title: Effects of sphingolipid synthesis inhibition on cholesterol gallstone formation in C57BL/6J mice.
abstract: BACKGROUND
  Sphingolipids play a very important role in cell membrane formation, signal transduction and plasma lipoprotein metabolism. The first rate-limiting step in the sphingolipid biosynthetic pathway is catalyzed by serine palmitoyltransferase (SPT), and myriocin is a potent and specific inhibitor of SPT. We investigated the impact of SPT inhibition on cholesterol gallstone formation in C57BL/6J mice.
  
  
  METHODS
  Three groups of eight-week-old C57BL/6J mice were utilized. Each group consisted of 20 mice; group A, B, and C were fed normal chow, lithogenic diet with phosphate buffered saline, and lithogenic diet with myriocin (0.3 mg/kg), respectively, for 6 weeks. The ceramide levels in both serum and bile were assessed by high performance liquid chromatography analysis. Protein expression of ERK, JNK and p38 in the extracted gallbladder were determined by Western-blot analysis.
  
  
  RESULTS
  Myriocin treatment caused a significant decrease in the rate of cholesterol gallstone formation. The lithogenic diet mice (group B) showed the highest ceramide activities in both the serum and bile among all the tested groups and there was significant suppression of the ceramide levels in both the serum and bile of the myriocin-treated mice (group C, p < 0.05). Phosphorylation of p38 in the gallbladder was increased in the lithogenic-diet mice and the expression of phosphorylated p38 was significantly suppressed in the myriocin treated mice.
  
  
  CONCLUSIONS
  SPT inhibition by myriocin suppressed gallstone formation and the levels of ceramide in both the serum and bile. p38 in the cellular signaling pathways might be associated with cholesterol gallstone formation.
authors.affiliation: Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea.
authors.forename: Beom Jae
authors.initials: BJ
authors.lastname: Lee
authors.forename: Jae Seon
authors.initials: JS
authors.lastname: Kim
authors.forename: Byung Kyu
authors.initials: BK
authors.lastname: Kim
authors.forename: Sung Joo
authors.initials: SJ
authors.lastname: Jung
authors.forename: Moon Kyung
authors.initials: MK
authors.lastname: Joo
authors.forename: Seung Goun
authors.initials: SG
authors.lastname: Hong
authors.forename: Jang Soo
authors.initials: JS
authors.lastname: Kim
authors.forename: Ji Hoon
authors.initials: JH
authors.lastname: Kim
authors.forename: Jong Eun
authors.initials: JE
authors.lastname: Yeon
authors.forename: Jong-Jae
authors.initials: JJ
authors.lastname: Park
authors.forename: Kwan Soo
authors.initials: KS
authors.lastname: Byun
authors.forename: Young-Tae
authors.initials: YT
authors.lastname: Bak
authors.forename: Hwan-Soo
authors.initials: HS
authors.lastname: Yoo
authors.forename: Seikwan
authors.initials: S
authors.lastname: Oh
mesh_terms: D000818:Animals; D001646:Bile / Q000378:metabolism; D015153:Blotting, Western; D002518:Ceramides / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D004195:Disease Models, Animal; D048049:Extracellular Signal-Regulated MAP Kinases / Q000096:biosynthesis; D005229:Fatty Acids, Monounsaturated / Q000008:administration & dosage*; D005704:Gallbladder / Q000378:metabolism; D042882:Gallstones / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D007166:Immunosuppressive Agents / Q000008:administration & dosage*; D048031:JNK Mitogen-Activated Protein Kinases / Q000096:biosynthesis; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D013107:Sphingolipids / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D016896:Treatment Outcome; D014280:Triglycerides / Q000097:blood
chemical_list: D002518:Ceramides; D005229:Fatty Acids, Monounsaturated; D007166:Immunosuppressive Agents; D013107:Sphingolipids; D014280:Triglycerides; D002784:Cholesterol; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; C001996:thermozymocidin