title: Pharmacologic inhibition of sphingomyelin synthase (SMS) activity reduces apolipoprotein-B secretion from hepatocytes and attenuates endotoxin-mediated macrophage inflammation.
abstract: Sphingomyelin synthase (SMS) plays an important role in plasma atherogenic lipoprotein metabolism, inflammation, and the development of atherosclerosis. To understand whether the impaired apoB secretion and inflammation response is a direct result from lack of SMS activity, in this study, we prepared a series of compounds that inhibit SMS activity. Further, we characterized Dy105, the most potent inhibitor. We found that Dy105 treatment significantly reduces SM levels in SM-rich microdomain on cell membranes. Moreover, we found that SMS inhibition reduces apoB secretion in a human hepatoma cell line and reduces the activation of NFκB and p38, a MAP kinase, in bone marrow derived macrophages. These studies provided further evidence that SMS activity regulates atherogenic lipoprotein metabolism and inflammatory responses. Pharmacologic inhibition of SMS may be a new therapy for atherosclerosis by reducing apoB secretion, and reducing inflammation.
authors.affiliation: School of Pharmacy Fudan University, Shanghai, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Lou
authors.affiliation: School of Pharmacy Fudan University, Shanghai, China.
authors.forename: Jibin
authors.initials: J
authors.lastname: Dong
authors.affiliation: School of Pharmacy Fudan University, Shanghai, China.
authors.forename: Yali
authors.initials: Y
authors.lastname: Li
authors.affiliation: School of Pharmacy Fudan University, Shanghai, China.
authors.forename: Tingbo
authors.initials: T
authors.lastname: Ding
authors.affiliation: School of Pharmacy Fudan University, Shanghai, China.
authors.forename: Tingting
authors.initials: T
authors.lastname: Bi
authors.affiliation: School of Pharmacy Fudan University, Shanghai, China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Li
authors.affiliation: School of Pharmacy Fudan University, Shanghai, China.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Deng
authors.affiliation: School of Pharmacy Fudan University, Shanghai, China.
authors.forename: Deyong
authors.initials: D
authors.lastname: Ye
authors.affiliation: School of Pharmacy Fudan University, Shanghai, China; Department of Cell Biology, SUNY Downstate Medical Center, Brooklyn, New York United States of America.
authors.forename: Xian-Cheng
authors.initials: XC
authors.lastname: Jiang
mesh_terms: D000097:Acetonitriles / Q000494:pharmacology; D000818:Animals; D001055:Apolipoproteins B / Q000378:metabolism*; D050197:Atherosclerosis / Q000276:immunology / Q000473:pathology; D001854:Bone Marrow Cells / Q000276:immunology / Q000378:metabolism; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D004731:Endotoxins; D004789:Enzyme Activation; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000276:immunology; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D013109:Sphingomyelins / Q000378:metabolism*; D017855:Transferases (Other Substituted Phosphate Groups) / Q000037:antagonists & inhibitors*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D000097:Acetonitriles; D001055:Apolipoproteins B; D004731:Endotoxins; D016328:NF-kappa B; D013109:Sphingomyelins; D048051:p38 Mitogen-Activated Protein Kinases; D017855:Transferases (Other Substituted Phosphate Groups); C070186:phosphatidylcholine-ceramide phosphocholine transferase