Sphingolipids and cellular cholesterol homeostasis. Effect of ceramide on cholesterol trafficking and HMG CoA reductase activity

Subbaiah, Papasani V.; Sowa, Jennifer M.; Singh, Devinder

doi:10.1016/j.abb.2008.03.019

Cited by 16 publications

(15 citation statements)

References 43 publications

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“…7 Indeed, this lipid messenger was shown to be able to interfere with both distribution and metabolism of cholesterol. 47,48 In conclusion, our study provides several lines of evidence showing that RTX significantly interferes with BCR signaling by targeting proximal components of the BCR cascade, including decreased BCR expression and disturbances of BCR membrane dynamics, although the respective contribution of these 2 events, perhaps coordinated, should be determined. BCR inhibition might contribute to RTX immunosuppressive property.…”

Section: Discussionmentioning

confidence: 99%

Rituximab inhibits B-cell receptor signaling

Kheirallah

Caron

Gross

et al. 2010

Blood

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Section: Discussionmentioning

confidence: 99%

Rituximab inhibits B-cell receptor signaling

Kheirallah

Caron

Gross

et al. 2010

Blood

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“…NPD is a lysosomal storage disease characterized by the lysosomal accumulation of SM and cholesterol and aberrant expan- sion of the lysosomal compartment (49,(51)(52)(53)(54). Inactivating and partial-loss-of-function mutations in the SMPD1 gene that encodes ASM are the cause of NPD types A and B, respectively.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Acid Sphingomyelinase Depletes Cellular Phosphatidylserine and Mislocalizes K-Ras from the Plasma Membrane

Cho

Hoeven

Zhou

et al. 2016

Molecular and Cellular Biology

143

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e K-Ras must localize to the plasma membrane for biological activity; thus, preventing plasma membrane interaction blocks KRas signal output. Here we show that inhibition of acid sphingomyelinase (ASM) mislocalizes both the K-Ras isoforms K-Ras4A and K-Ras4B from the plasma membrane to the endomembrane and inhibits their nanoclustering. We found that fendiline, a potent ASM inhibitor, reduces the phosphatidylserine (PtdSer) and cholesterol content of the inner plasma membrane. These lipid changes are causative because supplementation of fendiline-treated cells with exogenous PtdSer rapidly restores K-Ras4A and K-Ras4B plasma membrane binding, nanoclustering, and signal output. Conversely, supplementation with exogenous cholesterol restores K-Ras4A but not K-Ras4B nanoclustering. These experiments reveal different operational pools of PtdSer on the plasma membrane. Inhibition of ASM elevates cellular sphingomyelin and reduces cellular ceramide levels. Concordantly, delivery of recombinant ASM or exogenous ceramide to fendiline-treated cells rapidly relocalizes K-Ras4B and PtdSer to the plasma membrane. K-Ras4B mislocalization is also recapitulated in ASM-deficient Neimann-Pick type A and B fibroblasts. This study identifies sphingomyelin metabolism as an indirect regulator of K-Ras4A and K-Ras4B signaling through the control of PtdSer plasma membrane content. It also demonstrates the critical and selective importance of PtdSer to K-Ras4A and K-Ras4B plasma membrane binding and nanoscale spatial organization. Ras proteins are small guanine nucleotide binding proteins that oscillate between active GTP-bound and inactive GDP-bound states. Activated Ras proteins transmit signals for cell proliferation and cell survival. Importantly, ϳ15% of all human tumors express mutant Ras proteins that are locked in the GTP-bound state (1). Of the three ubiquitously expressed Ras isoforms, H-, N-, and K-Ras, oncogenic mutant K-Ras is the most prevalent, being expressed in ϳ95% of pancreatic, ϳ45% of colorectal, and ϳ35% of lung cancers (1). Despite its importance, there are currently no clinically approved drugs that directly target oncogenic K-Ras. To date, Ras drug discovery efforts have focused largely on inhibitors of Ras downstream effectors, including B-Raf, C-Raf, phosphatidylinositol 3-kinase (PI3K), MEK, and extracellular signal-regulated kinase (ERK) (2). For example, B-Raf-specific inhibitors produce excellent albeit often short-lived responses in patients with B-Raf mutant melanoma (3), in part because of a perturbation of complex negative-feedback control loops (2). B-Raf inhibitors also paradoxically activate the mitogen-activated protein kinase (MAPK) cascade in melanoma cells expressing oncogenic mutant N-or K-Ras (4-6). Other highly promising approaches include compounds that covalently modify K-Ras proteins with a G12C mutation to abrogate effector interactions (7,8) and allosteric modulators that directly bind Ras to inhibit guanine nucleotide exchange factor (GEF)-mediated nucleotide exchange (9-11). Chronic i...

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“…Acyl-CoA:cholesterol acyltransferase (ACAT) activity in intact cells was measured by the conversion of labeled cholesterol to cholesteryl esters as described previously (39). Briefly, the cells were labeled in six-well (35 mm) plates with [ 3 H]cholesterol by incubation with 0.1 Ci of labeled cholesterol complexed with 20% M␤CD (final concentration of M␤CD, 0.05%) for 10 min at room temperature.…”

Section: Methodsmentioning

confidence: 99%

oxLDL-induced decrease in lipid order of membrane domains is inversely correlated with endothelial stiffness and network formation

Shentu

Titushkin

Singh

et al. 2010

American Journal of Physiology-Cell Physiology

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Shentu TP, Titushkin I, Singh DK, Gooch KJ, Subbaiah PV, Cho M, Levitan I. oxLDL-induced decrease in lipid order of membrane domains is inversely correlated with endothelial stiffness and network formation. Am J Physiol Cell Physiol 299: C218-C229, 2010. First published April 21, 2010; doi:10.1152/ajpcell.00383.2009.-Oxidized low-density lipoprotein (oxLDL) is a major factor in development of atherosclerosis. Our earlier studies have shown that exposure of endothelial cells (EC) to oxLDL increases EC stiffness, facilitates the ability of the cells to generate force, and facilitates EC network formation in three-dimensional collagen gels. In this study, we show that oxLDL induces a decrease in lipid order of membrane domains and that this effect is inversely correlated with endothelial stiffness, contractility, and network formation. Local lipid packing of cell membrane domains was assessed by Laurdan two-photon imaging, endothelial stiffness was assessed by measuring cellular elastic modulus using atomic force microscopy, cell contractility was estimated by measuring the ability of the cells to contract collagen gels, and EC angiogenic potential was estimated by visualizing endothelial networks within the same gels. The impact of oxLDL on endothelial biomechanics and network formation is fully reversed by supplying the cells with a surplus of cholesterol. Furthermore, exposing the cells to 7-ketocholesterol, a major oxysterol component of oxLDL, or to another cholesterol analog, androstenol, also results in disruption of lipid order of membrane domains and an increase in cell stiffness. On the basis of these observations, we suggest that disruption of lipid packing of cholesterol-rich membrane domains plays a key role in oxLDLinduced changes in endothelial biomechanics.angiogenesis; cholesterol; sphingomyelin; lipid packing OXIDIZED LOW-DENSITY LIPOPROTEIN (oxLDL) is well known to be accumulated in atherosclerotic lesions (48), and the level of oxLDL increases with hypercholesterolemia both in animal models of atherosclerosis (20, 21) and in humans (7,42). Multiple studies have shown that exposure to oxLDL results in endothelial dysfunction, including impairment of nitric oxide (NO) release (2), disruption of the endothelial barrier (14), and decrease in endothelial cell (EC) migration (32). Our studies focus on elucidating the impact of oxLDL on endothelial biomechanics and on the role of endothelial biomechanics in control of angiogenesis.Our earlier studies have shown that exposure to oxLDL significantly increases endothelial stiffness and facilitates the ability of endothelial cells to generate force (6). Furthermore, we have shown that endothelial cells freshly isolated from aortas of hypercholesterolemic pigs are significantly stiffer than cells isolated from aortas of control animals, indicating that diet-induced hypercholesterolemia results in significant changes in endothelial biophysical properties (6). Moreover, oxLDL-induced increase in endothelial stiffness and force generation is associated with an...

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Sphingolipids and cellular cholesterol homeostasis. Effect of ceramide on cholesterol trafficking and HMG CoA reductase activity

Cited by 16 publications

References 43 publications

Rituximab inhibits B-cell receptor signaling

Rituximab inhibits B-cell receptor signaling

Inhibition of Acid Sphingomyelinase Depletes Cellular Phosphatidylserine and Mislocalizes K-Ras from the Plasma Membrane

oxLDL-induced decrease in lipid order of membrane domains is inversely correlated with endothelial stiffness and network formation

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