Learning from Disease

While there are many ways to study the body’s normal way of processing cholesterol, some of the field’s greatest findings came from studying patients who have problems that disrupt the pathway.

Familial Hypercholesterolemia

In 1985, Michael S. Brown and Joseph L. Goldstein of the University of Texas Southwestern Medical Center won the Nobel Prize in Physiology or Medicine for discovering low-density lipoprotein (LDL) receptors, which pull packaged cholesterol from the bloodstream into cells. The pair had been studying patients with familial hypercholesterolemia (FH), an inherited disposition for high cholesterol. Individuals with a genetic mutation associated with FH have cholesterol two to three times higher than average. Those who carry two copies of this mutation have cholesterol levels five times higher than average. By the time these patients are in their teens, they have atherosclerosis.

In the 1970s, Brown and Goldstein grew cells from FH patients in a dish and compared them with cells from healthy individuals. They found that the normal cells had many more copies of a specialized receptor—the LDL receptor. Cells from patients with the most severe cases of FH didn’t have any of the surface receptors. Since cells can’t take in cholesterol in the form of LDL, it accumulates quickly in the arteries, leading to the unusually early onset of atherosclerosis.

Not all cases of FH can be explained by mutations in the LDL receptor. Helen Hobbs analyzed the genes of families from Lebanon and Sardinia who had inherited high cholesterol levels but no mutations in the receptor. She pinpointed another gene—dubbed ARH, after autosomal recessive hypercholesterolemia. The protein product of ARH binds to the LDL receptor to help it pull LDL into a cell.

While some cases of FH still puzzle doctors and scientists, the discoveries of these proteins in the LDL processing pathway have helped lead to drugs that lower blood cholesterol levels in FH patients and others with high cholesterol.


While dietary cholesterol comes only from meat, plants have related sterol molecules. When humans eat plants, these sterols are rejected by cells lining the gut and directed back to the intestines for removal. “It’s amazing that the body can recognize these minute differences between molecules,” says Helen Hobbs.

But in patients with sitosterolemia, plant sterols are taken in just like cholesterol. The extra sterols in the body lead to premature atherosclerosis. In 2000, Hobbs zeroed in on the gene mutations that cause sitosterolemia. Two proteins, called ABCG5 and ABCG8, normally pump plant sterols—and cholesterol—from liver cells into bile and from intestinal cells back into the gut lumen for removal from the body. In sitosterolemia patients, mutations in either one of these proteins prevent the transport of sterols to the gut. Pharmaceuticals that hijack this pathway of cholesterol removal not only could treat sitosterolemia but also could lower cholesterol levels in people without the mutations.

Niemann-Pick Disease

Named after two doctors, Niemann-Pick disease was first described in medical journals at the beginning of the 20th century. The disease is characterized by deterioration of the nervous system and the buildup of cholesterol in organs, especially the spleen and liver. Symptoms begin in childhood.

Almost 100 years later, scientists began to uncover what causes this cholesterol buildup. In 95 percent of cases of the variant called type C Niemann-Pick disease (there are multiple variants, A–D), mutations in proteins called NPC1 are to blame.

When an LDL particle is first taken into a cell through an LDL receptor, it ends up inside a lysosome—a compartment where the cholesterol molecules can be released into the rest of the cell and the other components of LDL can be degraded. The NPC proteins, it turns out, are integral for this processing, and the Brown–Goldstein lab has turned their attention to understanding why. “Mutations in NPC proteins make cholesterol get stuck in lysosomes,” says Russell DeBose-Boyd. “But we really don’t have a clue as to how that works. It’s a big question in the field.” And it’s a question whose answer, like other lessons from diseases, could lead to strides in understanding normal cholesterol pathways.

Tangier Disease

Like Niemann-Pick disease, Tangier disease leads to a buildup of cholesterol in organs. But it also causes a severe drop in high-density lipoprotein (HDL) levels. There are only about 50 cases worldwide and all have been traced to a mutation in the ABCA1 gene.

Once cholesterol is freed inside a cell, it can be used by the cell, or it can be released as HDL. HDL particles leave the cell through a transporter called ABCA1—the protein that’s mutated in Tangier disease and also a protein that LXR activates to pump cholesterol out of the cell. So affected patients not only have cholesterol filling their cells, they also have no HDL—considered the good kind of cholesterol—circulating in their blood. The correlation between HDL and heart disease is still murky.

“I think one of the biggest misunderstandings in the public about cholesterol relates to HDL,” says Hobbs. “People are obsessed with tracking their HDL levels, but it’s really not clear how important it is. Just because there’s a robust inverse relationship between coronary artery disease and HDL levels doesn’t mean that [the molecule] is causative. No one has shown that yet.”

-- Sarah C.P. Williams
HHMI Bulletin, May 2011

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