Hepatic inflammatory cytokine production can be regulated by modulating sphingomyelinase and ceramide synthase 6.
Int J Mol Med
; 39(2): 453-462, 2017 Feb.
Article
in En
| MEDLINE
| ID: mdl-28035360
ABSTRACT
Chronic inflammation is associated with the pathogenesis of type 2 diabetes and diabetic complications, and palmitate has been nominated as a candidate for the molecular link between these disorders. Recently, a crucial role of ceramide in inflammation and metabolic diseases has been reported. Therefore, in this study, we investigated whether ceramide formation is involved in palmitateinduced hepatic inflammation in vitro and in vivo. Ceramide can be generated either by the de novo pathway or by sphingomyelin degradation, and six different ceramide synthases (CerS) determine the specific acyl chain length of ceramide in mammals. We examined the roles of CerS and sphingomyelinases (SMases) in the secretion of inflammatory cytokines, such as tumour necrosis factor (TNF)α, interleukin (IL)1ß, and IL6 in Hep3B cells. Among the six CerS, CerS6 overexpression uniquely elevated TNFα secretion via p38 mitogenactivated protein kinase (MAPK) activation. In addition, the treatment of CerS6 overexpressing cells with palmitate synergistically increased cytokine secretion. However, neither palmitate treatment nor CerS6 overexpression altered lipopolysaccharide (LPS)-induced cytokine secretion. Instead, the activation of acidic (A)SMase was involved in LPSinduced cytokine secretion via the MAPK/NFκB pathway. Finally, the suppression of ceramide generation via ASMase inhibition or de novo ceramide synthesis decreased highfat dietinduced hepatic cytokine production in vivo. On the whole, our results revealed that CerS6 played a role in TNFα secretion, and palmitate augmented inflammatory responses in pathophysiological conditions in which CerS6 is overexpressed. In addition, ASMase activation was shown to be involved in LPSinduced inflammatory processes, suggesting that the modulation of CerS6 and ASMase may be a therapeutic target for controlling hepatic inflammation.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Sphingomyelin Phosphodiesterase
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Cytokines
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Inflammation Mediators
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Hepatocytes
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Sphingosine N-Acyltransferase
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Membrane Proteins
Limits:
Animals
Language:
En
Journal:
Int J Mol Med
Journal subject:
BIOLOGIA MOLECULAR
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GENETICA MEDICA
Year:
2017
Type:
Article