Homozygous sitosterolemia is an autosomally inherited recessive disorder of sterol metabolism. Patients with homozygous sitosterolemia can present with accelerated atherosclerosis with initial CHD events occurring in childhood. In addition, these patients can have tendon xanthomas, hemolytic episodes, as well as arthritis and arthralgias. These patients have increased levels of a wide range of plant sterols, including sitosterol, that are excessively absorbed and inadequately excreted, leading to dramatic increases in tissue deposition. A low sterol diet provides only limited reduction in sitosterol levels and currently available medical treatments, such as bile salt binding resins, are usually insufficiently effective or poorly tolerated. Two ABCG transporters (ABCG5 and ABCG8) have recently been identified as defective in these patients. Normally, sitosterol is preferentially secreted into the bile; in contrast, in patients with homozygous sitosterolemia, the proportion of sitosterol in bile is reduced, leading to delayed clearance-despite increased plasma concentrations and markedly increased whole-body sitosterol stores. Thus, both increased absorption and diminished excretion underlie the elevations in plant sterol levels in these patients. Studies have also been initiated with a member of a new class of therapeutic agents that are specific cholesterol absorption inhibitors, being developed to treat hypercholesterolemia. In the current study, the efficacy, safety, and longterm tolerability of this drug will be studied in patients with homozygous sitosterolemia. Studies have been initiated to investigate and evaluate the clinical defects in patients lacking the gene in order to better understand the physiologic importance in total sterol metabolism. We have initiated additional studies in order to better understand the gastrointestinal absorption and plasma metabolism of cholesterol and sitosterol in patients with homozygous sitosterolemia in order to understand the mechanisms of action that could lead to reductions in both plant sterol and LDL cholesterol levels in these patients, thereby providing important clinical benefits. Further studies are underway in healthy patients in order to elucidate the physiologic role of the newly described ABCG transporters in normal physiology.
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