To provide an update on recent advances made in our mechanistic and pathophysiological understanding of the rare human disease Sitosterolemia, the role of ABCG5/ABCG8 in sterol trafficking and how newer data implicate a more wider role in the body.
Sitosterolemia is caused by a genetic defect of sterolins (ABCG5/ABCG8) mapped to the STSL locus. Polymorphic variations in STSL have been linked to lipid levels and gallstone disease in whites. Newer studies now link this locus to a more diverse ethnic group for gallstone disease, susceptibility to biliary cancer, and show variants that alter sterolin function. Intriguingly, carriers of a mutant allele seem to show protection against carotid wall disease. Although the ‘promoter’ region of the STSL is minimal, regulatory regions responsive to liver X receptor have remained elusive, but no longer; two intronic regions in ABCG8 have now been identified. Xenosterol accumulation leads to loss of abdominal fat, infertility, and premature death. Xenosterol accumulation in mouse platelet membranes leads to platelet hyperactivation, increased microparticle formation, and reduced αIIbβ3 surface expression. In humans, phytosterols may promote liver injury in parenteral nutrition-associated liver disease.
Progress in understanding sterolin function is beginning to show that xenosterols can be toxic and are involved on pathogenesis, and the role of ABCG5/ABCG8 may extend into other metabolic processes by altering intracellular sterol metabolism.
aClement J. Zablocki Veterans Affairs Medical Center, Milwaukee, Wisconsin, USA
bDivision of Endocrinology, Metabolism and Clinical Nutrition, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
Correspondence to Shailendra B. Patel, Division of Endocrinology, Metabolism and Clinical Nutrition, Medical College of Wisconsin, HRC 4850, 8701 Watertown Plank Rd, Milwaukee, WI 53226, USA. Tel: +1 414 955 5645; e-mail: email@example.com