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31.
Bikman BT Guan Y Shui G Siddique MM Holland WL Kim JY Fabriàs G Wenk MR Summers SA 《The Journal of biological chemistry》2012,287(21):17426-17437
Fenretinide is a synthetic retinoid that is being tested in clinical trials for the treatment of breast cancer and insulin resistance, but its mechanism of action has been elusive. Recent in vitro data indicate that fenretinide inhibits dihydroceramide desaturase, an enzyme involved in the biosynthesis of lipotoxic ceramides that antagonize insulin action. Because of this finding, we assessed whether fenretinide could improve insulin sensitivity and glucose homeostasis in vitro and in vivo by controlling ceramide production. The effect of fenretinide on insulin action and the cellular lipidome was assessed in a number of lipid-challenged models including cultured myotubes and isolated muscles strips incubated with exogenous fatty acids and mice fed a high-fat diet. Insulin action was evaluated in the various models by measuring glucose uptake or disposal and the activation of Akt/PKB, a serine/threonine kinase that is obligate for insulin-stimulated anabolism. The effects of fenretinide on cellular lipid levels were assessed by LC-MS/MS. Fenretinide negated lipid-induced insulin resistance in each of the model systems assayed. Simultaneously, the drug depleted cells of ceramide, while promoting the accumulation of the precursor dihydroceramide, a substrate for the reaction catalyzed by Des1. These data suggest that fenretinide improves insulin sensitivity, at least in part, by inhibiting Des1 and suggest that therapeutics targeting this enzyme may be a viable therapeutic means for normalizing glucose homeostasis in the overweight and diabetic. 相似文献
32.
Qian Zhang Cornelia Hunke Yin Hoe Yau Vernon Seow Sumarlin Lee Lukas Bahati Tanner Xue Li Guan Markus R. Wenk Guntur Fibriansah Pau Ling Chew Petra Kukkaro Goran Biukovi? Pei-Yong Shi Susana Geifman Shochat Gerhard Grüber Shee-Mei Lok 《The Journal of biological chemistry》2012,287(48):40525-40534
Newly assembled dengue viruses (DENV) undergo maturation to become infectious particles. The maturation process involves major rearrangement of virus surface premembrane (prM) and envelope (E) proteins. The prM-E complexes on immature viruses are first assembled as trimeric spikes in the neutral pH environment of the endoplasmic reticulum. When the virus is transported to the low pH environment of the exosomes, these spikes rearrange into dimeric structures, which lie parallel to the virus lipid envelope. The proteins involved in driving this process are unknown. Previous cryoelectron microscopy studies of the mature DENV showed that the prM-stem region (residues 111–131) is membrane-associated and may interact with the E proteins. Here we investigated the prM-stem region in modulating the virus maturation process. The binding of the prM-stem region to the E protein was shown to increase significantly at low pH compared with neutral pH in ELISAs and surface plasmon resonance studies. In addition, the affinity of the prM-stem region for the liposome, as measured by fluorescence correlation spectroscopy, was also increased when pH is lowered. These results suggest that the prM-stem region forms a tight association with the virus membrane and attracts the associated E protein in the low pH environment of exosomes. This will lead to the surface protein rearrangement observed during maturation. 相似文献
33.
Monowarul M. Siddique Benjamin T. Bikman Liping Wang Li Ying Erin Reinhardt Guanghou Shui Markus R. Wenk Scott A. Summers 《PloS one》2012,7(9)
Sphingolipid biosynthesis is potently upregulated by factors associated with cellular stress, including numerous chemotherapeutics, inflammatory cytokines, and glucocorticoids. Dihydroceramide desaturase 1 (Des1), the third enzyme in the highly conserved pathway driving sphingolipid biosynthesis, introduces the 4,5-trans-double bond that typifies most higher-order sphingolipids. Surprisingly, recent studies have shown that certain chemotherapeutics and other drugs inhibit Des1, giving rise to a number of sphingolipids that lack the characteristic double bond. In order to assess the effect of an altered sphingolipid profile (via Des1 inhibition) on cell function, we generated isogenic mouse embryonic fibroblasts lacking both Des1 alleles. Lipidomic profiling revealed that these cells contained higher levels of dihydroceramide than wild-type fibroblasts and that complex sphingolipids were comprised predominantly of the saturated backbone (e.g. sphinganine vs. sphingosine, dihydrosphingomyelin vs. sphingomyelin, etc.). Des1 ablation activated pro-survival and anabolic signaling intermediates (e.g. Akt/PKB, mTOR, MAPK, etc.) and provided protection from apoptosis caused by etoposide, a chemotherapeutic that induces sphingolipid synthesis by upregulating several sphingolipid biosynthesizing enzymes. These data reveal that the double bond present in most sphingolipids has a profound impact on cell survival pathways, and that the manipulation of Des1 could have important effects on apoptosis. 相似文献
34.
Hebbar S Lee E Manna M Steinert S Kumar GS Wenk M Wohland T Kraut R 《Journal of lipid research》2008,49(5):1077-1089
We have designed a tagged probe [sphingolipid binding domain (SBD)] to facilitate the tracking of intracellular movements of sphingolipids in living neuronal cells. SBD is a small peptide consisting of the SBD of the amyloid precursor protein. It can be conjugated to a fluorophore of choice and exogenously applied to cells, thus allowing for in vivo imaging. Here, we present evidence to describe the characteristics of the SBD association with the plasma membrane. Our experiments demonstrate that SBD binds to isolated raft fractions from human neuroblastomas and insect neuronal cells. In protein-lipid overlay experiments, SBD interacts with a subset of glycosphingolipids and sphingomyelin, consistent with its raft association in neurons. We also provide evidence that SBD is taken up by neuronal cells in a cholesterol- and sphingolipid-dependent manner via detergent-resistant microdomains. Furthermore, using fluorescence correlation spectroscopy to assay the mobility of SBD in live cells, we show that SBD's behavior at the plasma membrane is similar to that of the previously described raft marker cholera toxin B, displaying both a fast and a slow component. Our data suggest that fluorescently tagged SBD can be used to investigate the dynamic nature of glycosphingolipid-rich detergent-resistant microdomains that are cholesterol-dependent. 相似文献
35.
Wan Yun Ho Jer-Cherng Chang Kenneth Lim Amaury Cazenave-Gassiot Aivi T. Nguyen Juat Chin Foo Sneha Muralidharan Ashley Viera-Ortiz Sarah J.M. Ong Jin Hui Hor Ira Agrawal Shawn Hoon Olubankole Aladesuyi Arogundade Maria J. Rodriguez Su Min Lim Seung Hyun Kim John Ravits Shi-Yan Ng Markus R. Wenk Edward B. Lee Greg Tucker-Kellogg Shuo-Chien Ling 《The Journal of cell biology》2021,220(9)
36.
37.
Stephan-Olav Wenk Jochen Kruip 《Journal of chromatography. B, Analytical technologies in the biomedical and life sciences》2000,737(1-2)
New porous materials have been tested for their potential to speed up purification of membrane proteins. As an example the purification of photosystem I, a light-driven electron pump from the cyanobacterium Synechocystis PCC6803, was optimized. The combination of two HPLC steps (an anion-exchange chromatography followed by a hydrophobic interaction chromatography) yields homogeneous monomeric or trimeric photosystem I as determined by gel filtration and gel electrophoresis. In comparison to traditional purification schemes our method is at least three-times faster and allows for easy scale-up. 相似文献
38.
Esther Shuyi Gan Wei Fun Cheong Kuan Rong Chan Eugenia Ziying Ong Xiaoran Chai Hwee Cheng Tan Sujoy Ghosh Markus R Wenk Eng Eong Ooi 《The EMBO journal》2017,36(10):1348-1363
Dengue virus (DENV) has been found to replicate in lymphoid organs such as the lymph nodes, spleen, and liver in post‐mortem analysis. These organs are known to have low oxygen levels (~0.5–4.5% O2) due to the vascular anatomy. However, how physiologically low levels of oxygen affect DENV infection via hypoxia‐induced changes in the immune response remains unknown. Here, we show that monocytes adapted to 3% O2 show greater susceptibility to antibody‐dependent enhancement of DENV infection. Low oxygen level induces HIF1α‐dependent upregulation of fragment crystallizable gamma receptor IIA (FcγRIIA) as well as HIF1α‐independent alterations in membrane ether lipid concentrations. The increased FcγRIIA expression operates synergistically with altered membrane composition, possibly through increase membrane fluidity, to increase uptake of DENV immune complexes for enhanced infection. Our findings thus indicate that the increased viral burden associated with secondary DENV infection is antibody‐dependent but hypoxia‐induced and suggest a role for targeting hypoxia‐induced factors for anti‐dengue therapy. 相似文献
39.
Functional Interactions between Sphingolipids and Sterols in Biological Membranes Regulating Cell Physiology 总被引:1,自引:0,他引:1
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Xue Li Guan Cleiton M. Souza Harald Pichler Gisle Dewhurst Olivier Schaad Kentaro Kajiwara Hirotomo Wakabayashi Tanya Ivanova Guillaume A. Castillon Manuele Piccolis Fumiyoshi Abe Robbie Loewith Kouichi Funato Markus R. Wenk Howard Riezman 《Molecular biology of the cell》2009,20(7):2083-2095
Sterols and sphingolipids are limited to eukaryotic cells, and their interaction has been proposed to favor formation of lipid microdomains. Although there is abundant biophysical evidence demonstrating their interaction in simple systems, convincing evidence is lacking to show that they function together in cells. Using lipid analysis by mass spectrometry and a genetic approach on mutants in sterol metabolism, we show that cells adjust their membrane composition in response to mutant sterol structures preferentially by changing their sphingolipid composition. Systematic combination of mutations in sterol biosynthesis with mutants in sphingolipid hydroxylation and head group turnover give a large number of synthetic and suppression phenotypes. Our unbiased approach provides compelling evidence that sterols and sphingolipids function together in cells. We were not able to correlate any cellular phenotype we measured with plasma membrane fluidity as measured using fluorescence anisotropy. This questions whether the increase in liquid order phases that can be induced by sterol–sphingolipid interactions plays an important role in cells. Our data revealing that cells have a mechanism to sense the quality of their membrane sterol composition has led us to suggest that proteins might recognize sterol–sphingolipid complexes and to hypothesize the coevolution of sterols and sphingolipids. 相似文献
40.
Zhao X Burger M Liu Y Das MK Combs W Wenk JF Guccione JM Kassab GS 《Journal of biomechanical engineering》2011,133(3):031006
Although left ventricular (LV) coronary sinus lead dislodgement remains a problem, the risk factors for dislodgement have not been clearly defined. In order to identify potential risk factors for acute lead dislodgement, we conducted dynamic finite element simulations of pacemaker lead dislodgement in marginal LV vein. We considered factors such as mismatch in lead and vein diameters, velocity of myocardial motion, branch angle between the insertion vein and the coronary sinus, degree of slack, and depth of insertion. The results show that large lead-to-vein diameter mismatch, rapid myocardial motion, and superficial insertion are potential risk factors for lead dislodgement. In addition, the degree of slack presents either a positive or negative effect on dislodgement risk depending on the branch angle. The prevention of acute lead dislodgment can be enforced by inducing as much static friction force as possible at the lead-vein interface, while reducing the external force. If the latter exceeds the former, dislodgement will occur. The present findings underscore the major risk factors for lead dislodgment, which may improve implantation criterion and future lead design. 相似文献