Thrombocytopenia and Platelet Abnormalities in High-Density Lipoprotein Receptor–Deficient Mice

Dole, Vandana S.; Matusková, Jana; Vasile, Eliza; Yesilaltay, Ayce; Bergmeier, Wolfgang; Bernimoulin, Michael; Wagner, Denisa D.; Krieger, Monty

doi:10.1161/atvbaha.108.162347

Cited by 73 publications

(91 citation statements)

References 50 publications

(56 reference statements)

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“…Hypercholesterolemia must also contribute to the altered RBC metabolism in SR-BI-deficient mice. The high plasma FC:TC ratio in SR-BI Ϫ/Ϫ mice has also been correlated with thrombocytopenia (31). If fully deficient and liverdeficient mice for SR-BI similarly displayed diminished platelet counts (ϳ2-fold), CETP expression in the latter model partially restored platelet counts, whereas no significant effect was seen in SR-BI Ϫ/Ϫ mice (Fig.…”

Section: Impact Of Cetp Expression On Plasma Cholesterol Levels and Hmentioning

confidence: 89%

Cholesteryl Ester Transfer Protein Expression Partially Attenuates the Adverse Effects of SR-BI Receptor Deficiency on Cholesterol Metabolism and Atherosclerosis

Bouhassani

Gilibert

Moreau

et al. 2011

Journal of Biological Chemistry

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Scavenger receptor SR-BI significantly contributes to HDL cholesterol metabolism and atherogenesis in mice. However, the role of SR-BI may not be as pronounced in humans due to cholesteryl ester transfer protein (CETP) activity. To address the impact of CETP expression on the adverse effects associated with SR-BI deficiency, we cross-bred our SR-BI conditional knock-out mouse model with CETP transgenic mice. CETP almost completely restored the abnormal HDL-C distribution in SR-BI-deficient mice. However, it did not normalize the elevated plasma free to total cholesterol ratio characteristic of hepatic SR-BI deficiency. Red blood cell and platelet count abnormalities observed in mice liver deficient for SR-BI were partially restored by CETP, but the elevated erythrocyte cholesterol to phopholipid ratio remained unchanged. Complete deletion of SR-BI was associated with diminished adrenal cholesterol stores, whereas hepatic SR-BI deficiency resulted in a significant increase in adrenal gland cholesterol content. In both mouse models, CETP had no impact on adrenal cholesterol metabolism. In diet-induced atherosclerosis studies, hepatic SR-BI deficiency accelerated aortic lipid lesion formation in both CETP-expressing (4-fold) and non-CETP-expressing (8-fold) mice when compared with controls. Impaired macrophage to feces reverse cholesterol transport in mice deficient for SR-BI in liver, which was not corrected by CETP, most likely contributed by such an increase in atherosclerosis susceptibility. Finally, comparison of the atherosclerosis burden in SR-BI liver-deficient and fully deficient mice demonstrated that SR-BI exerted an atheroprotective activity in extra-hepatic tissues whether CETP was present or not. These findings support the contention that the SR-BI pathway contributes in unique ways to cholesterol metabolism and atherosclerosis susceptibility even in the presence of CETP.Epidemiological studies have demonstrated that high density lipoprotein cholesterol is a strong, independent, inverse predictor of the risk of coronary heart disease. High plasma levels of the major apolipoprotein of HDL, APOA-I, have been also shown to predict decreased risk of coronary heart disease. One major atheroprotective mechanism by which HDL/APOA-I may protect against atherosclerosis involves the transport of excess cholesterol from peripheral tissues, including macrophages, to the liver, bile, and eventually feces for excretion, a process known as reverse cholesterol transport.The scavenger receptor SR-BI is an 82-kDa glycosylated plasma membrane protein that binds HDL/APOA-I with high affinity and stimulates the bi-directional flux of cholesterol between cells and extracellular HDL particles. In mice, SR-BI, encodeed by the Scarb1 gene, is a major determinant of HDL metabolism in mice and is protective against atherosclerosis. Indeed, hepatic overexpression of SR-BI markedly reduces plasma HDL-C levels, increases biliary secretion of cholesterol, and decreases atherosclerosis (1-3), whereas deficiency of this receptor resu...

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Section: Impact Of Cetp Expression On Plasma Cholesterol Levels and Hmentioning

confidence: 89%

Cholesteryl Ester Transfer Protein Expression Partially Attenuates the Adverse Effects of SR-BI Receptor Deficiency on Cholesterol Metabolism and Atherosclerosis

Bouhassani

Gilibert

Moreau

et al. 2011

Journal of Biological Chemistry

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“…Cholesterol quartiles derived from NHANES [2005][2006] were used to analyze both surveys: 1 ) HDL-C [low ( р 41.83 mg/dl), medium (>41.83-51.38 mg/dl), high (>51. .93 mg/dl), very high(>62.93 mg/dl)]; and 2 ) non-HDL-C [low ( р 114.42 mg/dl), medium (>114.42-140.1 mg/dl), high window of cholesterol content, above which it, along with erythrocyte and platelet lifespan, is compromised ( 4,6,17 ).…”

Section: Discussionmentioning

confidence: 99%

“…Our sensitivity analysis, nonetheless, indicates that the relationships do persist after several common conditions affecting blood cell levels and cholesterol are excluded. Although the ratio of free cholesterol:TC has been linked to platelet abnormalities in mouse and man ( 4,46 ), we were unable to analyze free cholesterol as it was not measured in the NHANES. Also, the ABO blood group type, recently shown in a genome-wide association study to be associated with LDL-C ( 47 ), was not determined in NHANES.…”

Section: Discussionmentioning

confidence: 99%

Relationship between serum cholesterol and indices of erythrocytes and platelets in the US population

Fessler

Rose

Zhang

et al. 2013

Journal of Lipid Research

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“…Emerging evidence indicates that SR-BI is a multi-functional protein. In addition to mediating intracellular cholesterol uptake from HDL, SR-BI has been shown to activate eNOS in endothelial cells (23)(24)(25)(26), induce apoptosis (27,28), modulate erythrocyte development (29,30), and platelet function (31)(32)(33)(34) mediate the entrance of hepatitis C virus (35), regulate lymphocyte homeostasis and autoimmunity (36), and regulate thymocyte apoptosis in sepsis (37). Mutations in human SR-BI induce a number of pathological phenotypes observed in SR-BI-null mice, indicating the importance of SR-BI in human (38 -47).…”

mentioning

confidence: 99%

Hepatic Scavenger Receptor BI Protects Against Polymicrobial-induced Sepsis through Promoting LPS Clearance in Mice

Guo

Zheng

Ai³

et al. 2014

Journal of Biological Chemistry

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Background: We utilized Scarb1I179N mice, a model deficient in hepatic SR-BI, to determine the role of hepatic SR-BI in sepsis. Results: Upon cecal ligation and puncture (CLP), Scarb1 I179N mice had a 3.5-fold increase in fatality associated with an impaired LPS clearance. Conclusion: Hepatic SR-BI protects against sepsis through promoting LPS clearance. Significance: Promoting hepatic SR-BI-mediated LPS clearance may provide a therapeutic approach for sepsis.

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Thrombocytopenia and Platelet Abnormalities in High-Density Lipoprotein Receptor–Deficient Mice

Cited by 73 publications

References 50 publications

Cholesteryl Ester Transfer Protein Expression Partially Attenuates the Adverse Effects of SR-BI Receptor Deficiency on Cholesterol Metabolism and Atherosclerosis

Cholesteryl Ester Transfer Protein Expression Partially Attenuates the Adverse Effects of SR-BI Receptor Deficiency on Cholesterol Metabolism and Atherosclerosis

Relationship between serum cholesterol and indices of erythrocytes and platelets in the US population

Hepatic Scavenger Receptor BI Protects Against Polymicrobial-induced Sepsis through Promoting LPS Clearance in Mice

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