Genetic modification in mice lowers cholesterol and homocysteine by half

June 13, 2004

Canadian scientists report that mice genetically altered so as to lack either of the two different pathways through which humans, mice, and other animals provide lipids for high density and low density lipoproteins (HDL and LDL) did not appear to suffer any ill effects. But animals from both groups had markedly lower levels of cholesterol in their blood stream. Alteration of one of the pathways also lowered blood levels of homocysteine by 50 percent.

Speaking June 13, at the annual meeting of the American Society for Biochemistry and Molecular Biology (ASBMB)/ 8th International Union of Biochemistry and Molecular Biology Conference (IUBMB) in Boston, Dr. Dennis Vance said the results suggest an unique therapeutic approach to lowering LDL cholesterol and homocysteine levels, both known risk factors for cardiovascular disease.

Dr. Vance is Canada Research Chair in Molecular and Cell Biology of Lipids. A leader in the biochemistry of lipids, he has spent his career understanding how the body regulates the manufacture of certain lipids and their functions in the human body. The new study reported at ASBMB focuses on the two methods or pathways by which the liver makes phosphatidylcholine (PC), the key building block of cell membranes in humans and other animals - and an important component of the HDL and LDL lipoproteins that carry fat and cholesterol in the blood stream.

The CT pathway contributes about 70 percent of the PC in the liver and the PEMT pathway contributes the other 30 percent. When the researchers genetically altered the mice so that their livers lacked either the CT or the PEMT pathway, the mice appeared normal and bred normally. But in each case, whether the CT or the PEMT pathway was missing, levels of lipoproteins were decreased by as much as half.

This suggests, said Dr. Vance, that pharmacological inhibition of the manufacture of PC in the liver might be a useful approach to lower LDL in the blood stream. The animals altered genetically so as not to have a PEMT pathway for the creation of PC also had a 50 percent decrease in homocysteine in the blood. Again, says Dr. Vance, pharmacological inhibition of PEMT might lower the levels of homocysteine in blood, thus lowering risk and incidence of cardiovascular disease.
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In addition to Dr. Vance, other researchers in the study are Dr. Zhaoyu Li, Dr. Rene Jacobs, Dr. Luis Agellon, Dr. Yang Zhao, from the University of Alberta in Edmonton; Dr. Cecilia Devlin and Dr. Ira Tabas from the Department of Medicine, Columbia University, New York; and Dr. John Brosnan, Dr. Lori Stead, and Dr. Margaret Brosnan, from Memorial University of Newfoundland.

Funding for the work came from the Canadian Institutes of Health Research, the National Institutes of Health (USA), the Canadian Foundation for Innovation, and the Alberta Heritage Foundation for Medical Research.

The presentation is part of an ASBMB session on molecular and cellular biology of lipids chaired by Dr. Vance.

With more than 11,900 members, the American Society of Biochemist and Molecular Biology is a nonprofit scientific and education organization dedicated to promoting understanding of the molecular nature of life processes.

Federation of American Societies for Experimental Biology

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