Cell Membrane Protein Reduces Cholesterol

The UW-Madison study provides new insights into the nature of lipoprotein overproduction in people with familial hypercholesterolemia (FH), an inherited disease that affects one in 500 people. The research also explains how statins, a class of medications taken by several million Americans, work to lower blood cholesterol levels.

Low-density lipoprotein (LDL) carries cholesterol to other cells in the body that need it. People whose blood levels of LDL - the "bad" cholesterol - are too high have an increased risk of heart disease. Individuals with FH have extremely high levels of LDL and are at high risk for heart attacks at an early age.

"In the 1970s researchers discovered that the LDL receptor is responsible for removing most of the cholesterol from blood," according to Alan Attie, a biochemist in the College of Agricultural and Life Sciences. "They showed that a mutation in the gene that codes for the LDL receptor causes FH. Most people thought that the receptor's major function was to clear LDL from blood."

However, scientists later found that people with FH have high LDL levels not only because they clear it from their blood too slowly, but also because they produce too much, Attie says. "Ours is the first study that explains the paradox of why people with FH produce too much LDL," he says. "We showed that functional LDL receptors increase the degradation of apolipoprotein B inside liver cells."

Apolipoprotein B (apoB) is the major protein component of very low-density lipoprotein, which is made by liver cells and converted to LDL in the blood. The rate of apoB production in liver cells - and thus LDL production - is determined by how much apoB is degraded inside the cells before they secrete very low-density lipoprotein into the blood.

Attie led the research team, which included Jaap Twisk, Donald Gillian-Daniel, Angie Tebon, Lin Wang, and Hugh Barrett. Barrett is with the University of Western Australia in Perth; the others were with the UW-Madison at the time the research was done. Twisk is now with the University of Leiden in the Netherlands, and Wang is at the University of California-San Diego in La Jolla, Calif.

The scientists studied liver cells from mice with functional LDL receptors and mice with mutant, nonfunctional receptors. Mice with the mutation showed symptoms analogous to those of people with FH. Their average blood cholesterol level was more than three times that of mice with functioning receptors.

The researchers examined how the presence or absence of LDL receptors affected the secretion of apoB from mouse liver cells. They studied apoB secretion from cells with receptors, from cells with the mutation, and from mutant cells they altered by introducing unusually large numbers of functional receptors.

"We found that although all three types of cells synthesized the same amount of apoB, they degraded different amounts before secreting it," Attie says.

The study found that liver cells with functional receptors degraded 55 percent of the apoB they made before releasing it. Liver cells with FH-like mutant receptors degraded only 20 percent of the apoB they made. However, when large numbers of functional receptors were added to those same mutant cells, they degraded 90 percent of the apoB they synthesized before secreting it.

The results also explain why statin medications - which include the brands Lipitor, Zocor, Pravachol, Lescol, Mevacor and Baycol - are effective in lowering serum LDL levels. As a class of pharmaceuticals, statins inhibit cholesterol production. Liver cells respond to this decrease in cholesterol by producing more LDL receptors on their surfaces. It's long been believed that the additional receptors lowered blood cholesterol levels by clearing LDL-cholesterol from the plasma. Attie notes, however, that statins do not improve the removal of LDL-cholesterol in many people, yet result in lower LDL-cholesterol levels anyway.

"Several studies have shown that statins reduce cholesterol production," Attie says. "We've shown that cells with the most LDL receptors have the lowest production of apoB. By stimulating the production of receptors, statins lower the amount of LDL that is produced."

The UW-Madison scientists are now focusing their efforts on discovering the mechanism by which the LDL receptor limits apoB and LDL production.

The research was supported by state funding to the College of Agricultural and Life Sciences and a grant from the National Heart, Lung and Blood Institute.