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)‑α, interleukin (IL)‑1β, and IL‑6 in Hep3B cells. Among the six CerS, CerS6 overexpression uniquely elevated TNF‑α 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 lipopolysaccharide (LPS)-induced cytokine secretion. Instead, the activation of acidic (A)‑SMase was involved in LPS‑induced cytokine secretion via the MAPK/NF‑κB 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‑α 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.

One-year results of a clinical trial of olipudase alfa enzyme replacement therapy in pediatric patients with acid sphingomyelinase deficiency

“…These results are consistent with observations in adult patients with ASMD. 12 , 13 It is hypothesized that ceramide, a promotor of cytokine release and inflammation, 27 , 28 may mediate this response. In the first-in-human phase 1 study of olipudase alfa in adults with ASMD type B, acute phase inflammatory reactions that were either preceded or accompanied by large increases in plasma ceramide levels occurred 12 to 24 hours after single doses ≥0.3 mg/kg.…”

Sex-specific plasma lipid profiles of ME/CFS patients and their association with pain, fatigue, and cognitive symptoms

“…A negative correlation observed between oxylipins and cognitive difficulties and physical pain among females with ME/CFS may suggest a protective role of these oxylipins in ME/CFS. Interestingly, LA-derived oxylipins have been associated with increased inflammatory pain [ 39 ] and correlate with increased levels of pro-inflammatory interleukin-6 (IL-6) in human plasma after prolonged and intensive exercise known to lead to high levels of inflammatory mediators [ 40 ]. They also reduce the number of regulatory T-cells which correlates with increased susceptibility of autoimmune and chronic inflammatory diseases [ 41 – 44 ].…”

Screening for Susceptibility-Related Factors and Biomarkers of Xianling Gubao Capsule-Induced Liver Injury

“…Inflammation is not only a physiological response to harmful stimuli but also an important factor to the pathogenesis of various metabolic disorders (Kim et al, 2017). As shown in Figure 6B, 12 significant metabolites accountable for class discrimination were enriched into 10 metabolic pathways.…”