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CHORI Scientists Identify Novel Cholesterol Modulator

A new study by CHORI scientist Marisa Wong Medina, PhD, identifies for the first time that alternative splicing is an important player in the maintenance of cholesterol levels in the cell, and thus could play an important role in regulating blood cholesterol levels that impact heart disease, the number one cause of death in the United States.

"Alternative splicing is a process by which certain portions of a gene's coding regions, known as exons, are cut from the gene in a way that affects the function of the resulting protein or enzyme," explains Dr. Medina. "The idea that alternative splicing plays a role in cholesterol regulation hasn't quite gained traction yet in the field of lipid research. However, this study demonstrates that alternative splicing influences the proper balance of cholesterol in the cell at the gene pathway, thus implicating it as a novel and important new mechanism that impacts cholesterol."

“This study demon-
strates that alternative splicing is a novel and important new mechanism that impacts cholesterol.”


It has been well established that the cholesterol biosynthesis pathway, which is responsible for maintaining cholesterol levels within a cell, is very tightly regulated at many different levels, in response to variation in cholesterol content within a cell.

"This means that among the many things that regulate how much cholesterol a cell produces, low cholesterol levels in a cell activate cholesterol-producing pathways in order to increase cholesterol biosynthesis, and thus the amount of cholesterol in the cell," says Dr. Medina.

One of the critically important enzymes that becomes activated is 3-hydroxy-3-methylglutaryl coenzyme A reductase, or HMGCR. Similarly, low cholesterol levels don't just stimulate cholesterol production in the cell, but they also stimulate uptake of cholesterol from the plasma (or blood) into the cell through what is called the low density lipoprotein receptor, or LDLR.

"Previous literature has shown that both HMGCR and LDLR undergo alternative splicing that results in functionally relevant changes associated with human disease," says Dr. Medina. "In the case of cholesterol biosynthesis and uptake, the alternative splicing reduces protein or enzyme activity, thereby reducing cholesterol biosynthesis and uptake."

What Dr. Medina's study shows for the first time is that exposing cells to conditions of extreme cholesterol depletion results in a reduction in alternative splicing, which would thus increase the activity of the proteins and enzymes responsible for stimulating cholesterol biosynthesis and uptake. When cholesterol is added back into these depleted environments, alternative splicing increases, thereby decreasing cholesterol biosynthesis and uptake. These changes were seen not only in HMGCR and LDLR, but also in other genes in the cholesterol biosynthesis pathway as well.

"We also found that these changes in alternative splicing occur in vivo, as monkeys fed a cholesterol supplemented had increased alternative splicing compared to those fed a control diet," says Dr. Medina. "Thus, there is a high likelihood that this process also occurs in people as well."

In addition, Dr. Medina and her colleagues demonstrated that a specific splicing factor, polypyrimidine tract binding protein 1, or PTBP1, not only regulates gene splicing, but itself appears to be cholesterol regulated.

“When cells are deprived of cholesterol, this influences PTBP1 levels and causes it to decrease the amount of splicing that occurs. Overall, the results suggest that maybe we could harness alternative splicing as a way to regulate the cholesterol biosynthesis and uptake pathways.”

While utilizing the groundbreaking results from this study to actually modulate an individual's plasma cholesterol levels is a long way off, the data provided by Dr. Medina opens new avenues of research into cholesterol management.

"Alternative splicing has been long been thought of as simply a way of increasing protein diversity. This finding tells us that despite decades of research investigating the pathways involved in cholesterol homeostasis, that there are still many more layers of regulation that have yet to be considered," says Dr. Medina.

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Friday, June 10, 2011 9:55 AM

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