SCIENTIST FINDS CLUE TO HIGHER LEVEL OF CHOLESTEROL IN SOME AS
THEY AGE

Author: By Judy Foreman, Globe Staff

Date: Tuesday, April 25, 1989
Page: 9
Section: NATIONAL/FOREIGN

Dr. Joseph L. Goldstein, a professor of molecular genetics at the University of Texas Southwestern Medical Center in Dallas, presented preliminary data in support of this still-unproved hypothesis for acquired cholesterol receptor abnormalities at a forum on cardiovascular diseases yesterday at Boston University. Goldstein won the Nobel Prize in 1985 with his colleague Michael Brown.

Goldstein and Brown discovered that protein receptors on the surface of cells grab cholesterol out of the blood, where it is carried around by a substance called low density lipoprotein, or LDL.

The LDL receptors -- about 70 percent of which lie on the surface of liver cells -- pull cholesterol inside the cells, where it is used to make hormones, the cell membrane itself, vitamin D and other products.

Indeed, Goldstein noted yesterday, though cholesterol has a bad public image, it is actually "a Dr. Jekyll and Mr. Hyde thing. It's both vital and lethal."

It is only when too little cholesterol is removed from the blood -- as can happen when a person has too few or defective LDL receptors -- that cholesterol builds up in the bloodstream and forms plaque on artery walls, eventually clogging them so badly that heart attacks and strokes result. Half of all deaths in the United States result from this process, called atherosclerosis.

Some people -- about five percent of those who have heart attacks under age 60 -- inherit defective LDL receptors, making them exceedingly prone to heart attacks, even if they have no other cardiac risk factors. In fact, the Texas team treated one young girl who at 6 suffered a heart attack. She had inherited an LDL receptor deficiency from both parents.

But recently, Goldstein said, the team has been focusing its attention, not on people with inherited defects in LDL receptors, but on people who seem to acquire deficiencies of LDL receptors over time when exposed to the standard American diet.

In animal experiments to date, Goldstein said, high-fat, high-cholesterol diets lead to a "profound suppression of LDL receptors," perhaps because of a feedback mechanism inside cells which tells the cell there is plenty of cholesterol available within its membrane and that, therefore, the cell need not make any more LDL receptors.

Although this results in a harmonious steady state condition, called homeostasis inside the cell, it can be dangerous for the body as a whole
because it means cholesterol is not being removed from the bloodstream at a normal rate.

Cells both draw cholesterol in from the blood through LDL receptors and synthesize cholesterol from scratch. Regardless of which way cholesterol is produced, the feedback mechanisms can signal the cell not to make any more LDL receptors.

Goldstein and his team are now zeroing in on the precise mechanism through which the genes that make LDL receptors are turned off when there is an ample supply of cholesterol inside the cell. But so far, he said, "We don't know the exact mechanism of suppression of transcription," a genetic process through which proteins such as receptors are made.

In a separate presentation yesterday, Dr. Aram V. Chobanian, dean of the Boston University School of Medicine, said that studies in his lab show that hypertension -- high blood pressure -- can greatly accelerate the process of atherosclerosis in a person whose cholesterol levels are already too high.

"This fits," added Chobanian, "with Japanese and Chinese data showing that people with high hypertension but low cholesterol have less atherosclerosis."

FOREMA;04/24 NIGRO ;04/27,10:19 CHOLES25