2006 Fiscal Year Final Research Report Summary
Mechanism of cellular cholesterol release
| Project/Area Number |
17590945
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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 |
Metabolomics
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| Research Institution | Nagoya City University |
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Principal Investigator |
DOHMAE Sumiko Nagoya City University, Graduate School of Medical Sciences, Assistant Professor, 大学院医学研究科, 講師 (70227700)
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| Co-Investigator(Kenkyū-buntansha) |
YOKOYAMA Shinji Nagoya City University, Graduate School of Medical Sciences, Professor, 大学院医学研究科, 教授 (10142192)
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| Project Period (FY) |
2005 – 2006
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| Keywords | HDL / ABCA1 / ABCA7 / cholesterol |
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| Research Abstract |
Various kinds of cells were investigated for their response to lipid-free apolipoproteins to analyze the mechanism of apolipoprotein-mediated HDL generation. major results are as follows.
1. The mechanism for the assembly of HDL with cellular lipid by ABCA1 and helical apolipoprotein was investigated in hepatocytes. We found that the main mechanism for HDL assembly by endogenous apoA-I in HepG2 cells is an autocrine-like reaction in which apoA-I is secreted and then interacts with cellular ABCA1 to generate HDL.
2. The assembly of HDL by helical apolipoprotein and cellular lipid was studied using HEK293 cells to which ecdysone-inducible human ABCA1 or human ABCA7 was transfected. We found that ABCA1 generates cholesterol-rich and cholesterol-poor HDL and that the former is more prominently dependent on the increase of ABCA1 expression. ABCA7 produces this HDL subfraction only as a very minor component.
3. Serum amyloid A (SAA) is an acute phase reactant and is found as an apolipoprotein associated with plasma HDL in acute or chronic inflammation. Cellular lipid release and generation of HDL by this protein were investigated, in comparison with the reactions by apolipoprotein A-I (apoA-I). The obtained results demonstrated that SAA generates cholesterol-containing HDL directly with cellular lipid and that the reaction is mediated by ABCA1 and ABCA7.
4. Promoter analysis of the ABCA7 gene identified a new exon in upstream of the initiation methionine codon. At 5' upstream of this exon was the ABCA7 proximal promoter containing multiple binding sites of transcription factors including SRE. We found that the ABCA7 gene is regulated by sterol in the opposite direction to ABCA1 through SRE/SREBP2 and that expression of ABCA7 by this regulation is associated with phagocytic activity.
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