Assessment of sterol metabolism in sitosterolemia
| dc.contributor.author | Othman, Rgia Ali | |
| dc.contributor.examiningcommittee | Eck, Peter (Human Nutritional Sciences)Mhanni, Aziz (Biochemistry & Medical Genetics) Frohlich, Jiri (University of British Colombia) | en_US |
| dc.contributor.supervisor | Myrie, Semone (Human Nutritional Sciences) Jones, Peter (Food Science) | en_US |
| dc.date.accessioned | 2014-10-27T18:02:42Z | |
| dc.date.available | 2014-10-27T18:02:42Z | |
| dc.date.issued | 2012-02 | en_US |
| dc.date.issued | 2013-12 | en_US |
| dc.date.issued | 2014-11 | en_US |
| dc.degree.discipline | Human Nutritional Sciences | en_US |
| dc.degree.level | Doctor of Philosophy (Ph.D.) | en_US |
| dc.description.abstract | Sitosterolemia (STSL) is a sterol storage disorder characterized by very high plasma plant sterol (PS) and 5α-stanol levels, and leads to premature atherosclerosis, xanthomas, macrothrombocytopenia and endocrine disruption. Ezetimibe (EZE), a sterol absorption inhibitor, reduces plasma PS levels in STSL but its effect on tissue pool of sterols has not been investigated yet. The research objectives were to assess if EZE reduces whole body sitosterol and cholesterol pool sizes, improves cholesterol homeostasis, enhance hematologic profile and reduce endocrine disruption in STSL. EZE effects on circulating levels of cholestanol and its precursors (cholesterol and bile acid derivative 7α-hydroxy-4-cholesten-3-one, 7α-H-C4) relative to exogenous stanols (sitostanol) were also studied. Eight STSL patients were taken off EZE for 14 wks. After 4 wks off EZE they received intravenous doses of D7-sitosterol and 18O-cholesterol for sterol pool sizes assessments, and oral doses of 13C-cholesterol and deuterium oxide to measure fractional cholesterol absorption and synthesis rates. EZE (10 mg/d) was resumed and stable isotopes testing repeated. Measurement parameters included isotopic sterol enrichments, blood cell count, plasma and red blood cell (RBC) PS, cholesterol and its precursor (lathosterol), 5α-stanols and plasma 7α-H-C4, and thyroid hormones levels. EZE reduced plasma levels of sitosterol and total cholesterol, whole body sitosterol and cholesterol pool sizes and fractional cholesterol absorption rate while increasing cholesterol synthesis, production and clearance rates. EZE increased platelet count and decreased platelet size without affecting RBC indices of size or mass. A substantial decrease in circulating sitostanol but moderate decrease of cholestanol was noted with EZE. EZE increased lathosterol but not 7α-H-C4, suggesting increases in cholesterol biosynthesis and thus precursor availability for synthesis of cholestanol. In summary, EZE reduces body stores of PS and cholesterol, and increases cholesterol turnover by reducing cholesterol absorption and enhancing its synthesis and clearance. EZE reduces circulating PS and 5α-stanol levels, and improves macrothrombocytopenia and thyroid disruption. Endogenous cholestanol in STSL is mainly derived from cholesterol but not bile acid synthesis pathway. These data suggest that EZE may reduce the risks of developing premature atherosclerosis, bleeding and hormone disruption, thereby reinforcing the rationale for the use of EZE in treatment of STSL. | en_US |
| dc.description.note | February 2015 | en_US |
| dc.identifier.citation | Othman RA and Moghadasian MH. Experimental and clinical evidence of cardiovascular benefits of plant sterols. 2012. In Moghadisian MH and Eskin NAM.(Eds.), Functional Foods and Cardiovascular Disease (Chap.6). Taylor & Francis. ISBN: 978-1-4200-7110-8. | en_US |
| dc.identifier.citation | Othman RA, Myrie SB, Jones PJ. Non-cholesterol sterols and cholesterol metabolism in sitosterolemia. Atherosclerosis. 2013 Dec;231(2):291-9. | en_US |
| dc.identifier.citation | Othman RA, Myrie SB, Mymin D, Merkens L, Roullet J, Steiner RD, and Jones PJ. Ezetimibe therapy favorably modulates platelet counts and hematologic parameters in homozygous sitosterolemia patients. The Journal of Paediatrics. 2014; in print. | en_US |
| dc.identifier.uri | http://hdl.handle.net/1993/24317 | |
| dc.language.iso | eng | en_US |
| dc.publisher | Taylor & Francis | en_US |
| dc.publisher | Elsevier, Inc. | en_US |
| dc.rights | open access | en_US |
| dc.subject | Plant sterols | en_US |
| dc.subject | Sitosterol pool size | en_US |
| dc.subject | Cholesterol pool size | en_US |
| dc.subject | Cholesterol turnover | en_US |
| dc.subject | Macrothrombocytopenia | en_US |
| dc.subject | Endocrine disruption | en_US |
| dc.subject | Ezetimibe | en_US |
| dc.title | Assessment of sterol metabolism in sitosterolemia | en_US |
| dc.type | doctoral thesis | en_US |
| local.subject.manitoba | yes | en_US |