Abstract
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.
Highlights
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
These findings corroborated earlier data in animal models demonstrating that ABCG5/G8 mRNAs were responsive to dietary cholesterol as well as Liver X receptor (LXR) and retinoid X receptor agonists in a LXR - and LXR -dependent fashion [70]
These studies indicate that the absence of intestinal ABCG5/G8 does not lead to increased cholesterol absorption and, the reduced fecal neutral sterol excretion (FNSE) observed in whole-body ABCG5/G8-deficient mice could be driven by dramatically decreased biliary cholesterol secretion
Summary
ABCG5 and ABCG8 were key suspects in regulating cholesterol homeostasis in atherosclerotic CVD (ASCVD) This was supported by the clinical observations of severe, and sometimes fatal, atherosclerosis in humans with sitosterolemia (though see below). The mechanistic connection remains to be addressed, was the link between a presumed hypermorphic variant, D19H, in ABCG8 and gallbladder cancer risk [25, 29]. By its nature, requires multiple genetic changes to occur and how this would be caused or accelerated by the sitosterolemia locus remains to be explored. It is not clear whether the variant alters the kinds of xenosterols that are concentrated
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