Ceramide synthase 4 deficiency in mice causes lipid alterations in sebum and results in alopecia

Ebel, Philipp; Imgrund, Silke; Dorp, Katharina vom; Hofmann, Kristina; Maier, Helena J.; Drake, Helena; Degen, Joachim; Dörmann, Peter; Eckhardt, Matthias; Franz, Thomas; Willecke, Klaus

doi:10.1042/bj20131242

Cited by 68 publications

(63 citation statements)

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“…CerS3- Significance was determined by Student's t test. *P < 0.05, **P < 0.01, ***P < 0.001. generated ultra-long sphingolipids play key roles in the homeostasis of skin barrier function (34), whereas deficiency of CerS4 is associated with skin disorders such as irreversible alopecia (35,36).…”

Section: Discussionmentioning

confidence: 99%

Ceramide synthesis regulates T cell activity and GVHD development

Sofi¹,

Heinrichs²,

Dany³

et al. 2017

JCI Insight

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Section: Discussionmentioning

confidence: 99%

Ceramide synthesis regulates T cell activity and GVHD development

Sofi¹,

Heinrichs²,

Dany³

et al. 2017

JCI Insight

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“…Here we briefly describe the (Laviad et al, 2008). Suborgan-and cell-specific CerS distribution is described according to protein expression (Ginkel et al, 2012;Jennemann et al, 2012;Ebel et al, 2013Ebel et al, , 2014Kremser et al, 2013) …”

Section: Introductionmentioning

confidence: 99%

The effect of altered sphingolipid acyl chain length on various disease models

Park

2015

Biological Chemistry

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Sphingolipids have emerged as an important lipid mediator in intracellular signalling and metabolism. Ceramide, which is central to sphingolipid metabolism, is generated either via a de novo pathway, by attaching fatty acyl CoA to a long-chain base, or via a salvage pathway, by degrading pre-existing sphingolipids. As a 'sphingolipid rheostat' has been proposed, the balance between ceramide and sphingosine-1-phosphate has been the object of considerable attention. Ceramide has recently been reported to have a different function depending on its acyl chain length: six ceramide synthases (CerS) determine the specific ceramide acyl chain length in mammals. All CerS-deficient mice generated to date show that sphingolipids with defined acyl chain lengths play distinct pathophysiological roles in disease models. This review describes recent advances in understanding the associations of CerS with various diseases and includes clinical case reports.

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“…CerS3 KO mice are lethal shortly after birth due to skin barrier disruption (2), and it was shown that CerS3 is also required for meiotic cytokinesis during spermatogenesis (15). CerS4-deficient mice show agerelated hair loss (6), due to altered stem cell maintenance (16), and CerS6-deficient mice show behavioral abnormalities, including hind limb clasping (12). The diverse phenotypes of CerS mice suggest that ceramides exhibit chain length-specific functions.…”

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confidence: 99%

“…However, the data on ceramidedependent inhibition of AKT are largely derived from cell culture studies where water-soluble synthetic C 2 -ceramide was added exogenously to the culture medium to examine the 49-228-73-62639; E-mail: m.hoch@uni-bonn.de. 6 The abbreviations used are: CerS, ceramide synthase; NBD, 7-nitro-2-1,3-benzoxadiazol-4-yl; oxa-1,3-diazol-4-yl)); TAG, triglyceride; S1P, sphingosine 1-phosphate; WAT, white adipose tissue; eWAT, epididymal WAT; ANOVA, analysis of variance; HFD, high fat diet; LFD, low fat diet; ACC, acetyl-CoA carboxylase; AMPK, AMP-activated protein kinase; AKT, protein kinase B/Akt. …”

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Ceramide Synthase 5 Is Essential to Maintain C16:0-Ceramide Pools and Contributes to the Development of Diet-induced Obesity

Gosejacob

Jäger

Dorp

et al. 2016

Journal of Biological Chemistry

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113

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Ceramides are bioactive sphingolipids, which are composed of sphingoid bases carrying acyl chains of various lengths. Ceramides are synthesized by a family of six ceramide synthases (CerS) in mammals, which produce ceramides with different N-linked acyl chains. Increased ceramide levels are known to contribute to the development of obesity and insulin resistance. Recently, it has been demonstrated that the ceramide acylation pattern is of particular importance for an organism to maintain energy homeostasis. However, which of the CerS family members are involved in this process is not yet completely known. Using newly developed CerS5 knock-out mice, we show here that CerS5 is essential to maintain cellular C 16:0 sphingolipid pools in lung, spleen, muscle, liver, and white adipose tissue. Glycerophospholipid levels in CerS5-deficient mice were not altered. We found a strong impact of CerS5-dependent ceramide synthesis in white adipose tissue after high fat diet feeding. In skeletal muscle, liver, and spleen, C 16:0 -ceramide levels were altered independent of feeding conditions. The loss of CerS5 is associated with reduced weight gain and improved systemic health, including maintenance of glucose homeostasis and reduced white adipose tissue inflammation after high fat diet challenge. Our findings indicate that reduction of endogenous C 16:0 -ceramide by genetic inhibition of CerS5 is sufficient to ameliorate obesity and its comorbidities.Ceramide synthases are sphingosine N-acyltransferases and represent an important metabolic hub in the ceramide synthesis pathway (Fig. 1A). They acylate sphingoid bases with fatty acid acyl chains of different length and saturation ( Fig. 1B) (1-6), thereby creating ceramides with diverse biological properties (7-9). The ceramide synthase enzyme family contains six members (CerS1-6) 6 in mammals (1, 9, 10). The individual enzymes differ in their substrate specificity and show different expression patterns (Fig. 1A) (1, 11). CerS1 is specifically expressed in muscle and neurons and has strong substrate specificity toward C 18:0 -CoA (1, 4, 11), whereas CerS2 and CerS4 are broadly expressed with specificity toward very long chain C 20: 0 -26:0 CoAs and C 18:0 -C 22:0 CoAs, respectively (1, 11). CerS3 is highly expressed in the epidermis and testis showing a substrate specificity for ultra-long chain CoAs (2, 10). CerS6 is expressed in most tissues at low levels and shows substrate specificity toward long chain C 14:0 -16:0 -CoAs (Fig. 1B) (1, 11, 12). CerS5 expression has also been studied at the mRNA level and is expressed in most tissues at low levels (11) and has a specificity toward the long chain CoAs C 14:0 -18:0 (1).Most murine CerS family members have also been characterized using knock-out (KO) mouse models. CerS1-deficient mice show behavioral abnormalities and Purkinje cell loss (4, 13), whereas CerS2 knock-out mice develop hepatocarcinomas and show myelination defects (3,5,14). CerS3 KO mice are lethal shortly after birth due to skin barrier disruption (2), and it was s...

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Ceramide synthase 4 deficiency in mice causes lipid alterations in sebum and results in alopecia

Cited by 68 publications

References 54 publications

Ceramide synthesis regulates T cell activity and GVHD development

Ceramide synthesis regulates T cell activity and GVHD development

The effect of altered sphingolipid acyl chain length on various disease models

Ceramide Synthase 5 Is Essential to Maintain C16:0-Ceramide Pools and Contributes to the Development of Diet-induced Obesity

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