Cholesterol reduction is focus of research grant

A four-year, $1 million grant from the National Heart, Lung, and Blood Institute may lead to new tools to prevent ac-cumulation of cholesterol inthe body.

A study is being led by Daniel Ory, M.D., assistant professor of medicine.

While accumulation of dietary cholesterol can be deleterious, cholesterol is an essential component of all cells in the body.

“Cells need cholesterol for normal maintenance of membrane integrity,” Ory said. “Without it, our cells would die.”

The natural mechanisms of the cell work to keep internal levels of cholesterol balanced. If there is too little cholesterol coming into the cell from a person’s diet, it will stimulate cholesterol production.

The reverse also is true: If too much is coming in, the cell will activate mechanisms that pump out cholesterol. Then highdensity lipoprotein particles, also called “good” cholesterol, pick up excess cholesterol and carry it out of the body.

“The cell has two competing needs,”Ory said. “It wants to make sure it has enough cholesterol, but if it has too much it will initiate the expression of genes involved in getting rid of it.”

With this grant, Ory’s team will continue examining the role of two proteins, Niemann-Pick type C1 (NPC1) and Niemann-Pick type C2 (NPC2), in this delicate balance of cholesterol moderation.

The proteins are named for their role in NPC2 C disease, a condition in which cholesterol inappropriately accumulates within the cell. In 95 percent of these cases, the gene responsible for making NPC1 is deficient; a failure in the gene for NPC2 accounts for the other 5 percent.

Based on the team’s previous research, Ory’s team thinks these two proteins are part of the internal machinery that manages excess cholesterol.

“Given that heart disease still is the No. 1 cause of death among Americans, there is a need for additional drugs to be developed to deal with excess cholesterol within the cell,” Ory said. “We hope that by understandingthese pathways better, we can begin to develop new agents to shift the balance toward excretion of cholesterol as opposed to accumulation.”

Investigators Stephen L. Ristvedt, Ph.D., assistant professor of medical psychology in psychiatry, and Elizabeth G. McFarland, M.D., associate professor of radiology, review patient-response forms.