ChREBP is normally expressed in the liver and in fat and muscle. In the first of two studies, Dr. Uyeda studied mice lacking the gene for ChREBP. Without the gene, mice cannot make the ChREBP protein and do not effectively convert sugar to fat. Even when fed a normal diet, the mice had high levels of glucose in their bloodstreams. Called glucose intolerance, this condition is often seen in patients with diabetes.

The researchers then fed the mutant mice a high-carbohydrate diet. Unable to convert the large excess of sugar into fat, the mice could not create enough energy to survive.

The liver is the primary depot for the sugar to fat conversion. In the second study, Dr. Uyeda and Dr. Bonnie Miller, assistant professor of internal medicine and co-author of the study, collected liver cells from mice lacking the ChREBP gene and compared them to liver cells from normal mice to determine what happened to genes associated with fat formation.

The researchers grew the cells in a high-glucose solution to mimic the high-carbohydrate diet the mice were fed in the previous study. They found that unlike normal liver cells, liver cells from mice lacking ChREBP were unable to turn on fat-formation genes. The researchers then used biochemical assays to show that ChREBP binds directly to the DNA of fat formation genes, turning them on.

"I think one of the most exciting findings of these studies is that a single transcription factor is directly responsible for increasing expression of multiple enzymes for making fatty acids," Dr. Miller said. "This is significant because ChREBP makes sure that glucose is only converted to fat when it is in excess. It coordinates glucose breakdown and energy storage via fat."

Other contributors to the first study were Drs. Katsumi Iizuka and
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Contact: Megha Satyanarayana
megha.saty@utsouthwestern.edu
214-648-3404
UT Southwestern Medical Center
18-Oct-2004