Effects of sphingolipid synthesis inhibition on cholesterol gallstone formation in C57BL/6J mice.
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.
Lee
Beom Jae
BJ
Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea.
Kim
Jae Seon
JS
Kim
Byung Kyu
BK
Jung
Sung Joo
SJ
Joo
Moon Kyung
MK
Hong
Seung Goun
SG
Kim
Jang Soo
JS
Kim
Ji Hoon
JH
Yeon
Jong Eun
JE
Park
Jong-Jae
JJ
Byun
Kwan Soo
KS
Bak
Young-Tae
YT
Yoo
Hwan-Soo
HS
Oh
Seikwan
S
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
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