By David N. Leff
Q: What do the following foods have in common: Nuts, seeds, chocolate, olives, avocado, corn oil, wheat germ, yams?
A: For one thing, all of the above are derived from the plant kingdom. For another, they're all high in fat content, which in plants is called sitosterol. For a third, that fatty ingredient - in every one of these treats - is highly toxic to the human body.
Which is why the human digestive system has evolved a fiendishly sophisticated strategy for bouncing sitosterol as fast as it's ingested. "It's not known why sitosterols are so toxic," observed molecular pharmacologist David Mangelsdorf. "The body lets cholesterol in, but it doesn't allow the very closely related compounds called sitosterols to enter - even though chemically and structurally, they are almost identical."
Mangelsdorf, a Howard Hughes investigator at the University of Texas Southwestern Medical Center in Dallas, continued: "Cholesterol is something that we need some of; it's a required constituent of our body's biochemistry, and also used to make steroid hormones and bile acids. Your body can make it, and can also get it from the diet.
"But sitosterols, to which the body is highly sensitive, are very harmful. So the body has evolved a mechanism that selectively pumps these sitosterols back out as they are coming in. It also pumps out the cholesterol, but there are other transporters that allow cholesterol to enter. These transporters are exquisitely sensitive in detecting the sitosterols and getting rid of them, but allowing the cholesterol back in.
"Most absorption of lipids and cholesterol," Mangelsdorf went on, "occurs in the first segment of the small intestine. These proteins are also expressed on the liver, so if any sitosterols do escape into the circulation, the liver can selectively take them up, and pump them back into the intestine, to be excreted."
A Tale Of Two Sisters
When a metabolic monkey wrench fouls up this machinery, the toxic sitosterol piles up in the body, and a rare disease called sitosterolemia kicks in.
It was in 1971 that two sisters, students at the University of Iowa, were examined at the university hospital with puzzlingly similar symptoms. Both suffered from painful xanthomas - cholesterol accretions - on the tendons of their knees and heels. The Journal of Clinical Investigation reported on their case in 1973 (v. 52, 9a): "b-Sitosterolemia: A newly described lipid storage disease in two sisters."
Some 200 sitosterolemia patients are known, but many more are thought to exist throughout the world. They accumulate large amounts of plant sterols in their tissues, have high cholesterol blood levels, and develop potentially fatal coronary heart disease early in life.
Today's Science, dated Dec. 1, 2000, carries an article titled "Accumulation of dietary cholesterol in sitosterolemia caused by mutations in adjacent ABC transporters." Its senior author is molecular and clinical geneticist Helen Hobbs, a close collaborator of Mangelsdorf at the Dallas medical center. Among the paper's co-authors is molecular biologist Bei Shan, director of the lipid disorder program at Tularik Inc. in South San Francisco.
"In collaboration with Helen Hobbs," Shan told BioWorld Today, "we discovered two genes in nine of her sitosterolemia patients. We started the project," he recounted, "and identified an agonist to a nuclear receptor called LXR - 'liver X receptor.' We used this LXR agonist trying to find the genes."
(Mangelsdorf, who first identified LXR some years ago, described it as "the regulator of genes involved in the mechanism by which sterols are absorbed in the intestines and ABC transporters that control efflux of sitosterols from the body. LXR acts as a cholesterol sensor." It senses the load of sterol in the liver, intestines and peripheral tissues. When that concentration is high, it seeks to get rid of the excess cholesterol by a number of mechanisms. And those involve a specific up-regulation of a number of genes responsible for eliminating cholesterol from the body. One set of these genes is the ABC transporters, which transport the lipids out of the cell. And that's where the sitosterolemia transporters come in.")
Shan went on: "So we identified the first gene, which we called ABCG5, and then started collaborating with Helen Hobbs. She has been working in this field for a very long time, and first identified a gene mutation in these patients. Then we suspected there must be another gene in the same chromosomal locus. So Helen discovered that second gene, ABCG8. When we put the two genes together, head-to-head, they were only 300 nucleotides apart. So we identified mutations in both.
"Sitosterolemia is a very well-known genetic disease," Shan pointed out, "but its patient population is very small. The reason people are particularly interested in it is because all these genetic disease models provide very good tools to study their mechanism. So I think we are lucky to find it."
'Multibillion Dollar Market' Beckons
He foresees that the finding in the Science paper should promote new drug discoveries. "You can have an additional way to lower cholesterol, for which the statins represent a multibillion dollar market. So that definitely will increase. This new discovery will certainly open a new window for novel cholesterol-lowering agents."
Mangelsdorf is equally bullish. "Several companies," he observed, "are now looking avidly at these orphan LXR receptors as drug targets. The idea was that if you gave a synthetic drug that activated this LXR, you could identify many of the genes that are involved in getting rid of sterol metabolism in the diet and in the body.
"Tularik," he recounted, "did DNA microarray analyses. That is, they gave mice the drug their DNA chip turned up, which activates LXR, and looked at the genes that are turned on and off. One of the genes thus identified was one of these transporters. It's a synthetic lipid, a sulfonamide derivative, screened in a compound library drug screen, with some structure-activity relationship work done to enhance it, to make it a very high affinity drug to activate this LXR receptor.
"Subsequent to that work, now going on," Mangelsdorf continued, "it will be used to show how elevating this in a normal setting might increase or decrease sitosterol - and cholesterol - flow to the body. Because they are able to be induced," he concluded, "their expression is regulated by the drug."