Sphingomyelinases and Liver Diseases

Insausti-Urkia, Naroa; Solsona-Vilarrasa, Estel; Garcı́a-Ruiz, Carmen; Fernández‐Checa, José C.

doi:10.3390/biom10111497

Cited by 34 publications

(22 citation statements)

References 186 publications

(210 reference statements)

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“…The intracellular accumulation of Cer occurs through two significant routes of synthesis: de novo synthesis via ceramide synthase serine palmitoyltransferase (SPT) and hydrolysis of the membrane sphingomyelin by neutral sphingomyelinase (NSM)/ASM [ 26 , 28 ]. However, recent studies suggested that the elevated level of Cer in stress response is an outcome of ASM-mediated sphingomyelin hydrolysis [ 9 , 10 ]. Our previous findings have demonstrated that imipramine participates in the amelioration of LPS-induced pulmonary inflammation in mice by suppressing the level of Cer [ 14 ].…”

Section: Discussionmentioning

confidence: 99%

“…Cer is primarily synthesized through sphingolipid metabolism. Sphingomyelin hydrolysis is one of the first pathways activated during the stress response, and sphingomyelinase serves as a crucial component in the regulation of this pathway [ 9 ]. Acid sphingomyelinase (ASM) is localized in the lysosomes and can be activated by diverse stress stimuli, such as oxidative stress, lipopolysaccharide (LPS), and tumor necrosis factor-α (TNF-α).…”

Section: Introductionmentioning

confidence: 99%

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Role of ASM/Cer/TXNIP signaling module in the NLRP3 inflammasome activation

et al. 2021

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Background This study aimed to explore the effects of ceramide (Cer) on NLRP3 inflammasome activation and their underlying mechanisms. Methods Lipopolysaccharide (LPS)/adenosine triphosphate (ATP)-induced NLRP3 inflammasome activation in J774A.1 cells and THP-1 macrophages was used as an in vitro model of inflammation. Western blotting and real-time PCR (RT-PCR) were used to detect the protein and mRNA levels, respectively. IL-1β and IL-18 levels were measured by ELISA. ASM assay kit and immunofluorescence were used to detect ASM activity and Cer content. Results Imipramine, a well-known inhibitor of ASM, significantly inhibited LPS/ATP-induced activity of ASM and the consequent accumulation of Cer. Additionally, imipramine suppressed the LPS/ATP-induced expression of thioredoxin interacting protein (TXNIP), NLRP3, caspase-1, IL-1β, and IL-18 at the protein and mRNA level. Interestingly verapamil, a TXNIP inhibitor, suppressed LPS/ATP-induced activation of TXNIP/NLRP3 inflammasome but did not affect LPS/ATP-induced ASM activation and Cer formation. TXNIP siRNA and verapamil inhibited C2-Cer-induced upregulation of TXNIP and activation of the NLRP3 inflammasome. In addition, the pretreatment of cells with sulfo-N-succinimidyl oleate (SSO), an irreversible inhibitor of the scavenger receptor CD36, blocked Cer-induced upregulation of nuclear factor-κB (NF-κB) activity, TXNIP expression, and NLRP3 inflammasome activation. Inhibition of NF-κB activation by SN50 prevented Cer-induced upregulation of TXNIP and activation of the NLRP3 inflammasome but did not affect CD36 expression. Conclusion This study demonstrated that the ASM/Cer/TXNIP signaling pathway is involved in NLRP3 inflammasome activation. The results documented that the CD36-dependent NF-κB-TXNIP signaling pathway plays an essential role in the Cer-induced activation of NLRP3 inflammasomes in macrophages.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Role of ASM/Cer/TXNIP signaling module in the NLRP3 inflammasome activation

et al. 2021

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“…The intracellular accumulation of Cer occurs through two signi cant routes of synthesis: de novo synthesis via ceramide synthase serine palmitoyltransferase (SPT) and hydrolysis of the membrane sphingomyelin by neutral sphingomyelinase (NSM)/ASM [26,28]. However, recent studies suggested that the elevated level of Cer in stress response is an outcome of ASM-mediated sphingomyelin hydrolysis [9,10]. Our previous ndings have demonstrated that imipramine participates in the amelioration of LPS-induced pulmonary in ammation in mice by suppressing the level of Cer [14].…”

Section: Discussionmentioning

confidence: 99%

“…Cer is primarily synthesized through sphingolipid metabolism. Sphingomyelin hydrolysis is one of the rst pathways activated during the stress response, and sphingomyelinase serves as a crucial component in the regulation of this pathway [9]. Acid sphingomyelinase (ASM) is localized in the lysosomes and can be activated by diverse stress stimuli, such as oxidative stress, lipopolysaccharide (LPS), and tumor necrosis factor-α (TNF-α).…”

Section: Introductionmentioning

confidence: 99%

Role of ASM/Cer/TXNIP signaling module in the NLRP3 inflammasome activation

Jiang

Shi

Cao

et al. 2021

Preprint

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Background: This study aimed to explore the effects of ceramide (Cer) on NLRP3 inflammasome activation and their underlying mechanisms.Methods: Lipopolysaccharide (LPS)/adenosine triphosphate (ATP)-induced NLRP3 inflammasome activation in J774A.1 cells and THP-1 macrophages was used as an in vitro model of inflammation. Western blotting and real-time PCR (RT-PCR) were used to detect the protein and mRNA levels, respectively. IL-1β and IL-18 levels were measured by ELISA. ASM assay kit and immunofluorescence were used to detect ASM activity and Cer content.Results: Imipramine, a well-known inhibitor of ASM, significantly inhibited LPS/ATP-induced activity of ASM and the consequent accumulation of Cer. Additionally, imipramine suppressed the LPS/ATP-induced expression of thioredoxin interacting protein (TXNIP), NLRP3, caspase-1, IL-1β, and IL-18 at the protein and mRNA level. Interestingly verapamil, a TXNIP inhibitor, suppressed LPS/ATP-induced activation of TXNIP/NLRP3 inflammasome but did not affect LPS/ATP-induced ASM activation and Cer formation. TXNIP siRNA and verapamil inhibited C2-Cer-induced upregulation of TXNIP and activation of the NLRP3 inflammasome. In addition, the pretreatment of cells with sulfo-N-succinimidyl oleate (SSO), an irreversible inhibitor of the scavenger receptor CD36, blocked Cer-induced upregulation of nuclear factor-κB (NF-κB) activity, TXNIP expression, and NLRP3 inflammasome activation. Inhibition of NF-κB activation by SN50 prevented Cer-induced upregulation of TXNIP and activation of the NLRP3 inflammasome but did not affect CD36 expression.Conclusion: This study demonstrated that the ASM/Cer/TXNIP signaling pathway is involved in NLRP3 inflammasome activation. The results documented that the CD36-dependent NF-κB-TXNIP signaling pathway plays an essential role in the Cer-induced activation of NLRP3 inflammasomes in macrophages.

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“…Both have been well-characterized for their contribution to signaling pathways and their roles in diverse pathologies, including liver diseases. Insausti-Urkia et al [ 25 ] summarize the physiological functions of neutral and acid sphingomyelinases and their role in chronic and metabolic liver diseases.…”

mentioning

confidence: 99%