Xenosterolemia: emerging molecular and clinical insights

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Elucidation of the crystal structure of the ATP-binding cassette sub-family G, members 5 and 8 (ABCG5G8) heterodimer responsible for excretion of xenosterols (sterols other than cholesterol) from the liver and into the intestinal lumen is providing insights into its function at a molecular level [1▪▪]. Both monomers have a transmembrane domain and a nucleotide-binding site; the latter interrelate, changing conformation upon binding ATP. Another determinant of the levels of xenosterols in the blood is the relative rate of absorption of these sterols and of cholesterol by the Niemann-Pick C1-like 1 (NPC1L1) transporter. Structural studies have demonstrated that the sterol-binding pocket in the N-terminal domain is in a closed conformation, with a degree of flexibility that could allow for preferential binding of cholesterol [2]. Thus, several mechanisms act selectively to minimize xenosterol levels in blood: reduced uptake by NPC1L1, excretion by ABCG5G8 from liver and intestine, preferential O-acylation of cholesterol by O-acyltransferase 2 [3▪▪], and preferential esterification of cholesterol by Acyl-Coenzyme A: Cholesterol acyltransferase 2 (ACAT2). The observation that levels of plant sterols in the plasma of individuals with xenosterolemia vary considerably, suggests that variation in these processes may modify the clinical severity of the disease.
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