title: 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.
authors.affiliation: Department of Biochemistry, School of Medicine, Gachon University, Incheon 406‑799, Republic of Korea.
authors.forename: Min Hee
authors.initials: MH
authors.lastname: Kim
authors.affiliation: Division of Haematology and Oncology, Department of Internal Medicine, Gachon University Gil Medical Centre, Incheon 405‑760, Republic of Korea.
authors.forename: Hee Kyung
authors.initials: HK
authors.lastname: Ahn
authors.affiliation: Department of Biochemistry, School of Medicine, Gachon University, Incheon 406‑799, Republic of Korea.
authors.forename: Eun-Ji
authors.initials: EJ
authors.lastname: Lee
authors.affiliation: Department of Biochemistry, School of Medicine, Gachon University, Incheon 406‑799, Republic of Korea.
authors.forename: Su-Jeong
authors.initials: SJ
authors.lastname: Kim
authors.affiliation: Department of Biochemistry, School of Medicine, Ewha Womans University, Seoul 158‑710, Republic of Korea.
authors.forename: Ye-Ryung
authors.initials: YR
authors.lastname: Kim
authors.affiliation: Department of Biochemistry, School of Medicine, Ewha Womans University, Seoul 158‑710, Republic of Korea.
authors.forename: Joo-Won
authors.initials: JW
authors.lastname: Park
authors.affiliation: Department of Biochemistry, School of Medicine, Gachon University, Incheon 406‑799, Republic of Korea.
authors.forename: Woo-Jae
authors.initials: WJ
authors.lastname: Park
mesh_terms: D000818:Animals; D016207:Cytokines / Q000378:metabolism*; D003891:Desipramine / Q000008:administration & dosage; D059305:Diet, High-Fat; D005229:Fatty Acids, Monounsaturated / Q000008:administration & dosage; D022781:Hepatocytes / Q000378:metabolism*; D018836:Inflammation Mediators / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation; D015398:Signal Transduction; D013108:Sphingomyelin Phosphodiesterase / Q000378:metabolism*; D013109:Sphingomyelins / Q000378:metabolism; D051049:Sphingosine N-Acyltransferase / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D016207:Cytokines; D005229:Fatty Acids, Monounsaturated; D018836:Inflammation Mediators; D008565:Membrane Proteins; D016328:NF-kappa B; D013109:Sphingomyelins; D014409:Tumor Necrosis Factor-alpha; C506123:CERS6 protein, human; D051049:Sphingosine N-Acyltransferase; D048051:p38 Mitogen-Activated Protein Kinases; D013108:Sphingomyelin Phosphodiesterase; D003891:Desipramine; C001996:thermozymocidin