Cholesterol, like other sterols, is an essential component of our cell membranes. However, high cholesterol intake and absorption can cause ill health, and so the body has evolved ways to regulate its absorption from our diet. A striking exception to this occurs in sitosterolemia, a rare, recessive human disorder that causes increased intestinal absorption of dietary sterols, including plant sterols and cholesterol, and premature coronary heart disease. Now, researchers have discovered two novel ATP-binding cassette (ABC) transporter genes that are mutated in sitosterolemia sufferers.

The genes were identified by a combined microarray and candidate-gene approach. Reasoning that the sitosterolemia locus might be regulated by a nuclear hormone receptor ( LXR) that mediates cholesterol homeostasis, the researchers used microarrays to search for mouse transcripts that were upregulated in response to an LXR ligand. One such transcript encoded a novel ABC transporter, ABCG5, that mapped to the human sitosterolemia locus. Its gene turned out to be adjacent to another locus, transcribed in the opposite direction, that contained a second transporter gene, ABCG8. Sitosterolemia patients were found to have mutations in either gene.

Sitosterolemia sufferers accumulate large amounts of plant sterols in their tissues that are not normally absorbed. Or so it was thought. Berge et al.'s findings indicate that plant sterols, such as sitosterol, are absorbed by intestinal cells but are then pumped back into the gut lumen by ABC transporters, such as ABCG5 and ABCG8. It remains to be investigated whether subtle defects in these proteins or their regulation underlie our varied responses to high-cholesterol diets.