Molecular mechanism of ATP-dependent transporters involvedinl in lipid homeostasis in brain

2007 Fiscal Year Final Research Report Summary

• Project/Area Number: 16380070
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Applied biochemistry
• Research Institution: Kyoto University
• Principal Investigator: UEDA Kazumitsu Kyoto University, Division of Applied Life Sciences, Professor (10151789)
• Project Period (FY): 2004 – 2007
• Keywords: brain / cholesterol / ABC proteins / lipids / transporters / lifestyle associated diseases / Alzheimer disease / sphingomyelin

Research Abstract

Molecular mechanism of ATP-dependent transporters involved in lipid homeostasis in brain was investigated
1) Functional analysis of ABCA1. ABCA1 plays a major role in cholesterol homeostasis in our body and brain. However, the mechanisms is still not clear. To explore the mechanism of ABCA1-mediated HDL formation, we expressed human ABCA1 in insect Sf9 cells and purified it. Purified ABCA1 showed robust ATPase activity when reconstituted in liposomes made of synthetic phosphatidylcholine. The results suggest that the ATPase activity of ABCA1 is stimulated preferentially by phospholipids with choline head groups, phosphatidylcholine and sphingomyelin.
2) The effects of the cellular sphingomyelin level on HDL formation by ABCA1. When sphingomyelin content was reduced, apoA-I-dependent cholesterol efflux by ABCA1 increased 1.65-fold. Exogenously added sphingomyelin significantly reduced the apoA-I-dependent efflux of cholesterol.
3) Functional analysis of ABCG1. We have shown that ABCG1 mediates the efflux of not only cholesterol but also sphingomyelin (SM) and phosphatidylcholine. We examined whether it plays an important role in the ABCG1-mediated efflux of cholesterol. The results suggest that the ABCG1-mediated efflux of cholesterol and SM is dependent on the cellular SM level and distribution of cholesterol in the plasma membrane.

Research Products

• [Journal Article] Sphingomyelin-dependence of cholesterol efflux mediated by ABCG1. (2007)
  • Author(s): Sano O, Kobayashi A, Nagao K, Kumagai K, Kioka N, Hanada K, Ueda K, Matsuo M.
  • Journal Title: J Lipid Res. 48(11) Pages: 2377-84
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Bile Salt-Dependent Efflux of Cellular Phospholipids Mediated by ATP Binding Cassette Protein B4. (2007)
  • Author(s): Morita, S.-y. Kobayashi, A., Takanezawa, Y., Kioka, N., Handa, T., Arai, H., Matsuo, M., Ueda, K.
  • Journal Title: Hepatology, 46 Pages: 188-199
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Enhanced apoA-I-dependent cholesterol efflux by ABCA1 from sphingomyelin-deficient CHO cells. (2007)
  • Author(s): Nagao, K., Takahashi, K., Hanada, K., Kioka, N., Matsuo, M., and Ueda, K.,
  • Journal Title: J Biol Chem. 282 Pages: 14868-74
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Cholesterol fill-in model mechanism for substrate recognition by ABC proteins. (2007)
  • Author(s): Kimura, Y., Kodan, A., Matsuo, M., and Ueda, K.
  • Journal Title: J Bioenerg. Biomembr. 39(5-6), Pages: 447-52
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Mechanism of multi-drug recognition by MDR1/ABCB1. (2007)
  • Author(s): Kimura, Y., Morita, S.-y., Matsuo, M., and Ueda, K.
  • Journal Title: Biochem J. 401 Pages: 597-605
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Modulation of drug-stimulated ATPase activity of human MDR1/P-glycoprotein by cholesterol. (2007)
  • Author(s): Kimura, Y., Kioka, N., Kato, H., Matsuo, M., Ueda, K.
  • Journal Title: Cancer Sci. 98, Pages: 1303-1310
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Sphingomyelin-dependence of cholesterol efflux mediated by ABCG1 (2007)
  • Author(s): Sano, O., Kobayashi, A., Nagao, K., Kumagai, K., Kioka, N., Hanada, K., Ueda, K., Matsuo, M
  • Journal Title: J Lipid Res 48(11) Pages: 2377-84
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Bile Salt-Dependent Efflux of Cellular Phospholipids Mediated by ATP Binding Cassette Protein B4 (2007)
  • Author(s): Morita, S.-y., Kobayashi, A., Takanezawa, Y., Kioka, N., Handa, T., Arai, H., Matsuo, M., Ueda, K
  • Journal Title: Hepatology 46 Pages: 188-199
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Enhanced apoA-I-dependent cholesterol efflux by ABCA1 from sphingomyelin-deficient CHO cells (2007)
  • Author(s): Nagao, K., Takahashi, K., Hanada, K., Kioka, N., Matsuo, M., Ueda, K
  • Journal Title: J Biol Chem 282 Pages: 14868-74
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Cholesterol fill-in model mechanism for substrate recognition by ABC proteins (2007)
  • Author(s): Kimura, Y., Kodan, A., Matsuo, M., Ueda, K
  • Journal Title: J Bioenerg. Biomembr 39(5-6) Pages: 447-52
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Mechanism of multi-drug recognition by MDR1/ABCB1 (2007)
  • Author(s): Kimura, Y., Morita, S.-y., Matsuo, M., Ueda, K
  • Journal Title: Biochem 401 Pages: 597-605
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Modulation of drug-stimulated ATPase activity of human MDR1/P-glycoprotein by cholesterol (2007)
  • Author(s): Kimura, Y., Kioka, N., Kato, H., Matsuo, M., Ueda, K
  • Journal Title: Cancer Sci 98 Pages: 1303-1310
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Characterization and classification of ATP-binding cassette transporter ABCA3 mutants in fatal surfactant deficiency. (2006)
  • Author(s): Matsumura Y, Ban N, Ueda K, Inagaki N.
  • Journal Title: J Biol Chem. 281, Pages: 24503-34514
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Efflux of sphingomyelin, cholesterol and phosphatidylcholine by ABCG1. (2006)
  • Author(s): Kobayashi, A., Takanezawa, Y., Hirata, T., Shimizu, Y., Misasa, K., Kioka, N., Arai, H., Ueda, K., and Matsuo, M.
  • Journal Title: J Lipid Res. 47, Pages: 1791-1802
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Serum amyloid A generates high density lipoprotein with cellular lipid in an ABCA1-or ABCA7-dependent manner. (2006)
  • Author(s): Abe-Dohmae, S., Kato, K. H., Kumon, Y., Hu, W., Ishigami, H., Iwamoto, N., Okazaki, M., Wu, C. A., Tsujita, M., Ueda, K. and Yokoyama, S.
  • Journal Title: J Lipid Res. 47, Pages: 1542-1550
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Purification and ATPase Activity of Human ABCA1. (2006)
  • Author(s): Takahashi, K., Kimura, Y., Kioka, N., Matsuo, M. and Ueda, K.
  • Journal Title: J Biol Chem, 281 Pages: 10760-10768
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] ABCA7, a molecule with unknown function, (2006)
  • Author(s): Abe-Dohmae, S., Ueda, K. and Yokoyama, S.
  • Journal Title: FEBS Lett. 580, Pages: 1178-1182
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Characterization and classification of ATP-binding cassette transporter ABCA3 mutants in fatal surfactant deficiency (2006)
  • Author(s): Matsumura, Y., Ban, N., Ueda, K., Inagaki, N
  • Journal Title: J Biol Chem 281 Pages: 34503-34514
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Efflux of sphingomyelin, cholesterol and phosphatidylcholine by ABCG1 (2006)
  • Author(s): Kobayashi, A., Takanezawa, Y., Hirata, T., Shimizu, Y., Misasa, K., Kioka, N., Arai, H., Ueda, K., Matsuo, M
  • Journal Title: J Lipid Res 47 Pages: 1791-1802
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Serum amyloid A generates high density lipoprotein with cellular lipid in an ABCA1- or ABCA7-dependent manner (2006)
  • Author(s): Abe-Dohmae, S., Kato, K.H., Kumon, Y., Hu, W., Ishigami, H., Iwamoto, N., Okazaki, M., Wu, C.A., Tsujita, M., Ueda, K., Yokoyama, S
  • Journal Title: J Lipid Res 47 Pages: 1542-1550
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Purification and ATPase Activity of Human ABCA1 (2006)
  • Author(s): Takahashi, K., Kimura, Y., Kioka, N., Matsuo, M., Ueda, K
  • Journal Title: J Biol Chem 281 Pages: 10760-10768
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] ABCA7 a molecule with unknown function (2006)
  • Author(s): Abe-Dohmae, S., Ueda, K., Yokoyama, S
  • Journal Title: FEBS Lett 580 Pages: 1178-1182
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Detection of ABCA7-positive cells in salivary glands from patients with Sjogren's syndrome. (2005)
  • Author(s): Toda, Y., Aoki, R., Ikeda, Y., Azuma, Y., Kioka, N., Matsuo, M., Sakamoto, M., Mori, S., Fukumoto, M., and Ueda, K.
  • Journal Title: Pathol. Int. 55, Pages: 639-643
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Cloning of ABCA17, anovel, rodent sperm-specific ATP-binding cassette(ABC)transporter that regulates intracellular lipid metabolism. (2005)
  • Author(s): Ban, N., Sasaki, M., Sakai, H., Ueda, K., and Inagaki, N.
  • Journal Title: Biochem J 389 Pages: 577-585
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Heterogeneity of High Density Lipoprotein Generated by ABCA1 and ABCA7. (2005)
  • Author(s): Hayashi, M., Abe-Dohmae, S., Okazaki, M., Ueda, K., and Yokoyama, S.
  • Journal Title: J Lipid Res 46 Pages: 1703-1711
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Fenofibric acid, an active form of fenofibrate, increases apolipoprotein A-l-mediated high-density lipoprotein biogenesis by enhancing transcription of ATP-binding cassette transporter A1 gene in a liver X receptor-dependent manner. (2005)
  • Author(s): Arakawa, R., Tamehiro, N., Nishimaki-Mogami, T., Ueda, K., and Yokoyama, S.
  • Journal Title: Arterioscler Thromb Vasc Biol 25 Pages: 1193-1197
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] KATP channel interaction with adenine nucleotides. (2005)
  • Author(s): Matsuo, M., Kimura, Y., and Ueda, K.
  • Journal Title: J. Mol. Cell. Cardiol. 38 Pages: 907-916
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Detection of ABCA7-positive cells in salivary glands from patients with Sjogren's syndrome (2005)
  • Author(s): Toda, Y., Aoki, R., Ikeda, Y., Azuma, Y., Kioka, N., Matsuo, M., Sakamoto, M., Mod, S., Fukumoto, M., Ueda, K
  • Journal Title: Pathol. Int 55 Pages: 639-643
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Cloning of ABCA17, a novel, rodent sperm-specific ATP-binding cassette (ABC) transporter that regulates intracellular lipid metabolism (2005)
  • Author(s): Ban, N., Sasaki, M., Sakai, H., Ueda, K., Inagaki, N
  • Journal Title: Biochem 389 Pages: 577-585
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Heterogeneity of High Density Lipoprotein Generated by ABCA1 and ABCA7 (2005)
  • Author(s): Hayashi, M., Abe-Dohmae, S., Okazaki, M., Ueda, K., Yokoyama, S
  • Journal Title: J Lipid Res 46 Pages: 1703-1711
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Fenofibric acid, an active form of fenofibrate, increases apolipoprotein A-I-mediated high-density lipoprotein biogenesis by enhancing transcription of ATP-binding cassette transporter Al gene in a liver X receptor-dependent manner (2005)
  • Author(s): Arakawa, R., Tamehiro, N., Nishimaki-Mogami, T., Ueda, K., Yokoyama, S
  • Journal Title: Arterioscler Thromb Vasc Biol 25 Pages: 1193-1197
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] KATP channel interaction with adenine nucleotides (2005)
  • Author(s): Matsuo, M., Kimura, Y., Ueda, K
  • Journal Title: J. Mol. Cell. Cardiol 38 Pages: 907-916
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Human ABCA3, a product of a responsible gene for abca3 for fatal surfactant deficiency in newborns, exhibits unique ATP hydrolysis activity and generates intracellular multilamellar vesicles, (2004)
  • Author(s): Nagata, K., Yamamoto, A., Ban, N., Tanaka, AR., Matsuo, M., Kioka, N., Inagaki, N., and Ueda, K.
  • Journal Title: Biochem Biophys Res Commun, 324 Pages: 262-268
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] α1-syntrophin modulates turnover of ABCA1. (2004)
  • Author(s): Munehira, Y., Qhnishi, T., Kawamoto, S., Furuya, A., Shitara, K., Imamura, M., Yokota, T., Takeda, S. i., Amachi, T., Matsuo, M., Kioka, N. and Ueda, K.
  • Journal Title: J Biol Chem 279 Pages: 15091-15095
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Verapamil Increases the Apolipoprotein-Mediated Release of Cellular Cholesterol by Induction of ABCA1 Expression via an LXR-lndependent Mechanism. (2004)
  • Author(s): Suzuki, S., Nishimaki-Mogami, T., Tamehiro, N., Inoue, K., Arakawa, R., Abe-Dohmae, S., Tanaka, A. R., Ueda, K. and Yokoyama, S.
  • Journal Title: Arterioscler Thromb Vasc Biol 24 Pages: 519-525
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Microanalysis for MDR1 ATPase by high-performance liquid chromatography with a titanium dioxide column. (2004)
  • Author(s): Kimura, Y., Shibasaki, S., Morisato, K., Ishizuka, N., Minakuchi, H., Nakanishi, K., Matsuo, M., Amachi, T., Ueda, M. and Ueda, K.
  • Journal Title: Anal. Biochem 326 Pages: 262-266
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Human ABCA7 supports apolipoprotein-mediated release of cellular cholesterol and phospholipid to generate HDLA. (2004)
  • Author(s): Abe-Dohmae, S., Ikeda, Y., Matsuo, M., Hayashi, M., Okuhira, K. I., Ueda, K., and Yokoyama, S.
  • Journal Title: J Biol Chem 279(1) Pages: 604-11
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Human ABCA3, a product of a responsible gene for abca3 for fatal surfactant deficiency in newborns, exhibits unique ATP hydrolysis activity and generates intracellular multilamellar vesicles (2004)
  • Author(s): Nagata, K., Yamamoto, A., Ban, N., Tanaka, AR., Matsuo, M., Kioka, N., Inagaki, N., Ueda, K
  • Journal Title: Biochem Biophys Res Commun 324 Pages: 262-268
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] a1-syntrophin modulates turnover of ABCA1 (2004)
  • Author(s): Munehira, Y., Ohnishi, T., Kawamoto, S., Furuya, A., Shitara, K., Imamura, M., Yokota, T., Takeda, S.i., Amachi, T., Matsuo, M., Kioka, N., Ueda, K
  • Journal Title: J Biol Chem 279 Pages: 15091-15095
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Verapamil Increases the Apolipoprotein-Mediated Release of Cellular Cholesterol by Induction of ABCA1 Expression via an LXR-Independent Mechanism (2004)
  • Author(s): Suzuki, S., Nishimaki-Mogami, T., Tamehiro, N., Inoue, K., Arakawa, R., Abe-Dohmae, S., Tanaka, A.R., Ueda, K., Yokoyama, S
  • Journal Title: Arterioscler Thromb Vasc Biol 24 Pages: 519-525
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Microanalysis for MDR1 ATPase by high-performance liquid chromatography with a titanium dioxide column (2004)
  • Author(s): Kimura, Y., Shibasaki, S., Morisato, K., Ishizuka, N., Minakuchi, H., Nakanishi, K., Matsuo, M., Amachi, T., Ueda, M., Ueda, K
  • Journal Title: Anal. Biochem 326 Pages: 262-266
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Human ABCA7 supports apolipoprotein-mediated release of cellular cholesterol and phospholipid to generate HDLA (2004)
  • Author(s): Abe-Dohmae, S., Ikeda, Y., Matsuo, M., Hayashi, M., Okuhira, K.I., Ueda, K., Yokoyama, S
  • Journal Title: J Biol Chem 279(1) Pages: 604-11
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] Mechanism of membrane lipid efflux by ABC transporters (2007)
  • Author(s): Ueda, K
  • Organizer: FASEB Summer Research Conferences,
  • Place of Presentation: Vermont, USA
  • Year and Date: 20070609-14
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] Mechanism of membrane lipid efflux by ABC transporters (2007)
  • Author(s): Ueda, K
  • Organizer: FASEB Summer Research Conferences
  • Place of Presentation: Vermont, USA
  • Year and Date: 20070609-14
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] Comparative aspects of the function and mechanism of ABC proteins involved in xenobiotic efflux and lipid homeostasis (2007)
  • Author(s): Ueda, K.
  • Organizer: 1st FEBS Special meeting
  • Place of Presentation: Innsbruck, Austria
  • Year and Date: 20070304-10
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] Post-translational regulation of ABCA1 (2007)
  • Author(s): Ueda, K
  • Organizer: 2nd FEBS Special Meeting
  • Place of Presentation: Innsbruck, Austria
  • Year and Date: 20070301-08
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] Endocytosis and Recycling of ABCA1 and HDL formation (2007)
  • Author(s): Yuya Azuma,
  • Organizer: 2nd FEBS Special Meeting
  • Place of Presentation: Innsbruck, Austria
  • Year and Date: 20070301-08
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] Function and mechanism of ABC proteins involved in lipid homeostasis (2006)
  • Author(s): Ueda, K.
  • Organizer: FEBS Special Meeting European Lipidomics,
  • Place of Presentation: Noordwijkerhout, The Netherlands
  • Year and Date: 20061021-25
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] Function and mechanism of ABC proteins involved in lipid homeostasis (2006)
  • Author(s): Ueda, K
  • Organizer: FEBS Special Meeting European Lipidomics
  • Place of Presentation: Noordwijkerhout, The Netherlands
  • Year and Date: 20061021-25
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] ABC proteins in lipid homeostasis (2006)
  • Author(s): Ueda, K.
  • Organizer: Gordon Research Conference
  • Place of Presentation: Maine, USA
  • Year and Date: 20060813-18
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] Comparative aspects of the function and mechanism of ABC proteins involved in xenobiotic efflux and lipid homeostasis (2006)
  • Author(s): Ueda, K
  • Organizer: 1st FEBS Special meeting
  • Place of Presentation: Innsbruck, Austria
  • Year and Date: 20060304-10
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] Comparative aspects of MDR1 and other ABC proteins (2006)
  • Author(s): Ueda, K.
  • Organizer: NIH MDR symposium
  • Place of Presentation: Bethesda, USA
  • Year and Date: 2006-09-20
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] ABCA3 and other ABC proteins involved in lipid transport and intracellular lipid dynamics (2004)
  • Author(s): Ueda, K.
  • Organizer: The 2004 HDL Workshop
  • Place of Presentation: Crete, Greece
  • Year and Date: 20040902-06
  • Description: 「研究成果報告書概要(和文)」より