The elucidation of the molecular basis of the
rare disease,
sitosterolemia, has revolutionized our mechanistic understanding of how dietary
sterols are excreted and how
cholesterol is eliminated from the body. Two
proteins, ABCG5 and ABCG8, encoded by the
sitosterolemia locus, work as obligate dimers to pump
sterols out of hepatocytes and enterocytes. ABCG5/ABCG8 are key in regulating whole-body
sterol trafficking, by eliminating
sterols via the biliary tree as well as the intestinal tract. Importantly, these transporters keep xenosterols from accumulating in the body. The
sitosterolemia locus has been genetically associated with
lipid levels and downstream atherosclerotic disease, as well as formation of
gallstones and the risk of
gallbladder cancer. While polymorphic variants raise or lower the risks of these phenotypes, loss of function of this locus leads to more dramatic phenotypes, such as premature
atherosclerosis, platelet dysfunction, and
thrombocytopenia, and, perhaps, increased endocrine disruption and
liver dysfunction. Whether small amounts of xenosterol exposure over a lifetime cause pathology in normal humans with polymorphic variants at the
sitosterolemia locus remains largely unexplored. The purpose of this review will be to summarize the current state of knowledge, but also highlight key conceptual and mechanistic issues that remain to be explored.