Alberta Innovates- Health Solutions

Providing Vital Links to Health
In the developed world, we battle high cholesterol along with daily traffic. Too much fat in our diets, coupled with sedentary lives, lead to disease. One of them, heart disease, remains the number one killer in North America. We need cholesterol and other essential lipids (fats) to construct cells, make hormones, build nerves, and send signals-primary functions that are necessary for health and when altered cause disease.

Beyond modifying diet, increasing exercise, and in some cases taking cholesterol-lowering drugs, more knowledge is needed about the complex ways in which cholesterol and other lipids function in our bodies. A collaborative group of University of Alberta scientists is providing such knowledge; their contributions are recognized internationally and are providing the first steps towards therapies and perhaps cures for a number of diseases.

Heritage researcher Dr. Dennis Vance, an internationally acclaimed scientist, is acknowledged as the main force in establishing the University of Alberta as a presence in the lipid field. Dr. Vance is best known for his work on a lipid called phosphatidylcholine (PC), found in cell walls. He showed that when the production of PC is blocked, the liver makes less low-density lipoprotein ("bad" cholesterol). He also discovered another way in which PC is made: by a liver enzyme called PEMT. Delving further into PEMT function, he found a related enzyme, PEMT2, which turned out to slow the growth of liver cancer cells in laboratory experiments.

When he discovered that one gene makes both PEMT and PEMT2, the next step was to see what would happen when the gene was removed. Special "knock-out" mice missing the gene remained in good health, as long the mouse diet supplied enough of a vital substance called choline, which is used by the liver to make PC. However, when the mice were put on choline-free diets, Dr. Vance and his colleagues were astounded at the speed of decline. Deprived of the means of getting or making PC, the mice developed liver failure in three days.

He proposes that the reason the PEMT gene exists is to give animals an advantage in the wild when food is scarce. PC deficiencies can arise in humans during starvation, pregnancy, and lactation. In these situations, the body has an alternative way to get PC if diet cannot provide it.

And what about PEMT2's role in liver cancer? Dr. Vance's laboratory research showed that a missing PEMT/PEMT2 gene does not lead to premature liver cancer, but it could make the animals more susceptible to carcinogens. PEMT2 does slow the growth of liver cells in the lab, and when the liver grows rapidly, as it does in liver cancer, the expression of PEMT2 decreases. Whether this is a cause or effect remains to be determined. Dr. Vance is collaborating with an Italian scientist to study this further.

He points out that Dr. Charles Best, one of the four co-discoverers of insulin in 1922, was the first to recognize the importance of choline as a dietary component. Some 60 years later, Dr. Vance's breakthrough research on lipids has again shown the importance of choline and has placed him and his colleagues in the international scientific arena. It's a Canadian research story come full circle.

Dr. Dennis Vance is a Heritage Medical Scientist. He receives additional research support from the Medical Research Council of Canada (MRC), the Heart and Stroke Foundation of Alberta and the Northwest Territories and from Glaxo-Wellcome.

Heritage-funded students and/or fellows in Dr. Vance's lab are Mr. Vern Dolinsky and Dr. Kristin Waite. Mr. Chris Walkey, Dr. Marica Bakovic and Dr. Richard Lehner were Heritage-supported trainees during the early PEMT research.