Investigation on the transport mechanism of bile lipids
| Project/Area Number |
17390040
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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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 | The University of Tokyo |
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Principal Investigator |
SUZUKI Hiroshi The University of Tokyo, Faculty of Medicine, Professor, 医学部附属病院, 教授 (80206523)
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| Co-Investigator(Kenkyū-buntansha) |
SUGAWARA Yasuhiko The University of Tokyo, Faculty of Medicine, Assistant Professor, 医学部附属病院, 助教授 (90313155)
ITO Kousei The University of Tokyo, Faculty of Medicine, Assistant Professor, 医学部附属病院, 助教授 (30323405)
TAKADA Tappei The University of Tokyo, Faculty of Medicine, Research Associate, 医学部附属病院, 助手 (90376468)
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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 |
¥14,100,000 (Direct Cost: ¥14,100,000)
Fiscal Year 2006: ¥6,800,000 (Direct Cost: ¥6,800,000)
Fiscal Year 2005: ¥7,300,000 (Direct Cost: ¥7,300,000)
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| Keywords | lipids / biliary excretion / bile acids / cholesterol / genetic disease |
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| Research Abstract |
One of the therapeutic target of life-style related disease is lipid metabolism. In lipid homeostasis, intestinal absorption of dietary lipids and biliary excretion of lipids have important roles. Phospholipids, cholesterol and bile acids are secreted into bile across canalicular membrane of hepatocyte and it is believed to have significant interaction each other, although details in the process remain unclear. In the project, in order to reveal the transport mechanism of bile lipids on intestinal absorption and biliary excretion, we examined the substrate specificities and transport properties of transporters for phospholipids, cholesterol and bile acids in the liver and intestine.
Biliary excretion of phospholipids was investigated in in vitro system by using adenovirus containing human MDR3/ABCB4 gene. Transport assays with mammalian-derived cell lines showed MDR3-mediated efflux of phospholipids to bile acids. Additionally, point mutations reported on PFIC3 or ICP were introduced in the construct and defect in intracellular trafficking was observed in some case, showing typical molecular mechanism of the disease.
NPC1L1, an intestinal cholesterol importer, was analyzed using Caco-2 cells stably expressing NPC1L1. Uptake of cholesterol from bile-mimicked micelles with phospholipids, sterols and bile acids were examined and it was indicated that transport activity was higher for cholesterol than that for phytosterol and, ezetimibe, a new drug for hypercholesterolemia, could inhibit the uptake in a concentration-dependent manner.
BSEP/ABCB11 expression system was utilized to reveal the canalicular secretion of bile acids. Results suggested that no acceptor molecule is necessary for the transport of bile acids via BSEP, two of major mutations in BSEP cause PFIC2 by impaired intracellular trafficking of the transporter protein and there is a species difference in substrate recognition of rat Bsep and human BSEP, which reflects their own bile acid composition.
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Report
(3 results)
Research Products
(19 results)
