Regulation of Mammalian Physiology, Development, and Disease by the Sphingosine 1-Phosphate and Lysophosphatidic Acid Receptors

Blaho, Victoria A.; Hla, Timothy

doi:10.1021/cr200273u

Cited by 133 publications

(168 citation statements)

References 445 publications

(934 reference statements)

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“…Identifying the effectors of signaling sphingolipids is an area of ongoing research, with recent studies showing that intracellular targets include histone deacetylases (Hait et al 2009), Bcl-2 family proteins (Chipuk et al 2012), the ubiquitin ligase Traf2 , and kinases and phosphatases (for review, see Hannun and Obeid 2008). One of the best-characterized modes of sphingolipid signaling is seen for sphingosine-1-phosphate (S1P), which is an agonist for the G protein-coupled receptors (GPCRs) encoded by S1PR1-5 (for review, see Blaho and Hla 2011). These S1P receptors regulate a host of biological processes including immune cell trafficking, vascular permeability, and cardiac development; consequently, S1PRs are the focus of intensive drug development efforts that have recently yielded the multiple sclerosis drug fingolimod (Brinkmann et al 2010).…”

Section: Sphingolipid Modes Of Actionmentioning

confidence: 99%

“…LCB-Ps such as S1P are potent signaling molecules (Fyrst and Saba 2010;Blaho and Hla 2011), and they are also the sole substrates for a lyase enzyme that cleaves LCB-Ps to generate acyl aldehydes and phosphoethanolamine (Fig. 2).…”

Section: Sphingolipid Turnover and Degradationmentioning

confidence: 99%

“…Although the mechanisms that regulate sphingolipid headgroup modifications are the subject of ongoing investigation, I will focus here on the mechanisms that regulate levels of the core ceramide backbone and of other conserved metabolites. Additionally, the mechanisms used to acutely generate signaling sphingolipids are likely to be quite different from those that control steady-state levels (for reviews of sphingolipid signaling, see Hannun and Obeid 2008;Fyrst and Saba 2010;Blaho and Hla 2011).…”

Section: Mechanisms Of Sphingolipid Homeostasismentioning

confidence: 99%

“…Additionally, the activities of many transmembrane and peripheral membrane proteins are dependent on their close association with sphingolipids (Lingwood and Simons 2010). Over recent years, sphingolipids have been shown to participate in an increasingly wide range of biological processes that includes secretion, endocytosis, chemotaxis, neurotransmission, angiogenesis, and inflammation (Hannun and Obeid 2008;Lingwood and Simons 2010;Lippincott-Schwartz and Phair 2010;Blaho and Hla 2011;Lingwood 2011).…”

mentioning

confidence: 99%

“…This task requires balancing sphingolipid levels in conjunction with sterols and glycerolipids and adapting sphingolipid metabolism in response to physiological cues and external stresses. A need for tight regulatory control is further highlighted by the potent signaling activities of many sphingolipid biosynthetic intermediates such as sphingosines and ceramides (Hannun and Obeid 2008;Fyrst and Saba 2010;Blaho and Hla 2011). Additionally, because most sphingolipids cannot move freely between different organelles, cells must regulate multiple intracellular pools of sphingolipids as well as lipid transport between these sites.…”

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confidence: 99%

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Sphingolipid Homeostasis in the Endoplasmic Reticulum and Beyond

Breslow

2013

Cold Spring Harbor Perspectives in Biology

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Sphingolipids are a diverse group of lipids that have essential cellular roles as structural components of membranes and as potent signaling molecules. In recent years, a detailed picture has emerged of the basic biochemistry of sphingolipids-from their initial synthesis in the endoplasmic reticulum (ER), to their elaboration into complex glycosphingolipids, to their turnover and degradation. However, our understanding of how sphingolipid metabolism is regulated in response to metabolic demand and physiologic cues remains incomplete. Here I discuss new insights into the mechanisms that ensure sphingolipid homeostasis, with an emphasis on the ER as a critical regulatory site in sphingolipid metabolism. In particular, Orm family proteins have recently emerged as key ER-localized mediators of sphingolipid homeostasis. A detailed understanding of how cells sense and control sphingolipid production promises to provide key insights into membrane function in health and disease.

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Section: Sphingolipid Modes Of Actionmentioning

confidence: 99%

Section: Sphingolipid Turnover and Degradationmentioning

confidence: 99%

Section: Mechanisms Of Sphingolipid Homeostasismentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Sphingolipid Homeostasis in the Endoplasmic Reticulum and Beyond

Breslow

2013

Cold Spring Harbor Perspectives in Biology

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Gender differences in safety issues during Fingolimod therapy: Evidence from a real‐life Relapsing Multiple Sclerosis cohort

et al. 2017

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ObjectiveBenefits and risks of new therapies in Multiple Sclerosis (MS) must be balanced carefully and tailored to patients. We aimed to describe our experience with Fingolimod (FTY), correlating demographics, clinical and hematological features of the Relapsing MS (RMS) cohort with the occurring Adverse Events (AEs).Material and MethodsPretreatment screening tests, cardiological observation, and safety follow‐up data were analyzed in 225 RMS patients. Changes in continuous data were analyzed post hoc with Wilcoxon ranks test; categorical variables were examined using McNemar test. Two‐way repeated‐measures analysis of variance (ANOVA) was used to analyze differences between baseline characteristic of the cohorts and Liver Function Tests (LFT) alterations. Binary logistic regression models were used to identify which of the baseline factors influenced LFT alterations and the occurrence of infections.ResultsDuring 2 years of follow‐up 24 patients (10%) interrupted FTY. Discontinuation most often was due to AEs (n = 14) or breakthrough disease (n = 5). The most frequently AEs were infections (10.6%). After the first year patients showing an infectious episode were mostly female (p = .04). The infections did not correlate with the decrease in white blood cells or to lymphocyte count. AST and ALT alterations were observed mostly in males (p = .002 and p = .01, respectively), and increase in GGT was reported in subjects older at FTY beginning (p < .05).ConclusionsFor a patient‐centered safety monitoring of FTY, we may apply gender‐specific warnings, for the detection of transaminases abnormalities and infectious episodes.

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Histone methyltransferase Smyd2 contributes to blood‐brain barrier breakdown in stroke

Wang

Zhong

Cheng

et al. 2022

Clinical & Translational Med

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Background The blood‐brain barrier (BBB) plays a principal role in the healthy and diseased central nervous systems, and BBB disruption after ischaemic stroke is responsible for increased mortality. Smyd2, a member of the SMYD‐methyltransferase family, plays a vital role in disease by methylation of diverse substrates; however, little is known about its role in the pathophysiology of the brain in response to ischaemia‐reperfusion injury. Methods Using oxygen glucose deprivation and reoxygenation (OGD/R)‐induced primary brain microvascular endothelial cells (BMECs) and Smyd2 knockdown mice subjected to middle cerebral artery occlusion, we evaluated the role of Smyd2 in BBB disruption. We performed loss‐of‐function and gain‐of‐function studies to investigate the biological function of Smyd2 in ischaemic stroke. Results We found that Smyd2 was a critical factor for regulating brain endothelial barrier integrity in ischaemia‐reperfusion injury. Smyd2 is upregulated in peri‐ischaemic brains, leading to BBB disruption via methylation‐mediated Sphk/S1PR. Knockdown of Smyd2 in mice reduces BBB permeability and improves functional recovery. Using OGD/R‐induced BMECs, we demonstrated that Sphk/S1PR methylation modification by Smyd2 affects ubiquitin‐dependent degradation and protein stability, which may disrupt endothelial integrity. Moreover, overexpression of Smyd2 can damage endothelial integrity through Sphk/S1PR signalling. Conclusions Overall, these results reveal a novel role for Smyd2 in BBB disruption in ischaemic stroke, suggesting that Smyd2 may represent a new therapeutic target for ischaemic stroke.

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Regulation of Mammalian Physiology, Development, and Disease by the Sphingosine 1-Phosphate and Lysophosphatidic Acid Receptors

Cited by 133 publications

References 445 publications

Sphingolipid Homeostasis in the Endoplasmic Reticulum and Beyond

Sphingolipid Homeostasis in the Endoplasmic Reticulum and Beyond

Gender differences in safety issues during Fingolimod therapy: Evidence from a real‐life Relapsing Multiple Sclerosis cohort

Histone methyltransferase Smyd2 contributes to blood‐brain barrier breakdown in stroke

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