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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Intramural Research (Z01)
Project #
1Z01HL002064-04
Application #
7194067
Study Section
(MDB)
Project Start
Project End
Budget Start
Budget End
Support Year
4
Fiscal Year
2005
Total Cost
Indirect Cost
Name
U.S. National Heart Lung and Blood Inst
Department
Type
DUNS #
City
State
Country
United States
Zip Code
Shamburek, Robert D; Bakker-Arkema, Rebecca; Auerbach, Bruce J et al. (2016) Familial lecithin:cholesterol acyltransferase deficiency: First-in-human treatment with enzyme replacement. J Clin Lipidol 10:356-67
Shamburek, Robert D; Bakker-Arkema, Rebecca; Shamburek, Alexandra M et al. (2016) Safety and Tolerability of ACP-501, a Recombinant Human Lecithin:Cholesterol Acyltransferase, in a Phase 1 Single-Dose Escalation Study. Circ Res 118:73-82
van Deventer, Hendrick E; Miller, W Greg; Myers, Gary L et al. (2011) Non-HDL cholesterol shows improved accuracy for cardiovascular risk score classification compared to direct or calculated LDL cholesterol in a dyslipidemic population. Clin Chem 57:490-501
Miller, W Greg; Myers, Gary L; Sakurabayashi, Ikunosuke et al. (2010) Seven direct methods for measuring HDL and LDL cholesterol compared with ultracentrifugation reference measurement procedures. Clin Chem 56:977-86
Lindegaard, Marie L; Wassif, Christopher A; Vaisman, Boris et al. (2008) Characterization of placental cholesterol transport: ABCA1 is a potential target for in utero therapy of Smith-Lemli-Opitz syndrome. Hum Mol Genet 17:3806-13
Zhang, Jing; Hawari, Feras I; Shamburek, Robert D et al. (2008) Circulating TNFR1 exosome-like vesicles partition with the LDL fraction of human plasma. Biochem Biophys Res Commun 366:579-84
Freeman, Lita; Amar, Marcelo J A; Shamburek, Robert et al. (2007) Lipolytic and ligand-binding functions of hepatic lipase protect against atherosclerosis in LDL receptor-deficient mice. J Lipid Res 48:104-13
Sethi, Amar A; Amar, Marcelo; Shamburek, Robert D et al. (2007) Apolipoprotein AI mimetic peptides: possible new agents for the treatment of atherosclerosis. Curr Opin Investig Drugs 8:201-12
Basso, Federica; Freeman, Lita A; Ko, Carol et al. (2007) Hepatic ABCG5/G8 overexpression reduces apoB-lipoproteins and atherosclerosis when cholesterol absorption is inhibited. J Lipid Res 48:114-26
Nishiwaki, Masato; Ikewaki, Katsunori; Bader, Giovanni et al. (2006) Human lecithin:cholesterol acyltransferase deficiency: in vivo kinetics of low-density lipoprotein and lipoprotein-X. Arterioscler Thromb Vasc Biol 26:1370-5

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