Original ArticleEzetimibe Reduces Plant Sterol Accumulation and Favorably Increases Platelet Count in Sitosterolemia
Section snippets
Methods
Eight patients (5 males and 3 females, between 16 and 56 years of age) were recruited from Hutterite colonies in Manitoba, Canada (n = 4) and South Dakota, US (n = 4). All patients were identified as having homozygous ABCG8 S107X mutation (NM_022437.2:c.320C>G) and are related to a proband previously reported by Mymin et al21, 22 and Chong et al.23 All procedures involving human patients were approved by the University of Manitoba Biomedical Ethics board and written informed consent was
Results
All 8 initially recruited patients completed the study (Table I). Mean values of serum TC and LDL-cholesterol indicated mild hypercholesterolemia. All patients had elevated plasma and RBC levels of PS (Table I). The plasma and RBC concentrations of sitosterol and total PS were similar on average (P > .11), but the PS to TC ratio (PS/TC) tended to be higher in RBC than in plasma (P = .08; Table I). One subject had mild anemia (hemoglobin [Hb] = 11.7 g/dL; hematocrit = 37.7%), and stomatocytes
Discussion
The major finding of this study is that blocking intestinal absorption of PS with EZE in patients with STSL increases PLT number and decreases PLT size, and measures were correlated with reductions in blood PS concentrations. The minimal effect of EZE on blood cholesterol suggests that the improvements in PLT count and size were primarily because of improved PS homeostasis. The effect of EZE on PLT may potentially ameliorate the bleeding tendency in STSL.
Mutations in ABCG5/8 genes cause STSL,
References (43)
- et al.
Sitosterolemia
J Lipid Res
(1992) - et al.
Phytosterolemia and pseudohomozygous type II hypercholesterolemia in two Chinese patients
J Pediatr
(1991) - et al.
Phytosterolemia and hypercholesterolemia in childhood
J Pediatr
(1986) Sitosterolemia's stomatocytosis and macrothrombocytopenia
Blood
(2012)- et al.
Platelet hyperreactivity explains the bleeding abnormality and macrothrombocytopenia in a murine model of Sitosterolemia
Blood
(2013) - et al.
Plant sterols cause macrothrombocytopenia in a mouse model of sitosterolemia
J Biol Chem
(2008) - et al.
Intestinal cholesterol absorption inhibitor ezetimibe added to cholestyramine for sitosterolemia and xanthomatosis
Gastroenterology
(2006) - et al.
Phenotypic heterogeneity of sitosterolemia
J Lipid Res
(2004) - et al.
A population-based study of autosomal-recessive disease-causing mutations in a founder population
Am J Hum Genet
(2012) - et al.
Serum lipids, plant sterols, and cholesterol kinetic responses to plant sterol supplementation in phytosterolemia heterozygotes and control individuals
Am J Clin Nutr
(2012)
Phytosterolemia in children with parenteral nutrition-associated cholestatic liver disease
Gastroenterology
Non-cholesterol sterols and cholesterol metabolism in sitosterolemia
Atherosclerosis
Phytosterol feeding causes toxicity in ABCG5/G8 knockout mice
Am J Pathol
The effects of sterol structure upon sterol esterification
Atherosclerosis
Cholesterol and the cell membrane
Biochim Biophys Acta
Vegetable oils high in phytosterols make erythrocytes less deformable and shorten the life span of stroke-prone spontaneously hypertensive rats
J Nutr
Cholesterol bound to hemoglobin in normal human erythrocytes: a new form of cholesterol in circulation?
Clin Biochem
Rapeseed oil ingestion and exacerbation of hypertension-related conditions in stroke prone spontaneously hypertensive rats
Toxicology
Red cell and plasma plant sterols are related during consumption of plant stanol and sterol ester spreads in children with hypercholesterolemia
J Pediatr
The replacement of cholesterol by phytosterols and the increase of total sterol content in model erythrocyte membranes
Chem Phys Lipids
Influence of hypercholesterolemia on morphological and rheological characteristics of erythrocytes
Atherosclerosis
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2018, AtherosclerosisCitation Excerpt :In their clinical trial, Lütjohann et al. found no decrease (in point of fact a 2% increase) in cholesterol levels [6]. In a recent study by Othman et al., only a small 12% cholesterol decrease was found [7]. With respect to sitosterol levels similar, if less stark, differences exist compared to our cohort.
Supported by the Canadian Institutes of Health Research (MOP12339). The Sterol and Isoprenoid Research (STAIR; U54HD061939) Consortium is a part of the National Institutes of Health (NIH) Rare Diseases Clinical Research Network, supported through collaboration between the NIH Office of Rare Diseases Research at the National Center for Advancing Translational Science, and National Institute of Child Health and Human Development. R.O. was supported by the Libyan Scholarship Program and the Manitoba Health Research Council Graduate Student Fellowship. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. The authors declare no conflicts of interest.
Registered with www.ClinicalTrials.gov: NCT01584206.