May 30, 2008

Discovery Lecture chews the fat on brain cholesterol

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David Russell, Ph.D., delivered last week’s Discovery Lecture. (photo by Dana Johnson)

Discovery Lecture chews the fat on brain cholesterol

You might think of cholesterol as the thing to avoid in your diet or as the gunk that clogs up your arteries and contributes to heart disease.

It is. But cholesterol also has critical roles in the normal functioning of all the cells of your body — particularly in the brain.

At last week's Discovery Lecture, David Russell, Ph.D., the chair of Molecular Genetics at the University of Texas Southwestern Medical Center, discussed his group's research on cholesterol's function and the enzymes responsible for cholesterol turnover in the brain.

So what was it that attracted the attention of a “lipidologist,” a scientist who studies fat metabolism, to studying the brain?

As Russell noted, “the brain is an amazingly metabolic tissue. It makes up only about 2 percent of the body mass of most of us, accounts for about 20 percent of our total oxygen consumption, receives 15 percent of cardiac output…has over 400 miles of blood vessels…and in most of us, there's somewhere between 1 and 5 quadrillion synapses.”

“Those are all exciting facts and get the blood going of cell biologists and neuroscientists,” he noted, “but the 'Viagra' for lipidologists is that this tissue, that occupies 2 percent of the body mass, contains 30 percent of the body's cholesterol stores.”

One area of Russell's research focuses on the enzyme responsible for cholesterol turnover in the brain, called cholesterol 24-hydroxylase. He and colleagues have characterized this enzyme pathway in the brain and generated mice that lack the enzyme to determine the functional and behavioral roles of this metabolic pathway.

In his talk, he detailed the characteristics of these mice, including a fairly severe impairment in their ability to learn the location of a hidden platform in a murky pool of water — something that normal mice learn to do after just a few trials. They fail to find the platform, wandering around aimlessly. Interestingly, mice that have half the levels of cholesterol 24-hydroxylase show some learning impairment, but not nearly as severe as the mice lacking the enzyme.

Russell described his work to probe the nature of these deficits, including mechanisms that could possibly help bypass this defect and restore brain function.

Although the cholesterol 24-hydroxylase knockout mice are proving a great help in understanding this metabolic pathway, their poor learning ability — and the expense of producing and housing the mice — prompted Russell to describe their behavior as the “Texas Politician Phenotype.”

“They're dumb as fence posts, always look busy, and spend money like crazy.”

For a complete schedule of the Discovery Lecture Series and archived video of previous lectures, go to