The study's results are important because researchers previously thought there might be no new ways to exploit the LDL receptor pathway as a means of lowering LDL cholesterol.
High LDL cholesterol is a major risk factor for heart disease, heart attack and stroke because it contributes to the buildup of plaque that clogs the walls of arteries. It has become a leading cause of deaths worldwide, with figures in some industrialised countries reaching epidemic proportions.
Researchers at >UT Southwestern Medical Centre deleted the Pcsk9 gene in mice. The gene, present in both mice and humans, makes the PCSK9 protein, which normally gets rid of receptors that latch onto LDL cholesterol in the liver. Without this degrading protein, the mice had more LDL receptors and were thus able to take up more LDL cholesterol from their blood.
On average, mice lacking the Pcsk9 gene, had blood LDL cholesterol levels of 46 milligrams per decilitre, while wild-type mice had levels around 96 mg/dl, a difference of 52 per cent.
The research is consistent with findings from another recent UT Southwestern study showing that humans with mutations in their PCSK9 gene, which prevented them from making normal levels of PCSK9 protein, had LDL cholesterol levels 40 per cent lower than individuals without the mutation. This study was published in February in Nature Genetics.
"The expression of LDL receptors is the primary mechanism by which humans lower LDL cholesterol in the blood," said Dr Jay Horton, associate professor of internal medicine and molecular genetics and senior author of the study. "This research shows that in mice, deleting the PCSK9 protein results in an increase in LDL receptors and a significant lowering of LDL cholesterol."
Further experiments, which involved giving the mice statins, further enhanced LDL clearance from the blood. The findings suggest new drugs targeting PCSK9 may be able to act in conjunction with statin drugs to further lower LDL cholesterol levels. New cholesterol-lowering drugs based on blocking PCSK9 might be effective on their own as well, providing another option for individuals unable to take statins.
Statins increase the activity of a protein called SREBP-2, which activates the creation of more LDL receptors; however, Dr Horton's previous studies found that SREBP-2 also boosts the activity of the PCSK9 protein, which degrades those receptors.
"We looked at these competing effects and thought that if we removed the PCSK9 component completely, we would get a further increase in LDL receptors, and that's what happened," he said.
"The lower cholesterol levels of humans with mutations in PCSK9, combined with the results of our studies in mice, suggest that variations in the levels of the PCSK9 protein significantly affect blood cholesterol levels, and compounds that inhibit this protein may be useful for the treatment of high cholesterol," added Dr Horton.
The competing systems may have evolved to keep the body's cholesterol levels fine-tuned and to minimise big swings in cholesterol content in normal cells, since too much or too little cholesterol can damage or kill cells. He and his colleagues next will try to determine just how the PCSK9 protein degrades the LDL receptors.
The study is to be published in the >Proceedings of the National Academy of Sciences and available online this week.