D-fending the Colon: Bile component triggers vitamin D receptor

The protein that enables cells to respond to vitamin D also helps the gastrointestinal tract protect itself from an especially dangerous acid in bile, a new study suggests.

This unexpected finding about the protein–the vitamin D receptor–may help explain animal experiments and human-population studies suggesting that diets rich in vitamin D reduce the incidence of colon cancer.

“The vitamin D receptor probably evolved as a bile acid sensor of some kind,” says study coauthor David J. Mangelsdorf of the Howard Hughes Medical Institute at the University of Texas Southwestern Medical Center in Dallas.

Bile, which the liver produces, contains detergent-like acids that start the digestion of dietary fats in the intestines. Most of these acids are reabsorbed by the small or large intestines, but one, lithocholic acid, isn’t readily taken up there.

As a result, this bile acid moves into the colon–and that’s not good. Lithocholic acid can break apart DNA strands, form bonds with DNA that disrupt genes, and inhibit DNA repair. In studies, animals given high doses of the acid develop colon cancer more often than normal.

Indeed, since high-fat diets lead to the production of extra bile and presumably extra lithocholic acid, scientists suspect that lithocholic acid is part of the means by which high-fat diets increase a person’s risk of colon cancer.

“Of all the bile acids, in fact of all the substances in your body, this is probably the most toxic,” says Mangelsdorf.

Before considering the vitamin D receptor, he and his coworkers had studied two other proteins that contribute to bile acid metabolism. One bound to a broad range of bile acids, including lithocholic acid. The other bound just to lithocholic acid, but only weakly.

Realizing that the vitamin D receptor resembles these two proteins in structure, the investigators wondered whether it, too, binds to bile acids. They found that it “only interacts with lithocholic acid and some of its close metabolites. It doesn’t interact with any of the other bile acids,” says Mangelsdorf.

A series of experiments confirmed that lithocholic acid activates the vitamin D receptor to turn on genes. When bound to either vitamin D or lithocholic acid, the receptor triggers cells to make a detoxifying enzyme that destroys lithocholic acid, the scientists report in the May 17 Science.

The enzyme, called CYP3A4, seems to ensure that the colon isn’t normally exposed to too much lithocholic acid, says Mangelsdorf. Production of CYP3A4 in response to vitamin D may provide another mechanism by which diets rich in the vitamin inhibit colon cancer, he adds.

Kenneth E. Thummel of the University of Washington in Seattle suggests that the new findings could explain the difference in concentrations of CYP3A4 in various intestinal tissues. The enzyme’s presence may correlate with the amount of lithocholic acid, he speculates. Also, if people are found to generate different amounts of lithocholic acid in their bile, says Thummel, that may clarify why CYP3A4 activity can vary from person to person.