Hepatic inflammatory cytokine production can be regulated by modulating sphingomyelinase and ceramide synthase 6

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 palmitate-induced 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)-alpha, interleukin (IL)-1(3, and IL-6 in Hep3B cells. Among the six CerS, CerS6 overexpression uniquely elevated TNF-alpha secretion via p38 mitogen-activated 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 I ipopolysaccharide (LPS)-induced cytokine secretion. Instead, the activation of acidic (A)-SMase was involved in LPS-induced cytokine secretion via the MAPK/NF-kappa B pathway. Finally, the suppression of ceramide generation via A-SMase inhibition or de novo ceramide synthesis decreased high-fat diet-induced hepatic cytokine production in vivo. On the whole, our results revealed that CerS6 played a role in TNF-alpha secretion, and palmitate augmented inflammatory responses in pathophysiological conditions in which CerS6 is overexpressed. In addition, A-SMase activation was shown to be involved in LPS-induced inflammatory processes, suggesting that the modulation of CerS6 and A-SMase may be a therapeutic target for controlling hepatic inflammation.