Alberta Innovates- Health Solutions

We all know that including such fat-laden foods as hamburgers and French fries in our daily diets is a potential health risk.

Consuming high quantities of fat can expand waistlines and raise blood cholesterol levels, increasing the chance of heart disease.

The human body can make all the cholesterol it needs, so excess cholesterol from the foods we eat must be eliminated. The liver is the major organ involved in this disposal process. "Normally, cholesterol removal happens in two ways. Cholesterol can be secreted into bile directly, and eventually ends up in the small intestine. There, it mixes with cholesterol from dietary sources and, in turn, some cholesterol intended for disposal finds its way back into the body," explains Heritage researcher Dr. Luis Agellon, who is conducting research on how the liver gets rid of cholesterol. "The other removal method is the conversion of cholesterol into bile acids. Since bile acids can't be converted back into cholesterol, this is permanent removal from the body," says the Heritage researcher.

Dr. Agellon is studying a particular liver enzyme called cholesterol 7- -hydroxylase (cyp7) that plays a key role in converting cholesterol into bile acids. (Bile acids act the way dish detergent does on greasy dishes, solubilizing fat.) Dr. Agellon is trying to figure out why mice are so efficient at getting rid of their cholesterol. His findings could eventually lead to treatments for people with high-cholesterol problems. So far in studies Dr. Agellon has discovered that the human gene that codes for cyp7 and the corresponding mouse gene respond differently to regulation by fats.

"We know that cyp7 controls the conversion of cholesterol into bile acids. The amount of cyp7 produced in the liver is partly determined by the lipids in the diet," he comments. "Previously, it was thought that cholesterol turned on the cyp7 gene. Now, Dr. Agellon says, it is more likely a direct response to the fats with which cholesterol is ingested. "The exciting discovery in our lab is that the human gene can't respond to dietary fats like the mouse gene does," he says. "Part of the reason the conversion of cholesterol into bile acids may not be as efficient in humans is that the cyp7 gene can't respond to the fats in the diet."

This theory has been successfully tested in the lab using cultured liver cells. Dr. Agellon will next study genetically altered (transgenic) mice that carry the human cyp7 gene. If his initial observations are true, future studies in Dr. Agellon's lab will try to develop ways to improve the response of the human cyp7 gene to fats, to enable the liver to dispose of cholesterol more efficiently.

Dr. Luis Agellon is a Heritage Senior Scholar. He also receives support from the MRC and the Heart and Stroke Foundation of Alberta and the Northwest Territories.