cholesterol in the blood and an increased risk of heart disease. The findings could open up new avenues for treating this condition and, more broadly, for understanding the cellular transport of cholesterol in general.

"This work is fundamental to our understanding of the movement of cholesterol into cells," said Daniel Rader, M.D., director of the NHLBI's Division of Intramural Research. "These insights provide an important foundation for developing new therapies for preventing and treating heart disease."

The research, published in the journal Nature, focused on a protein called NPC1, which is mutated in individuals with familial hypercholesterolemia. NPC1 is found on the surface of cells and is essential for the uptake of low-density lipoprotein (LDL) cholesterol, the "bad" cholesterol that contributes to heart disease when present in high levels.

Using a combination of biochemical and imaging techniques, the team determined the precise steps involved in the endocytosis of LDL cholesterol. They found that NPC1 binds to LDL cholesterol on the cell surface and then undergoes a series of conformational changes that lead to the formation of a small vesicle containing LDL cholesterol. This vesicle is then transported into the cell, where it releases its cargo of cholesterol.

The researchers also identified several other proteins that play important roles in the endocytosis of LDL cholesterol, including the protein clathrin, which helps to form the small vesicles.

"Our findings provide a comprehensive understanding of the molecular events involved in the endocytosis of LDL cholesterol," said the study's lead author, Tobias Schmidt, Ph.D., a research fellow in the NHLBI's Division of Intramural Research. "This knowledge could inform the development of new drugs to treat familial hypercholesterolemia and other conditions in which cholesterol transport is disrupted."

In addition to providing insights into cholesterol transport, the findings could have broader implications for understanding the cellular transport of other molecules, as the endocytosis of LDL cholesterol involves several processes that are also used in the transport of other molecules into cells.

The research team included scientists from the NHLBI, the University of California, San Francisco, and the University of Texas Southwestern Medical Center.