Ceramide Involvement in Apoptosis and Apoptotic Diseases

Thevissen, Karin; François, Isabelle; Winderickx, Joris; Pannecouque, Christophe; Cammue, Bruno P. A.

doi:10.2174/138955706777435643

Cited by 57 publications

(32 citation statements)

References 83 publications

(94 reference statements)

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“…Elevated levels of C 2 /C 16 ceramides in turn activate caspases to initiate the apoptotic machinery (44). Incubation with phosphatidylinositol 3,5-bisphosphate, a highly specific inhibitor of acid sphingomyelinase (33), prevented the induction of apoptosis by microparticles in CACs, suggesting that microparticles induce apoptosis in CACs by increasing the intracellular levels of C 2 /C 16 ceramides.…”

Section: Discussionmentioning

confidence: 98%

Induction of apoptosis in circulating angiogenic cells by microparticles

Distler

Akhmetshina

Dees

et al. 2011

Arthritis & Rheumatism

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Section: Discussionmentioning

confidence: 98%

Induction of apoptosis in circulating angiogenic cells by microparticles

Distler

Akhmetshina

Dees

et al. 2011

Arthritis & Rheumatism

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“…This clone of MIN6 cells is better able to handle excess saturated FFA by desaturating them to less toxic species. Saturated FFAs, but not unsaturated FFAs, are substrates for ceramide production (47) and ceramide has been implicated in palmitate-induced ␤-cell apoptosis (30,46). Elevated SCD1 levels in human islets and MIN6 cells may also indirectly protect these cells from ER stress conditions.…”

Section: Discussionmentioning

confidence: 99%

Differential activation of ER stress and apoptosis in response to chronically elevated free fatty acids in pancreatic β-cells

Lai¹,

Bikopoulos²,

Wheeler³

et al. 2008

American Journal of Physiology-Endocrinology and Metabolism

137

133

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sure to elevated saturated free fatty acid (FFA) levels has been shown to induce endoplasmic reticulum (ER) stress that may contribute to promoting pancreatic ␤-cell apoptosis. Here, we compared the effects of FFAs on apoptosis and ER stress in human islets and two pancreatic ␤-cell lines, rat INS-1 and mouse MIN6 cells. Isolated human islets cultured in vitro underwent apoptosis, and markers of ER stress pathways were elevated by chronic palmitate exposure. Palmitate also induced apoptosis in MIN6 and INS-1 cells, although the former were more resistant to both apoptosis and ER stress. MIN6 cells were found to express significantly higher levels of ER chaperone proteins than INS-1 cells, which likely accounts for the ER stress resistance. We attempted to determine the relative contribution that ER stress plays in palmitate-induced ␤-cell apoptosis. Although overexpressing GRP78 in INS-1 cells partially reduced susceptibility to thapsigargin, this failed to reduce palmitate-induced ER stress or apoptosis. In INS-1 cells, palmitate induced apoptosis at concentrations that did not result in significant ER stress. Finally, MIN6 cells depleted of GRP78 were more susceptible to tunicamycin-induced apoptosis but not to palmitate-induced apoptosis compared with control cells. These results suggest that ER stress is likely not the main mechanism involved in palmitate-induced apoptosis in ␤-cell lines. Human islets and MIN6 cells were found to express high levels of stearoyl-CoA desaturase-1 compared with INS-1 cells, which may account for the decreased susceptibility of these cells to the cytotoxic effects of palmitate. endoplasmic reticulum; lipotoxicity; palmitate LIPOTOXICITY CONTRIBUTES to ␤-cell dysfunction during the development of type 2 diabetes (19,42,48). Chronically elevated levels of free fatty acids (FFAs), particularly saturated FFAs such as palmitate, have been shown to be cytotoxic to pancreatic ␤-cells (8, 10, 24, 30 -33, 41, 46, 50). The monounsaturated FFA oleate on the other hand has been shown to not cause apoptosis of ␤-cells in some studies (16,17,31,32,35), while other studies (11,24,27,33,50) found that it does, particularly those that used the INS-1 ␤-cell line.Palmitate-induced cytotoxicity can result from multiple mechanisms, such as increases in reactive oxygen species (8,18,33), ceramide, and nitric oxide (NO) levels (30, 45) and mitochondrial perturbations (8,18,33). In addition, recent studies (23-25) have shown that endoplasmic reticulum (ER) stress pathways are activated by chronic palmitate exposure.ER stress is caused when the protein folding capacity of the ER is not sufficient to deal with protein folding demands or when an excess of misfolded or aggregated proteins accumulate. Such conditions activate the unfolded protein response (UPR) that attempts to reduce the amount of new protein synthesis, increase folding capacity, and degrade terminally misfolded proteins (20, 53). Prolonged ER stress can lead to apoptosis induction (37, 53) and thus may contribute to palmitate-induced ␤-c...

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“…Second, SMase D causes severe tissue necrosis (17,39). Last, ceramide and ceramide-1-phosphate induce inflammation and/or trigger cell death (40)(41)(42)(43).…”

Section: Discussionmentioning

confidence: 99%

“…Inhibition probably arises because ceramide and ceramide-1-phosphate cannot substitute for sphingomyelin in some action that promotes CFTR gating, which is normally initiated primarily by phosphorylating the R domain. Independent of that, the lipid products of SMase-catalyzed sphingomyelin hydrolysis, ceramide, and ceramide-1-phosphate further aggravate the disease by triggering inflammation and cell death (40)(41)(42)(43). These adverse effects associated with SMase activity may be important contributors to the pathogenicity of bacterial infection in both CF and non-CF patients.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of CFTR Cl ⁻ channel function caused by enzymatic hydrolysis of sphingomyelin

Ramu

Lü

2007

Proc. Natl. Acad. Sci. U.S.A.

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Numerous mutations in the cystic fibrosis (CF) transmembrane conductance regulator (CFTR, a Cl − channel) disrupt salt and fluid transport and lead to the formation of thick mucus in patients' airways. Obstruction by mucus predisposes CF patients to chronic infections and inflammation, which become gradually harder to control and eventually fatal. Aggressive antibiotic therapy and supportive measures have dramatically lengthened CF patients' lives. Here, we report that sphingomyelinases (SMase) from human respiratory pathogens strongly inhibit CFTR function. The hydrolysis of sphingomyelin by SMase makes it more difficult to activate CFTR by phosphorylation of its regulatory domain. By inhibiting CFTR currents, SMase-producing respiratory tract bacteria may not only aggravate pulmonary infection in some CF patients but may also elicit a condition, analogous to CFTR deficiency, in non-CF patients suffering from bacterial lung infection.

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Ceramide Involvement in Apoptosis and Apoptotic Diseases

Cited by 57 publications

References 83 publications

Induction of apoptosis in circulating angiogenic cells by microparticles

Induction of apoptosis in circulating angiogenic cells by microparticles

Differential activation of ER stress and apoptosis in response to chronically elevated free fatty acids in pancreatic β-cells

Inhibition of CFTR Cl ⁻ channel function caused by enzymatic hydrolysis of sphingomyelin

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Ceramide Involvement in Apoptosis and Apoptotic Diseases

Cited by 57 publications

References 83 publications

Induction of apoptosis in circulating angiogenic cells by microparticles

Induction of apoptosis in circulating angiogenic cells by microparticles

Differential activation of ER stress and apoptosis in response to chronically elevated free fatty acids in pancreatic β-cells

Inhibition of CFTR Cl − channel function caused by enzymatic hydrolysis of sphingomyelin

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Inhibition of CFTR Cl ⁻ channel function caused by enzymatic hydrolysis of sphingomyelin