Mutation Boosts Cholesterol Clearance

They reported in the April 1, 2005, online edition of the Proceedings of the [U.S.] National Academy of Sciences that the livers of these mice had increased LDLr protein but not messenger RNA (mRNA). The additional LDLr protein led to greater clearance of circulating lipoproteins and decreased plasma cholesterol levels (46 mg/dl in the knockout- mice versus 96 mg/dl in control animals). These findings complement earlier reports that humans with mutations that disabled the PCSK9 gene had LDL cholesterol levels 40% lower than individuals without the mutation.

"The expression of LDL receptors is the primary mechanism by which humans lower LDL cholesterol in the blood,” said senior author Dr. Jay Horton, associate professor of internal medicine and molecular genetics at the University of Texas Southwestern Medical Center. "This research shows that in mice, deleting the PCSK9 protein results in an increase in LDL receptors and a significant lowering of LDL cholesterol. 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.”




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University of Texas Southwestern Medical Center