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Cholesterol Suppresses Protective Protein, Opens Cells to Injury

For more than 50 years, medical researchers have recognized a relationship between high levels of cholesterol circulating in the blood and an increase in cardiovascular disease. But researchers don't really understand why cholesterol causes hardening of the arteries, or atherosclerosis. They just know it does.

A team at St. Louis University in Missouri led by biochemist Jung San Huang worked on a study to understand how cholesterol does damage on a cellular level. His colleague Steven Fliesler says researchers have proposed many models to explain what happens after cholesterol is deposited on the cells that line large blood vessels

"That [kind of] cholesterol in various chemical forms is very prone to being oxidized, [and] the oxidized form of the cholesterol turns out to be very toxic to cells," says Dr. Fliesler. "Some theories indicate that these molecules can signal an inflammatory response, and the recruitment of cells in the immune system to actually attack the lining of the walls of the blood vessels."

Fliesler says their research found that in addition to stimulating an inflammatory response, cells with higher levels of cholesterol suppressed the activity of a key protein that's involved in protecting the heart and blood vessel cells. "Loading cells with cholesterol supplied from outside — not made by the cells themselves — caused a degradation, an increased degradation in the receptors that recognize Transforming Growth Factor Beta." That protective protein is also known as TGF-Beta.

Fliesler says they also found the reverse to be true; if they removed cholesterol from the cells, the receptors for TGF-Beta became more responsive. So, when cells had more cholesterol around, they couldn't respond to the TGF-Beta, which usually protects them. This resulted in the cells being more prone to injury.

Fliesler says the novel aspect of this work is the new realization that by lowering or raising serum cholesterol levels, one can modulate the signaling of transforming growth factor beta on various cell types.

He also says these discoveries have implications for the development of new medications that could enhance the protective action of TFG-Beta on the vulnerable cells of large blood vessels.

The team's research is being published in the Journal of Cell Science.