Their findings, published in todays edition of Science, reveal that the bodys natural mechanisms arent built to handle lithocholic acid, a toxic byproduct of dietary fat, in the volume generated by high-fat diets.

Dr. David Mangelsdorf, professor of pharmacology and investigator in the Howard Hughes Medical Institute (HHMI) at UT Southwestern, said observational evidence established a strong association between high-fat diets and colorectal cancer, but scientists could not explain the biological and biochemical mechanisms that formed the link.

The rate of colorectal cancer is much higher in the United States - where a high-fat diet is common - than in Japan, where people dont eat a lot of fat and colorectal cancer is almost nonexistent. But no one has understood why that is, he said.

The new findings show that at least part of the answer lies in the bodys inability to cope with large amounts of lithocholic acid, produced when the body processes cholesterol. The body produces bile acids when it breaks down cholesterol, part and parcel of dietary fat. Those bile acids go to the small intestine and are broken down into secondary bile acids, one of which is lithocholic acid.

Most secondary bile acids circulate to the liver, but only a little bit of lithocholic acid does so. Much of it remains in the small intestine, then moves into the colon, or large intestine.

Lithocholic acid is highly toxic, and it builds up in a high-fat diet, Mangelsdorf said. We dont know how it causes cancer; but it is known to cause cancer in mice, and people with colon cancer have high concentrations of it.

Scientists knew that a certain receptor controlled the small amount of lithocholic acid in the liver. Receptors are proteins that bind to
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Contact: Wayne Carter
Wayne.Carter@UTSouthwestern.edu
214-648-3404
UT Southwestern Medical Center
16-May-2002