| Project/Area Number |
17590114
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Medical pharmacy
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| Research Institution | Tohoku University |
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Principal Investigator |
MIYATA Masaaki Tohoku University Grad. Sch. Pyarm. Sci., Research Instructor, 大学院薬学研究科, 助手 (90239418)
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| Co-Investigator(Kenkyū-buntansha) |
NAGATA Kiyoshi Tohoku University Grad. sch. Pharm. Sci., Asscciate Professor, 大学院薬学研究科, 助教授 (80189133)
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| Project Period (FY) |
2005 – 2006
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| Project Status |
Completed (Fiscal Year 2006)
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| Budget Amount *help |
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2006: ¥1,300,000 (Direct Cost: ¥1,300,000)
Fiscal Year 2005: ¥2,200,000 (Direct Cost: ¥2,200,000)
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| Keywords | lithocholic acid / lipid metabolism / microarray / PCN / hepatotoxicity / cholestasis / phospholipid / リン脂質 |
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| Research Abstract |
Lithocholic acid (LCA) administration to experimental animals is known to cause delayed cholestatic liver injury. Protective mechanisms of LCA-induced liver damage were analyzed by co-treatment of mice with pregnenolone-16 a -carbonitrile (PCN) or quinacrine. First, we tried to explore a novel protective mechanism for LCA-induced cholestatic liver injury using microarray analysis. Time-dependent changes in gene expression and liver damage diagnostic markers were analyzed in mice fed a 0.6% LCA diet for 3 days (LCA3), 5 days (LCA5) and 9 days (LCA9). Significant increases in serum alanine aminotransferase and alkaline phosphatase activities were found in LCA5 and LCA9, respectively. More than 2-fold changes relative to control group were found in 57 (LCA3), 271 (LCA5) and 1426 (LCA9) out of 8451 probes in microarray assays. In this study, we have focused on lipid metabolism and transport. Expression levels of annexin A2 and phospholipid scramblase 1 were markedly increased in LCA5 and L
… More
CA9. Those of phosphatidic acid phosphatase 2A, 2C and lipoprotein lipase were also increased in LCA9. Marked changes in gene expression involved in lipid transfer between liver and plasma were also found in LCA9. On the other hand, decreases in gene expression involved in the energy production system such as β-oxidation and TCA cycle were observed in a time-dependent manner in LCA-fed mice. These data suggest disruption of lipid metabolism and transport in LCA-fed mice. These changes disappeared in mice co-treated with pregnenolone-16 a-carbonitrile (PCN) which protects against LCA-induced toxicity. Hepatic phospholipid, triacylglycerol and biliary phospholipid concentrations were decreased in LCA9, whereas the concentrations were increased in LCA/PCN co-treated mice. Furthermore, co-treatment of mice with phospholipase A2 inhibitor, quinacrine decreased LCA-induced liver injury and increased hepatic phospholipids concentration. These results suggest that the enhancement of hepatic phospholipids level is one of the protective mechanisms for LCA-induced cholestatic liver injury. Less
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