Down‐regulation of peroxisome proliferator‐activated receptor‐γ gene expression by sphingomyelins

Al-Makdissy, Nehmann; Bianchi, Arnaud; Younsi, Mohamed; Picard, E; Valet, Philippe; Martinet, Nadine; Dauça, Michel; Donner, M.

doi:10.1016/s0014-5793(01)02278-5

Cited by 6 publications

(3 citation statements)

References 53 publications

(46 reference statements)

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“…We previously reported that excess sphingomyelin in the membranes of 3T3-F442A adipocytes decreased PPARγ expression [ 14 ] and that the SM/CHOL ratio represented an important determinant of glucose transport [ 32 ] in preadipocytes. These findings led us to further study the effect of SM overabundance on the expression of the transcription factor SREBP because SREBP-1 is a key regulator of glucose metabolism.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, SM may affect cellular signaling. Membrane SM was negatively related to the transcription factor peroxisome proliferator–activated receptor-γ (PPARγ) mRNA levels in subcutaneous adipocytes of obese insulin-resistant women [ 13 ] and in SM-enriched 3T3-F442A adipocytes [ 14 ]. Recently, adipose PPARγ has been identified as an essential mediator of lipid and glucose homeostasis and of whole body insulin sensitivity [ 8 , 15 ].…”

Section: Introductionmentioning

confidence: 99%

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Regulation of SREBPs by Sphingomyelin in Adipocytes via a Caveolin and Ras-ERK-MAPK-CREB Signaling Pathway

et al. 2015

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Sterol response element binding protein (SREBP) is a key transcription factor in insulin and glucose metabolism. We previously demonstrated that elevated levels of membrane sphingomyelin (SM) were related to peroxisome proliferator–activated receptor-γ (PPARγ), which is a known target gene of SREBP-1 in adipocytes. However, the role of SM in SREBP expression in adipocytes remains unknown. In human abdominal adipose tissue from obese women with various concentrations of fasting plasma insulin, SREBP-1 proteins decreased in parallel with increases in membrane SM levels. An inverse correlation was found between the membrane SM content and the levels of SREBP-1c/ERK/Ras/PPARγ/CREB proteins. For the first time, we demonstrate the effects of SM and its signaling pathway in 3T3-F442A adipocytes. These cells were enriched or unenriched with SM in a range of concentrations similar to those observed in obese subjects by adding exogenous natural SMs (having different acyl chain lengths) or by inhibiting neutral sphingomyelinase. SM accumulated in caveolae of the plasma membrane within 24 h and then in the intracellular space. SM enrichment decreased SREBP-1 through the inhibition of extracellular signal-regulated protein kinase (ERK) but not JNK or p38 mitogen-activated protein kinase (MAPK). Ras/Raf-1/MEK1/2 and KSR proteins, which are upstream mediators of ERK, were down-regulated, whereas SREBP-2/caveolin and cholesterol were up-regulated. In SM-unmodulated adipocytes treated with DL-1-Phenyl-2-Palmitoylamino-3-morpholino-1-propanol (PPMP), where the ceramide level increased, the expression levels of SREBPs and ERK were modulated in an opposite direction relative to the SM-enriched cells. SM inhibited the insulin-induced expression of SREBP-1. Rosiglitazone, which is an anti-diabetic agent and potent activator of PPARγ, reversed the effects of SM on SREBP-1, PPARγ and CREB. Taken together, these findings provide novel insights indicating that excess membrane SM might be critical for regulating SREBPs in adipocytes via a MAPK-dependent pathway.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Regulation of SREBPs by Sphingomyelin in Adipocytes via a Caveolin and Ras-ERK-MAPK-CREB Signaling Pathway

et al. 2015

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“…Conversely, sphingolipids have been shown to antagonize the effects of PPAR-␥. Specifically, sphingomyelin downregulates PPAR-␥ gene expression in 3T3-F442 adipocytes and is an independent predictor of insulin resistance in obese women (184,185). Ceramide has similarly been shown to inhibit PPAR-␥ expression (186).…”

Section: Thiazolidinediones Glucose Transport Corticosteroids and mentioning

confidence: 99%

A Role for Sphingolipids in Producing the Common Features of Type 2 Diabetes, Metabolic Syndrome X, and Cushing’s Syndrome

2005

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Metabolic syndrome X and type 2 diabetes share many metabolic and morphological similarities with Cushing's syndrome, a rare disorder caused by systemic glucocorticoid excess. Pathologies frequently associated with these diseases include insulin resistance, atherosclerosis, susceptibility to infection, poor wound healing, and hypertension. The similarity of the clinical profiles associated with these disorders suggests the influence of a common molecular mechanism for disease onset. Interestingly, numerous studies identify ceramides and other sphingolipids as potential contributors to these sequelae. Herein we review studies demonstrating that aberrant ceramide accumulation contributes to the development of the deleterious clinical manifestations associated with these diseases. Diabetes 54:591-602, 2005

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Ceramide induces apoptosis via a peroxisome proliferator-activated receptor γ-dependent pathway

Wang

Shi

et al. 2006

Apoptosis

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Both of ceramide and PPARgamma ligand can trigger cancer cell apoptosis. We here show that C2-ceramide can modulate PPARgamma expression level and its transcriptional activity and results in apoptosis in HT29 cells. Administration of PPARgamma specific antagonist GW9662 partially prevents HT29 cells from apoptosis. Furthermore, MAP kinase pathway provided a potential modulation mechanism for PPARgamma pathway related with ceramide. Our results are the first to demonstrate that C2-ceramide induces apoptosis via a PPARgamma-dependent pathway.

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Down‐regulation of peroxisome proliferator‐activated receptor‐γ gene expression by sphingomyelins

Cited by 6 publications

References 53 publications

Regulation of SREBPs by Sphingomyelin in Adipocytes via a Caveolin and Ras-ERK-MAPK-CREB Signaling Pathway

Regulation of SREBPs by Sphingomyelin in Adipocytes via a Caveolin and Ras-ERK-MAPK-CREB Signaling Pathway

A Role for Sphingolipids in Producing the Common Features of Type 2 Diabetes, Metabolic Syndrome X, and Cushing’s Syndrome

Ceramide induces apoptosis via a peroxisome proliferator-activated receptor γ-dependent pathway

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