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Effects of sphingolipid synthesis inhibition on cholesterol gallstone formation in C57BL/6J mice
Author(s) -
Lee Beom Jae,
Kim Jae Seon,
Kim Byung Kyu,
Jung Sung Joo,
Joo Moon Kyung,
Hong Seung Goun,
Kim Jang Soo,
Kim Ji Hoon,
Yeon Jong Eun,
Park JongJae,
Byun Kwan Soo,
Bak YoungTae,
Yoo HwanSoo,
Oh Seikwan
Publication year - 2010
Publication title -
journal of gastroenterology and hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.214
H-Index - 130
eISSN - 1440-1746
pISSN - 0815-9319
DOI - 10.1111/j.1440-1746.2010.06246.x
Subject(s) - sphingolipid , ceramide , medicine , endocrinology , cholesterol , western blot , gallbladder , p38 mitogen activated protein kinases , signal transduction , glycosphingolipid , phosphorylation , mapk/erk pathway , biology , biochemistry , apoptosis , gene
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.