Marketed under brand names such as Lipitor and Zocor, the statin drugs help many patients keep their cholesterol in check. But this standard treatment doesn't work for everyone.
"People are still dying [from heart disease] even though they're on cholesterol-lowering drugs," says Helen H. Hobbs, an HHMI investigator at the University of Texas Southwestern Medical Center at Dallas and director of the Dallas Heart Disease Prevention Project, a study of heart disease in a population of 6,000 individuals. "Until Americans decide to give up their hamburgers and French fries, we have to figure out how to interrupt this disease in other ways."
Searching for new approaches, scientists are looking at the problem of cholesterol from a different angle. Rather than focusing on therapies that target production of cholesterol, which is essentially what statins do, researchers are concentrating on the way the body gets rid of surplus cholesteroland getting promising results.
An important breakthrough came not long ago when researchers identified a unique protein, called LXR (for liver X receptor), which appears to serve as a cellular "master switch" for removing excess cholesterol. A logical next step: Try to develop synthetic compounds that might control this intriguing switchand in turn control the leading culprit in heart disease.
CHOLESTEROL'S BAD RAP
Despite its rotten reputation in the doctor's office, cholesterol is essential to human health. Cells insert cholesterol into their membranes to help control which substances enter and leave the cells. Cholesterol also is the sole precursor of steroid hormones such as testosterone and estradiol, certain vitamins, and the bile acids in the liver.
How much cholesterol we need varies from person to person. Researchers estimate that a 155-pound male has about 100 grams of cholesterol in his body. Each day, the liver and other tissues produce 600 to 900 milligrams of cholesterol to meet the body's routine daily demands for the substance. We get into trouble when we have an excess of this tough-to-metabolize substancewhich the body cannot entirely get rid of.
The liver, being the only organ equipped to break down cholesterol efficiently, serves as a centralized treatment plant. However, it's limited by the countervailing effects of two distinct types of lipoprotein, the form in which cholesterol is carried in the blood. High-density lipoprotein (HDL), the so-called "good" cholesterol, picks up globules of cholesterol that cells have pumped to their outer membranes as if they have dropped off a bag of garbage at the curb. The HDLs then transport the cholesterol to the liver, where it is broken down in the bile. But low-density lipoprotein (LDL), or "bad" cholesterol, functions in an opposite fashion, bringing cholesterol from the liver into the body's cells.
The effects are not surprising. "Studies tell us that high levels of LDL and low levels of HDL are associated with atherosclerosis," says Hobbs. "Conversely, we know that if you lower plasma levels of LDL you have a profound [preventive] effect on the development of heart disease and a profound effect on reducing the incidence of coronary events in people with established heart disease."
Scientists have long hoped to define precisely how cells pump the excess cholesterol to their membranesa process that's commonly called "reverse transport"for pickup and disposal. That knowledge could pave the way for the design of drugs to manipulate the process. (Statins, the current drugs of choice, largely target an enzyme involved in the body's own production of cholesterol, a completely different cellular process than reverse transport.) About four years ago, a team of scientists provided an important first clue to the reverse-transport puzzle when they showed that a protein called ABCA1 transfers cholesterol from the cell membrane to HDL. This raised an obvious next question: What activates ABCA1?
The answer came soon thereafter from the laboratory of David J. Mangelsdorf, an HHMI investigator at the University of Texas Southwestern Medical Center at Dallas. As a postdoc, Mangelsdorf had cloned the genes of a dozen previously unknown protein receptors in the cell nucleus. Because the functions of these assumed hormone-binding proteins were unknown, scientists referred to them as "orphan nuclear receptors." Later, he discovered that one of these orphansLXRbound cholesterol metabolites.
Given that most nuclear receptors, once saturated with their activating ligand, signal for the transcription of specific genes, Mangelsdorf followed up with a series of experiments to determine which genes LXR mobilizes; the hope was that this information would lead to genes and proteins directly involved in the cholesterol-transport process. He observed that when mice were given small molecules that stimulated the LXR receptor, their production of ABCA1 was markedly increased. Although the details have yet to be fully worked out, this result suggests that an LXR-stimulating drug would increase cholesterol transport and boost HDL levels, both beneficial effects.
Actually, as Mangelsdorf and colleagues would show, this was just the tip of the LXR iceberg. In these same mice, the scientists noted a prominent decrease in cholesterol absorption. The explanation was that LXR signals ABCA1 to pump out the cholesterol in the intestine, thereby preventing it from being absorbed into the blood. Though this hypothesis has not been confirmed, it suggests that LXR has the potential to limit the absorption of dietary cholesterol, another greatly desired effect.
In the liver, the data are equally striking. Mangelsdorf reported that LXR activates a gene whose protein plays a key role in the synthesis of bile acids, meaning a ramping up of cholesterol degradationanother positive effect. There is also evidence that LXR activates other genes that transport cholesterol into the bile.