Ceramide inhibits pancreatic β‐cell insulin production and mitogenesis and mimics the actions of interleukin‐1β

Sjöholm, Åke

doi:10.1016/0014-5793(95)00470-t

Cited by 69 publications

(43 citation statements)

References 30 publications

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“…This is the first study to demonstrate that C2-ceramide inhibits proliferation and induces apoptosis in growth plate chondrocytes. Ceramide has been shown to induce apoptosis in a wide range of different cell types, including pancreatic b-cells (Sjoholm 1995), cardiomyocytes (de Vries et al 1997), astrocytes (Oh et al 2006) and articular chondrocytes (Sabatini et al 2000, Gilbert et al 2004.…”

Section: Discussionmentioning

confidence: 99%

“…Ceramide has been shown to inhibit IGF-Iinduced tyrosine phosphorylation of IRS-1 in myoblast and hepatic cells (Kanety et al 1996, Strle et al 2004). Ceramide has also been shown to induce apoptosis in a wide range of different cell types, including pancreatic b-cells (Sjoholm 1995), cardiomyocytes (de Vries et al 1997 and astrocytes (Oh et al 2006). Furthermore, ceramide has been shown to induce apoptosis, proteoglycan degradation and matrix metalloproteinase expression in articular chondrocytes (Sabatini et al 2000, Gilbert et al 2004.…”

Section: Introductionmentioning

confidence: 99%

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Ceramide inhibition of chondrocyte proliferation and bone growth is IGF-I independent

MacRae¹,

Burdon²,

Ahmed³

et al. 2006

Journal of Endocrinology

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Proinflammatory cytokines inhibit growth plate development. However, their underlying mechanisms of action are unclear. These effects may be mediated by ceramide, a sphingosine-based lipid second messenger, which is elevated in a number of chronic inflammatory diseases. To test this hypothesis, we determined the effects of C2-ceramide, a cell permeable ceramide analogue, on the growth of the ATDC5 chondrogenic cell line and on cultured fetal mice metatarsals. In ATDC5 cells, C2-ceramide significantly induced apoptosis at both 40 (82%; P!0 . 05) and 25 mM (53%; P!0 . 05). At 40 mM, C2-ceramide significantly reduced proliferation ([ 3 H]-thymidine uptake/mg protein) (62%; P!0 . 05). C2-ceramide did not markedly alter the differentiation state of the cells as judged by the expression of markers of chondrogenesis and differentiation (sox 9, collagen II and collagen X). The IGF-I signalling pathway is the major autocrine/paracrine regulator of bone growth. Both in the presence and absence of IGF-I, C2-ceramide (25 mM) induced an equivalent reduction in proliferation (60%; P!0 . 001). Similarly, C2-ceramide (40 mM) induced a 31% reduction in fetal metatarsal growth both in the presence and absence of IGF-I (both P!0 . 001). Furthermore, C2-ceramide reduced ADCT5 proliferation in the presence of AG1024, an IGF-I and insulin receptor blocker. Therefore, C2-ceramide-dependent inhibition appears to be independent of IGF-mediated stimulation of bone growth. Indeed, biochemical studies demonstrated that C2-ceramide (25 mM) pretreatment did not alter IGF-I-stimulated phosphorylation of insulin receptor substrate-1, Akt or P44/42 MAP kinase. In conclusion, C2-ceramide inhibits proliferation and induces apoptosis in growth plate chondrocytes through an IGF-I independent mechanism.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Ceramide inhibition of chondrocyte proliferation and bone growth is IGF-I independent

MacRae¹,

Burdon²,

Ahmed³

et al. 2006

Journal of Endocrinology

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“…The membrane-bound enzyme neutral sphingomyelinase 2 (nSMase2), encoded by the sphingomyelin phosphodiesterase 3 (Smpd3) gene, cleaves sphingomyelin to generate the lipid second messenger ceramide, which affects a variety of cellular process, including proliferation, apoptosis, and differentiation (31)(32)(33)(34). A deletion mutation in the Smpd3 gene was identified in fragilitas ossium (fro), a mouse model of osteogenesis imperfecta (35).…”

Section: Although Bone Morphogenic Protein (Bmp) Signaling Promotes Cmentioning

confidence: 99%

Bone Morphogenic Protein (BMP) Signaling Up-regulates Neutral Sphingomyelinase 2 to Suppress Chondrocyte Maturation via the Akt Protein Signaling Pathway as a Negative Feedback Mechanism

Kakoi

Maeda

Shinohara

et al. 2014

Journal of Biological Chemistry

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Background: It is not clear how BMP-induced chondrocyte maturation is cell-autonomously terminated. Results: BMP-2 induced the ceramide-generating enzyme neutral sphingomyelinase 2 (nSMase2) in chondrocytes, whereas silencing of nSMase2 enhanced maturation in an Akt signaling-dependent manner. Conclusion: nSMase2 signaling regulates BMP-induced chondrocyte maturation as a negative feedback mechanism. Significance: This study elucidated the novel link between BMP and lipid signaling in chondrogenesis.

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“…Importantly, both cell-permeant analogues of ceramide (28) and de novo ceramide synthesis (29) impair insulin secretion and mitogenesis in pancreatic β-cells and induce apoptosis (reviewed in (30)), supporting a critical regulatory role for ceramide in the metabolic dysfunction of these cells. In the search for the molecular signaling generated by 1-deoxysphinganine treatment, we explored the hypothesis that 1-deoxysphinganine uptake and conversion to 1-deoxy-dihydroceramide is necessary to exert its toxicity.…”

Section: -Deoxy-dihydroceramide Contributes To 1-deoxysphinganine-inmentioning

confidence: 99%

Deoxysphingolipids, a novel biomarker for type 2 diabetes, are cytotoxic for insulin-producing cells

Sonda

Züllig²,

Hornemann

et al. 2013

Pancreatology

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Irreversible failure of pancreatic -cells is the main culprit in the pathophysiology of diabetes mellitus, a disease that is now a major global epidemic. Recently, elevated plasma levels of deoxysphingolipids, including 1-deoxysphinganine, have been identified as novel biomarkers for the disease. In this study, we analyzed whether deoxysphingolipids directly compromise the functionality of insulinproducing Ins-1 cells and primary islets. Treatment with 1-deoxysphinganine induced dose-dependent cytotoxicity with senescent, necrotic and apoptotic characteristics and compromised glucose-stimulated insulin secretion. In addition, 1-deoxysphinganine altered cytoskeleton dynamics, resulting in intracellular accumulation of filamentous actin and activation of the RhoGTPase Rac1. Moreover, 1-deoxysphinganine selectively up-regulated ceramide synthase 5 expression and was converted to 1-deoxy-dihydroceramides, without altering normal ceramide levels. Inhibition of intracellular 1-deoxysphinganine trafficking and ceramide synthesis improved the viability of the cells, indicating that the intracellular metabolites of 1-deoxysphinganine contribute to its cytotoxicity. Analyses of signaling pathways identified JNK and p38 MAPK as antagonistic effectors of cellular senescence. Our results revealed that 1-deoxysphinganine is a cytotoxic lipid for insulin-producing cells, suggesting that the increased levels of this sphingolipid observed in diabetic patients may contribute to the reduced functionality of pancreatic -cells. Thus, targeting deoxy-sphingolipid synthesis may complement the currently available therapies of diabetes. Analyses of signaling pathways identified JNK and p38 MAPK as antagonistic effectors of cellular senescence. Our results revealed that 1-deoxysphinganine is a cytotoxic lipid for insulinproducing cells, suggesting that the increased levels of this sphingolipid observed in diabetic patients may contribute to the reduced functionality of pancreatic β-cells. Thus, targeting deoxysphingolipid synthesis may complement the currently available therapies of diabetes.

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Ceramide inhibits pancreatic β‐cell insulin production and mitogenesis and mimics the actions of interleukin‐1β

Cited by 69 publications

References 30 publications

Ceramide inhibition of chondrocyte proliferation and bone growth is IGF-I independent

Ceramide inhibition of chondrocyte proliferation and bone growth is IGF-I independent

Bone Morphogenic Protein (BMP) Signaling Up-regulates Neutral Sphingomyelinase 2 to Suppress Chondrocyte Maturation via the Akt Protein Signaling Pathway as a Negative Feedback Mechanism

Deoxysphingolipids, a novel biomarker for type 2 diabetes, are cytotoxic for insulin-producing cells

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