Battle Against Cholesterol Moves Ahead

Researchers at the University of Texas Southwestern Medical Center (UTSW) in Dallas have identified a key component in the battle to keep cholesterol, and resultant heart disease, under control, according to a paper released early on the web site of the Proceedings of the National Academy of Sciences. A team working with Hyock Joo Kwon has identified the small portion of a protein that regulates the level of low density lipids (LDL) "set loose" in the blood stream. High levels of LDLs in the blood stream are strongly associated with heart disease and coronary-artery disease, and cause the blockages in arteries feeding the heart that cause myocardial infarction (heart attacks).

Previous studies at UTSW had already identified that the protein proprotein convertase subtilisin/kexin type 9 (PCSK9) helps regulate the levels of LDLs in the blood stream, by blocking receptors in the liver and around the body to accept the LDLs. Most people have a pair of identical genes that produce PCSK9, but in the rest of the population, there are two forms of the gene, one that produces the form that blocks the receptors - and one that does not.

"The practical implication is that it defines the key interaction between the PCSK9 and the receptors, and possibly [help us] find therapies that will disrupt the cycle," said Jay Horton in a telephone interview. Horton is one of the co-authors of the paper. "PCSK9 protein definitely controls the number of receptors in the liver, is secreted into the blood, and seems to degrade the number of receptors around the body."

According to Horton, people with the normal gene paired with the mutant gene show a 15% decrease in LDLs in the blood, and a 47% lower incidence of heart disease. Other researchers at UTSW have identified that about 3% of the population have the mutant form of the gene.

Genes come in pairs, on chromosomes. A human being has 23 pairs of chromosomes, and not every chromosome is identical. Common genetic defects caused by a mutated gene that produce too much of a certain protein include some forms of diabetes, cystic fibrosis, and Tay-Sachs Disease.

"Two individuals have been identified who do not produce PCSK9 at all," Horton said. "There's no deleterious effect, and their LDLs come in at around 20, with no incidence of heart disease. Blocking this protein's function without adverse side effects looks promising."

Work was funded primarily by the National Institutes of Health. Hok's group developed the amino acid sequence changes that helped them identify which combinations would disrupt the activity of PCSK9, finding the key sequence that causes the PCSK9 to bind to the LDL receptors. Co-authors were Thomas A. Lagace, Markey C. McNutt, Jay D. Horton, and Johann Deisenhofer. Deisenhofer shared the Nobel Prize for Chemistry in 1988 for helping determine the processes in photosynthesis.

Hok had to personally take his crystals to Chicago for analysis, using equipment only available at two centers within the United States.