Plant Sterols Cause Macrothrombocytopenia in a Mouse Model of Sitosterolemia

Kruit, Janine K.; Drayer, A. Lyndsay; Bloks, Vincent W.; Blom, Nel R.; Olthof, Sandra; Sauer, Pieter J. J.; Haan, Gerald de; Kema, Ido P.; Vellenga, Edo; Kuipers, Folkert

doi:10.1074/jbc.m706689200

Cited by 40 publications

(36 citation statements)

References 47 publications

(50 reference statements)

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“…14,18 As shown in Figure 1A-B, Abcg8 Figure 1C) typically associated with human sitosterolemia. 11 These hematologic parameters were nearly identical in Abcg5-deficient mice fed an HS diet (not shown).…”

Section: Study Approvalmentioning

confidence: 99%

“…11,14 However, platelets from sitosterolemic humans or mice contain no abnormal inclusion bodies; they are simply large. Whole blood samples collected from Abcg8 2/2 mice fed an HS diet were stained with the cholesterol-binding fluorescent dye, filipin, and analyzed by flow cytometry.…”

Section: Study Approvalmentioning

confidence: 99%

“…11 Other diagnostic hematologic abnormalities include stomatocytic hemolysis, anemia, and loss of ristocetin-induced platelet agglutination, 11 which is a measure of the ability of platelet glycoprotein (GP) Ib to function as an adhesion receptor for von Willebrand factor (VWF). 12 We generated a mouse model of sitosterolemia in 2004 13 ; shortly thereafter, Kruit et al 14 found that that mice genetically deficient in Abcg5 fully recapitulate the macrothrombocytopenia seen in human sitosterolemia, a condition that can be corrected by treatment with the sterol-absorption inhibitor ezetimibe. 15 Recently, Chase et al identified a spontaneously occurring nonsense mutation in Abcg5 in trac/trac mice that also exhibits thrombocytopenia, cardiomyopathy, and decreased platelet activation responsiveness.…”

Section: Introductionmentioning

confidence: 99%

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Platelet hyperreactivity explains the bleeding abnormality and macrothrombocytopenia in a murine model of sitosterolemia

Kanaji

Montgomery

et al. 2013

Blood

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• Plant sterol accumulation in platelet membrane induces platelet hyperreactivity.• Internalization of the aIIbb3 complex and filamin A degradation cause macrothrombocytopenia and bleeding phenotype.Sitosterolemia is a rare, autosomal recessive disease caused by mutations in the adenosine triphosphate-binding cassette transporter genes ABCG5 or ABCG8 that result in accumulation of xenosterols in the body. Clinical manifestations include tendon xanthomas, premature coronary artery disease, hemolytic anemia, macrothrombocytopenia, and bleeding. Although the effect of sterol accumulation on the predisposition for atherosclerosis is evident, how xenosterol accumulation leads to defects in platelet physiology is unknown. Sitosterolemia induced in Abcg5-and Abcg8-deficient mice fed a high plant sterol diet resulted in accumulation of free sterols in platelet plasma membranes, leading to hyperactivatable platelets characterized by constitutive binding of fibrinogen to its aIIbb3 integrin receptor, internalization of the aIIbb3 complex, generation of plateletderived microparticles, and changes in the quantity and subcellular localization of filamin. The latter was associated with macrothrombocytopenia, shedding of GPIba, impaired platelet adhesion to von Willebrand factor, and inability to form stable thrombi. Plasma levels of soluble GPIba were strongly correlated with plasma sitosterol levels in samples from human sitosterolemic patients, implicating a similar mechanism of sterol-induced platelet passivation in the human disease. Intercalation of plant sterols into the plasma membrane therefore results in dysregulation of multiple platelet activation pathways, leading to macrothrombocytopenia and bleeding. (Blood. 2013;122(15):2732-2742

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Section: Study Approvalmentioning

confidence: 99%

Section: Study Approvalmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Platelet hyperreactivity explains the bleeding abnormality and macrothrombocytopenia in a murine model of sitosterolemia

Kanaji

Montgomery

et al. 2013

Blood

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“…Phytosterols may displace cholesterol in the cell membrane and interfere with the cell function. Indeed, the accumulation of phytosterols has been reported to cause blood-cell abnormalities (51)(52)(53) and even some neurological disorder (54). Currently, the mechanisms underlying the defense against phytosterol accumulation remain elusive.…”

Section: Npc1l1 Deletion Prevents Sitosterolemia 297mentioning

confidence: 99%

Genetic inactivation of NPC1L1 protects against sitosterolemia in mice lacking ABCG5/ABCG8

Tang

Lin

et al. 2009

Journal of Lipid Research

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Mice lacking Niemann-Pick C1-Like 1 (NPC1L1) (NPC1L1 2/2 mice) exhibit a defect in intestinal absorption of cholesterol and phytosterols. However, wild-type (WT) mice do not efficiently absorb and accumulate phytosterols either. Cell-based studies show that NPC1L1 is a much weaker transporter for phytosterols than cholesterol. In this study, we examined the role of NPC1L1 in phytosterol and cholesterol trafficking in mice lacking ATP-binding cassette (ABC) transporters G5 and G8 (G5/G8 2/2 mice). G5/G82/2 mice develop sitosterolemia, a genetic disorder characterized by the accumulation of phytosterols in blood and tissues. We found that mice lacking ABCG5/G8 and NPC1L1 [triple knockout (TKO) mice] did not accumulate phytosterols in plasma and the liver. TKO mice, like G5/G8 2/2 mice, still had a defect in hepatobiliary cholesterol secretion, which was consistent with TKO versus NPC1L1 2/2 mice exhibiting a 52% reduction in fecal cholesterol excretion. Because fractional cholesterol absorption was reduced similarly in NPC1L1 2/2 and TKO mice, by subtracting fecal cholesterol excretion in TKO mice from NPC1L1 2/2 mice, we estimated that a 25g NPC1L1 2/2 mouse may secrete about 4 mmol of cholesterol daily via the G5/G8 pathway. In conclusion, NPC1L1 is essential for phytosterols to enter the body in mice. The two ATP-binding cassette (ABC) half-transporters, G5 and G8, reside at the canalicular membrane of hepatocytes and the apical membrane of absorptive enterocytes where they function as heterodimers to transport cholesterol and noncholesterol sterols into the bile canaliculus and the gut lumen for fecal excretion (1-4). Mutations in either ABCG5 (G5) or ABCG8 (G8) cause sitosterolemia, a rare autosomal recessive disorder (5, 6). The hallmark of sitosterolemia is the accumulation of sitosterol and campesterol, two major plant-derived sterols, in the blood and tissues (7-10). In sitosterolemic patients and mice, the plasma cholesterol concentrations follow fluctuations in dietary cholesterol intake (2,11,12). Many sitosterolemic individuals develop xanthomas and premature coronary heart disease as a result of sterol deposition in the skin, tendons, and coronary arteries (13-15).Ezetimibe, a cholesterol absorption inhibitor (16), has been recently shown to effectively reduce the plasma phytosterol levels in sitosterolemic patients and mice (17,18). It can also completely reverse xanthomatosis when used in combination with low-dose cholestyramine therapy in a sitosterolemic patient (19). These findings suggest two possibilities: 1) there is a common pathway for intestinal absorption of cholesterol and phytosterols; or 2) ezetimibe simultaneously targets two independent transporters: one for cholesterol and the other for phytosterols.In search of the molecular target of ezetimibe, Altmann et al. (20) identified a polytopic transmembrane protein named Niemann-Pick C1-Like 1 (NPC1L1), which localizes at the brush border membrane of the small intestine and mediates intestinal absorption of cholesterol. Disrupti...

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“…STSL is caused by accumulation in the body of plant sterols as a consequence of mutations in the transporter responsible for their excretion in bile and gut [76]. Macrothrombocytopenia of STSL derives from a direct toxic effect of plant sterols on Mks and platelets [75][76][77].…”

Section: Other Pathogenetic Mechanismsmentioning

confidence: 99%

Pathogenesis and management of inherited thrombocytopenias: rationale for the use of thrombopoietin-receptor agonists

Pecci

2013

Int J Hematol

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Knowledge in the field of inherited thrombocytopenias (ITs) has considerably improved over the recent years. In the last 5 years, nine new genes whose mutations are responsible for thrombocytopenia have been identified, and this also led to the recognition of several novel nosographic entities, such as thrombocytopenias deriving from mutations in CYCS, TUBB1, FLNA, ITGA2B/ITGB3, ANKRD26 and ACTN1. The identification of novel molecular alterations causing thrombocytopenia together with improvement of methodologies to study megakaryopoiesis led to considerable advances in understanding pathophysiology of ITs, thus providing the background for proposing new treatments. Thrombopoietin-receptor agonists (TPO-RAs) represent an appealing therapeutic hypothesis for ITs and have been tested in a limited number of patients. In this review, we provide an updated description of pathogenetic mechanisms of thrombocytopenia in the different forms of ITs and recapitulate the current management of these disorders. Moreover, we report the available clinical and preclinical data about the role of TPO-RAs in ITs and discuss the rationale for the use of these molecules in view of pathogenesis of the different forms of thrombocytopenia of genetic origin.

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Plant Sterols Cause Macrothrombocytopenia in a Mouse Model of Sitosterolemia

Cited by 40 publications

References 47 publications

Platelet hyperreactivity explains the bleeding abnormality and macrothrombocytopenia in a murine model of sitosterolemia

Platelet hyperreactivity explains the bleeding abnormality and macrothrombocytopenia in a murine model of sitosterolemia

Genetic inactivation of NPC1L1 protects against sitosterolemia in mice lacking ABCG5/ABCG8

Pathogenesis and management of inherited thrombocytopenias: rationale for the use of thrombopoietin-receptor agonists

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