title: Sphingomyelin synthase 2 activity and liver steatosis: an effect of ceramide-mediated peroxisome proliferator-activated receptor γ2 suppression.
abstract: OBJECTIVE
  Sphingolipid de novo biosynthesis is related to nonalcoholic fatty liver disease or hepatic steatosis. However, the mechanism is still unclear. Sphingomyelin synthase (SMS), using ceramide as one of the substrates to produce sphingomyelin, sits at the crossroads of sphingolipid biosynthesis. SMS has 2 isoforms: SMS1 and SMS2. SMS2 is the major isoform in liver.
  
  
  RESULTS
  To investigate the relationship between liver SMS2 activity-mediated sphingolipid changes and hepatic steatosis, we used 2 mouse models: Sms2 liver-specific transgenic and Sms2 knockout mice. We found that Sms2 liver-specific transgenic livers have lower ceramide and higher sphingomyelin, whereas Sms2 knockout livers have higher ceramide and lower sphingomyelin. We also found that liver Sms2 overexpression promoted fatty acid uptake and liver steatosis, whereas Sms2 deficiency had an opposite effect in comparison with their respective controls. Importantly, the exogenous ceramide supplementation to Huh7 cells, a human hepatoma cell line, reduced the expression of peroxisome proliferator-activated receptor γ2 and its target genes, Cd36 and Fsp27. Peroxisome proliferator-activated receptor γ reporter analysis confirmed this phenomenon. Furthermore, peroxisome proliferator-activated receptor γ antagonist treatment significantly decreased triglyceride accumulation in Sms2 liver-specific transgenic liver.
  
  
  CONCLUSIONS
  We attributed these effects to ceramide that can suppress peroxisome proliferator-activated receptor γ2, thus reducing the expression of Cd36 and Fsp27 and reducing liver steatosis. After all, SMS2 inhibition in the liver could diminish liver steatosis.
authors: Department of Cell Biology, SUNY Downstate Medical Center, Brooklyn, NY 11203, USA.
authors: Yue
authors: Y
authors: Li
authors: Jibin
authors: J
authors: Dong
authors: Tingbo
authors: T
authors: Ding
authors: Ming-Shang
authors: MS
authors: Kuo
authors: Guoqing
authors: G
authors: Cao
authors: Xian-Cheng
authors: XC
authors: Jiang
authors: Zhiqiang
authors: Z
authors: Li
mesh_terms: D000818:Animals; D018955:CD36 Antigens / Q000378:metabolism; D045744:Cell Line, Tumor; D002518:Ceramides / Q000378:metabolism*; D002791:Cholesterol, Dietary; D004195:Disease Models, Animal; D015536:Down-Regulation; D005234:Fatty Liver / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000517:prevention & control; D005260:Female; D017930:Genes, Reporter; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D018345:Mice, Knockout; D008822:Mice, Transgenic; D047495:PPAR gamma / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D010713:Phosphatidylcholines / Q000378:metabolism; D013109:Sphingomyelins / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D017855:Transferases (Other Substituted Phosphate Groups) / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: D018955:CD36 Antigens; D002518:Ceramides; D002791:Cholesterol, Dietary; D047495:PPAR gamma; D010713:Phosphatidylcholines; D013109:Sphingomyelins; D017855:Transferases (Other Substituted Phosphate Groups); C543123:Sgms2 protein, mouse
keywords: CD36; ceramide; liver lipids; liver steatosis; peroxisome proliferator-activated receptor γ2; sphingolipids; sphingomyelin
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