Fenretinide Prevents Lipid-induced Insulin Resistance by Blocking Ceramide Biosynthesis

Bikman, Benjamin T.; Guan, Yuguang; Shui, Guanghou; Siddique, Monowarul Mobin; Holland, William L.; Kim, Ji Yun; Fabriás, Gemma; Wenk, Markus R.; Summers, Scott A.

doi:10.1074/jbc.m112.359950

Cited by 121 publications

(121 citation statements)

References 36 publications

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“…3H ). These data support the results from previous studies, which showed that fenretinide is a stimulator of SPT (13)(14)(15) but an inhibitor of DEGS ( 16,17 ).…”

Section: Fenretinide Inhibited the De Novo Synthesis Of Ceramide Aftesupporting

confidence: 92%

“…Early studies of fenretinide supported the hypothesis that fenretinide increased the de novo synthesis of ceramide by stimulating SPT (13)(14)(15). However, later studies ( 16,17 ) confi rmed that fenretinide increased dhCer, not ceramide levels. The later studies demonstrated that fenretinide was a potent inhibitor of DEGS ( 16,17 ).…”

Section: Quantitative Real-time Pcrmentioning

confidence: 95%

“…In previous studies, fenretinide has been confi rmed as an agonist for SPT (13)(14)(15) but also as a potent inhibitor for DEGS ( 16,17 ). Because SPT and DEGS are critical in the de novo pathway for ceramide biosynthesis, we hypothesized that fenretinide would interfere with ceramide synthesis induced by A .…”

Section: Fenretinide Inhibited the De Novo Synthesis Of Ceramide Aftementioning

confidence: 98%

“…However, later studies ( 16,17 ) confi rmed that fenretinide increased dhCer, not ceramide levels. The later studies demonstrated that fenretinide was a potent inhibitor of DEGS ( 16,17 ). In addition, fenretinide has been shown to have an anti-infl ammatory effect.…”

Section: Quantitative Real-time Pcrmentioning

confidence: 99%

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Fenretinide inhibited de novo ceramide synthesis and proinflammatory cytokines induced by Aggregatibacter actinomycetemcomitans

Valerio

Bielawski

2013

Journal of Lipid Research

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Sphingolipids play important roles in regulating cell growth, death, senescence, adhesion, migration, infl ammation, angiogenesis, and intracellular traffi cking. Among the sphingolipids, ceramides have been recognized as "second messengers" in modulating immune signaling transduction ( 1 ). Ceramides can be generated via three pathways ( 2 ) ( Fig. 1 ). The fi rst pathway is a de novo pathway, which occurs in the endoplasmic reticulum (ER) and possibly at ER-associated membranes, such as the perinuclear membrane and mitochondria-associated membranes. De novo synthesis of ceramides begins with the condensation of palmitate and serine to form 3-keto-dihydrosphingosine by serine-palmitoyl transferase (SPT). 3-Keto-dihydrosphingosine is reduced to dihydrosphingosine (dhSph) and followed by acylation to produce dihydroceramide (dhCer). Finally, dhCer is catalyzed by dihydroceramide desaturase (DEGS) to generate ceramides. The second pathway is the sphingomyelinase (SMase) pathway, which occurs in the plasma membrane and the endosomal/lysosomal compartments. Ceramides are generated by hydrolysis of sphingomyelin (SM) by SMase. The third pathway is the salvage pathway, which occurs in the acidic subcellular compartments, such as the late endosomes and the lysosomes. In the acidic subcellular compartments, complex sphingolipids and glycosphingolipids are degraded to form sphingosine (Sph). Sph can be converted to ceramides by ceramide synthase. Conversely, ceramides can Abstract Ceramides play an essential role in modulating immune signaling pathways and proinfl ammatory cytokine production in response to infectious pathogens, stress stimuli, or chemotherapeutic drugs. In this study, we demonstrated that Aggregatibacter actinomycetemcomitans , the path ogen for aggressive periodontitis, induced de novo synthesis of ceramide in Raw 264.7 cells. In addition, we identifi ed that fenretinide, a synthetic retinoid, suppressed the de novo synthesis of ceramide induced by A. actinomycetemcomitans. Moreover, fenretinide attenuated interleukin (IL)-1 ␤ , IL-6, and cyclooxygenase-2 mRNA expression induced by A. actinomycetemcomitans. Fenretinide also decreased IL-1 ␤ , IL-6, and prostaglandin E2 proinfl ammatory cytokine levels in Raw 264.7 cells induced by A. actinomycetemcomitans. However, fenretinide had no signifi cant effects on tumor necrosis factor alpha mRNA or protein levels. Furthermore, we showed that fenretinide inhibited the janus kinase-signal transducer and activator of transcription, phosphatidylinositol 3-kinase-Akt, protein kinase C, and nuclear factor-kappaB signaling pathways, whereas fenretinide up-regulated the mitogen-activated protein kinase signaling pathways after bacterial stimulation. This study emphasizes the de novo ceramide synthesis pathway in response to bacterial stimulation and demonstrates the anti-infl ammatory role of fenretinide in the bacteria-induced immune response.

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“…3H ). These data support the results from previous studies, which showed that fenretinide is a stimulator of SPT (13)(14)(15) but an inhibitor of DEGS ( 16,17 ).…”

Section: Fenretinide Inhibited the De Novo Synthesis Of Ceramide Aftesupporting

confidence: 92%

Section: Quantitative Real-time Pcrmentioning

confidence: 95%

Section: Fenretinide Inhibited the De Novo Synthesis Of Ceramide Aftementioning

confidence: 98%

Section: Quantitative Real-time Pcrmentioning

confidence: 99%

See 2 more Smart Citations

Fenretinide inhibited de novo ceramide synthesis and proinflammatory cytokines induced by Aggregatibacter actinomycetemcomitans

Valerio

Bielawski

2013

Journal of Lipid Research

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“…Blockade of Des1 produces an increase in dihydroceramides (dhCers), which have emerged as bioactive lipids and the target of several drugs ( 34 ), including fenretinide. Several studies have shown that cells respond to fenretinide treatment with a robust production of dhCers (35)(36)(37)(38)(39)(40)(41)(42)(43)(44), and that this increase induces autophagy ( 45,46 ). Furthermore, experimental evidence exists on the connection between resistance to fenretinide and increased S1P production ( 38,44 ) due to an increased SK activity and SK1 mRNA and protein levels ( 38 ).…”

Section: Des1 Enzyme Assaymentioning

confidence: 99%

Inhibition of dihydroceramide desaturase activity by the sphingosine kinase inhibitor SKI II

Cingolani

Casasampere

Sanllehí

et al. 2014

Journal of Lipid Research

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proapoptotic sphingosine (So) and ceramide (Cer). Thus, as central enzymes in modulating the Cer/S1P balance, SKs are attractive targets for cancer therapy ( 1 ). Two SKs exist in humans, SK1 and SK2. SK1 has been extensively studied and there is a large body of evidence that proves its role in promoting cell survival, proliferation, and neoplastic transformation ( 2-5 ). SK1 is also elevated in many human cancers, which appears to contribute to carcinogenesis, chemotherapeutic resistance, and poor patient outcome. SK2, however, has not been as well-characterized, and there are contradictions in the key physiological functions that have been proposed for this isoform. Despite this, many studies are now emerging that implicate SK2 in key roles in a variety of diseases, including the development of a range of solid tumors ( 6 ).The potential of SKs as therapeutic targets has boosted the development of small molecule inhibitors ( 4,(7)(8)(9)(10)(11)(12)(13)(14). A detailed characterization of their pharmacology, particularly their selectivity against human SK1 and SK2, has been published ( 15 ). The fi rst known SK inhibitors were long chain base analogs such as N , N -dimethyl-D-erythro-sphingosine (DMS) ( 16,17 ) and L-threo-dihydrosphingosine (safi ngol) ( 18-21 ). While DMS inhibits both SK1 and SK2 by (SGR 2009(SGR 1072, and the Fundació la Marató de TV3 (112130 and 112132 Abbreviations: CB5R, NADH-cytochrome b5 reductase; C16dhCer, N -hexadecanoyldihydrosphingosine ; CDH, ceramide dihexoside (lactosylceramide); Cer, ceramide; CerC6NBD, N -[6-[(7-nitro-2-1,3-benzoxadiazol-4-yl)amino]hexanoyl]-D-erythro-sphingosine; CMH, ceramide monohexoside (glucosyl and galactosylceramide); Des1, dihydroceramide desaturase; dhCDH, dihydroceramide dihexoside (lactosyldihydroceramide); dhCer, dihydroceramide; dhCerC6NBD, N -[6-[(7-nitro-2-1,3-benzoxadiazol-4-yl)amino]hexanoyl]-D-erythro-dihydrosphingosine; dhSM, dihydrosphingomyelin; DMS, N , N -dimethyl-D-erythro-sphingosine; FAD, fl avin adenine dinucleotide; LC3, microtubule-associated protein 1-light chain 3; MTT, 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide; NBD, 4-nitro-2,1,3-benzoxadiazole; PDB, Protein Data Bank; S1P, sphingosine-1-phosphate; SK, sphingosine kinase; SKI, sphingosine kinase inhibitor; So, sphingosine; TBST, TBS with 0.1% Tween 20; UPLC, ultraperformance LC . This work was supported by grants from the Spanish Ministry of Economy and Competitiveness (SAF2011-22444), the Generalitat de Catalunya

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Flavonoids as putative modulators of Δ4‐, Δ5‐, and Δ6‐desaturases: Studies in cultured hepatocytes, myocytes, and adipocytes

et al. 2018

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This study was conducted to screen flavonoids for affecting expression of desaturases involved in omega-3 fatty acid synthesis and ceramide (CER) metabolism. To this end, cultured HepG2 hepatocytes, C2C12 myocytes, and 3T3-L1 adipocytes were treated with nontoxic concentrations of 12 selected flavonoids and expression of Δ4-, Δ5-, and Δ6-desaturases (DEGS1, FADS1, and FADS2, respectively) was determined. The flavonoids tested were more cytotoxic to HepG2 and 3T3-L1 than to C2C12 cells. In HepG2 cells, FADS1 was induced by quercetin and FADS2 expression was increased by daidzein, genistein, and pratensein treatment. DEGS1 was increased by apigenin, luteolin, orobol, and quercetin administration. In differentiated C2C12 cells, substances had no inducing effect or even lowered target gene expression. Pratensein induced both FADS1 and FADS2 in differentiated 3T3-L1 cells and DEGS1 was increased by treatment with apigenin, genistein, luteolin, orobol, and quercetin. In conclusion, pratensein may be an interesting test compound for further studies in vitro and in vivo on omega-3 synthesis since it induces its rate-limiting enzyme FADS2. Apigenin, luteolin, orobol, and quercetin induced DEGS1 and thereby possibly synthesis of proapoptotic CER in malignant HepG2 cells and 3T3-L1. In contrast, in benign C2C12 cells, they did not elevate mRNA steady state levels of DEGS1. That may partly explain the higher resistance of C2C12 cells against flavonoids compared to the other cell lines. By affecting tumor cells and nontumor cells differently, these flavonoids may be promising substances for further research regarding anticancer properties. © 2018 BioFactors, 44(5): [485][486][487][488][489][490][491][492][493][494][495] 2018

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Fenretinide Prevents Lipid-induced Insulin Resistance by Blocking Ceramide Biosynthesis

Cited by 121 publications

References 36 publications

Fenretinide inhibited de novo ceramide synthesis and proinflammatory cytokines induced by Aggregatibacter actinomycetemcomitans

Fenretinide inhibited de novo ceramide synthesis and proinflammatory cytokines induced by Aggregatibacter actinomycetemcomitans

Inhibition of dihydroceramide desaturase activity by the sphingosine kinase inhibitor SKI II

Flavonoids as putative modulators of Δ4‐, Δ5‐, and Δ6‐desaturases: Studies in cultured hepatocytes, myocytes, and adipocytes

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