Sphingolipids and their metabolism in physiology and disease

Hannun, Yusuf A.; Obeid, Lina M.

doi:10.1038/nrm.2017.107

Cited by 1,406 publications

(1,532 citation statements)

References 181 publications

(213 reference statements)

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“…Sphingolipid signaling has been observed to play important roles in turning on cellular pathways (Olson et al, 2015; Hannun and Obeid, 2018). However, it has only recently been possible to achieve the sensitivity of mass spectrometry to measure the levels of early sphingolipid intermediates.…”

Section: Resultsmentioning

confidence: 99%

The UPR Activator ATF6 Responds to Proteotoxic and Lipotoxic Stress by Distinct Mechanisms

et al. 2018

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The unfolded protein response (UPR) is induced by proteotoxic stress of the endoplasmic reticulum (ER). Here we report that ATF6, a major mammalian UPR sensor, is also activated by specific sphingolipids, dihydrosphingosine (DHS) and dihydroceramide (DHC). Single mutations in a previously undefined transmembrane domain motif that we identify in ATF6 incapacitate DHS/DHC activation while still allowing proteotoxic stress activation via the luminal domain. ATF6 thus possesses two activation mechanisms: DHS/DHC activation and proteotoxic stress activation. Reporters constructed to monitor each mechanism show that phenobarbital-induced ER membrane expansion depends on transmembrane domain-induced ATF6. DHS/DHC addition preferentially induces transcription of ATF6 target lipid biosynthetic and metabolic genes over target ER chaperone genes. Importantly, ATF6 containing a luminal achromatopsia eye disease mutation, unresponsive to proteotoxic stress, can be activated by fenretinide, a drug that upregulates DHC, suggesting a potential therapy for this and other ATF6-related diseases including heart disease and stroke.

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Section: Resultsmentioning

confidence: 99%

The UPR Activator ATF6 Responds to Proteotoxic and Lipotoxic Stress by Distinct Mechanisms

et al. 2018

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“…Ceramides, members of the second largest class of membrane lipids, represent a family of more than 200 structurally related sphingolipids, compounds formed by a sphingoid base and a fatty acid linked via the amide bond (Hannun & Obeid, 2011, 2017). Over the past decades numerous studies have demonstrated that depending on their molecular structure, ceramides confer unique biophysical properties to the biological membranes (Castro, Prieto, & Silva, 2014).…”

Section: Introductionmentioning

confidence: 99%

“…Over the last 3 decades ceramides were established as second messengers regulating key cellular processes including cytoskeleton dynamics, endocytosis, protein transport and subcellular localization, cell cycle, autophagy, and apoptosis (Castro et al, 2014; Coant, Sakamoto, Mao, & Hannun, 2017; Dany & Ogretmen, 2015; Mullen, Hannun, & Obeid, 2012). Therefore, ceramides are indispensable for cellular homeostasis and control of fundamental functions, such as proliferation, migration, differentiation, adaptation to stress, survival, and senescence (Hannun & Obeid, 2008, 2017). …”

Section: Introductionmentioning

confidence: 99%

Ceramide Signaling and p53 Pathways

Jeffries¹,

Krupenko

2018

Advances in Cancer Research

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Ceramides, important players in signal transduction, interact with multiple cellular pathways, including p53 pathways. However, the relationship between ceramide and p53 is very complex, and mechanisms underlying their coregulation are diverse and not fully characterized. The role of p53, an important cellular regulator and a transcription factor, is linked to its tumor suppressor function. Ceramides are involved in the regulation of fundamental processes in cancer cells including cell death, proliferation, autophagy, and drug resistance. This regulation, however, can be pro-death or pro-survival depending on cancer type, the balance between ceramide species, the rate of their synthesis and utilization, and the availability of a specific array of downstream targets. This chapter highlights the central role of ceramide in sphingolipid metabolism, its role in cancer, specific effectors in ceramide pathways controlled by p53, and coregulation of ceramide and p53 signaling. We discuss the recent studies, which underscore the function of p53 in the regulation of ceramide pathways and the reciprocal regulation of p53 by ceramide. This complex relationship is based on several molecular mechanisms including the p53-dependent transcriptional regulation of enzymes in sphingolipid pathways, the activation of mutant p53 through ceramide-mediated alternative splicing, as well as modulation of the p53 function through direct and indirect effects on p53 coregulators and downstream targets. Further insight into the connections between ceramide and p53 will allow simultaneous targeting of the two pathways with a potential to yield more efficient anticancer therapeutics.

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“…1 Cer is known to be a key modulator of cancer cell growth and apoptosis; conversely, S1P acts as an anti-apoptotic tumor protective agent. 2, 3 Therefore, the levels and balance of natural Cer-Sph-S1P must be well controlled.…”

Section: Introductionmentioning

confidence: 99%

Dose dependent actions of LCL521 on acid ceramidase and key sphingolipid metabolites

Bai

Bielawska

Rahmaniyan

et al. 2018

Bioorganic & Medicinal Chemistry

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The function of acid ceramidase (ACDase), whose congenital deficiency leads to Farber disease, has been recognized to be vital to tumor cell biology, and inhibition of its activity may be beneficial in cancer therapy. Therefore, manipulation of the activity of this enzyme may have significant effect, especially on cancer cells. LCL521, Di-DMGB13, is a lysosomotropic inhibitor of ACDase. Here we define complexities in the actions of LCL521 on ACDase. Systematic studies in MCF7 cells showed dose and time divergent action of LCL521 on ACDase protein expression and sphingolipid levels. Low dose of LCL521 (1 μM) effectively inhibited ACDase in cells, but the effects were transient. A higher dose of LCL521 (10 μM) caused a profound decrease of sphingosine and increase of ceramide, but additionally affected the processing and regeneration of the ACDase protein, with biphasic and reversible effects on the expression of ACDase, which paralleled the long term changes of cellular sphingosine and ceramide. Finally, the higher concentrations of LCL521 also inhibited Dihydroceramide desaturase (DES-1). In summary, LCL521 exhibits significant effects on ACDase in a dose and time dependent manner, but dose range and treatment time need to be paid attention to specify its future exploration on ACDase targeted cancer treatment.

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Sphingolipids and their metabolism in physiology and disease

Cited by 1,406 publications

References 181 publications

The UPR Activator ATF6 Responds to Proteotoxic and Lipotoxic Stress by Distinct Mechanisms

The UPR Activator ATF6 Responds to Proteotoxic and Lipotoxic Stress by Distinct Mechanisms

Ceramide Signaling and p53 Pathways

Dose dependent actions of LCL521 on acid ceramidase and key sphingolipid metabolites

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