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 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 been initiated with a member of a new class of therapeutic agents that are specific cholesterol absorption inhibitors, being developed to treat hypercholesterolemia. The efficacy, safety, and longterm tolerability of two doses of the drug is being evaluated in patients with homozygous sitosterolemia. To understand the mechanism of action by which this drug reduces both plant sterol and LDL cholesterol levels in these patients, we are evaluating changes in gastrointestinal absorption and plasma metabolism of cholesterol and sitosterol in controls and patients with homozygous sitosterolemia. These studies in healthy patients and patients with homozygous sitosterolemia will help elucidate the physiologic role of the newly described ABCG transporters in normal and diseased states physiology, providing important insights into the drug?s clinical benefits.
Showing the most recent 10 out of 16 publications
