LAUSR

DOI:10.1097/MOL.0000000000000463 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 nucleotidebinding 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 sterolbinding 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 thatvariation intheseprocesses may modify the clinical severity of the disease. Reports of hematologic complications associated with xenosterolemia continue to appear, indicating that they are mechanistically related. These include stomatocytosis and macrothrombocytosis, with increased xenosterol content of platelets and erythrocytes, often with accompanying splenomegaly [4 & ,5 & ]. This leads to platelet fragility and bleeding episodes, a phenomenon that is reported in only a fraction of cases with elevated plant sterols. Emerging understanding of the molecular mechanisms involved in xenosterol absorption and secretion have now led to comprehensive therapeutic intervention [3 && ]. Ursodiol treatment is known to increase xenosterol excretion in normal animals and humans. However, it is now known that even in the absence of G5G8 activity there is an independent pathway, demonstrated in mice, by which biliary secretion of sterols is increased [6]. The addition of ezetimibe increases the excretion