40 C E/F Ligand Binding Domain, LBD activation function 2AF-2 E/F helix Two-hybrid GAL4 -helix12 DNA L/IXXI/VI GAL4DNA LXXLL

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1 8: orphan AD PPARs LXR 1980 FXR adopted A F 6 C DNA DNA Binding Domain DBD 2 Evans DNA cdna 5 -AGGTCA RXR 2 1 C E/F N A/B activation factor 1AF-1 cdna 48

2 40 C E/F Ligand Binding Domain, LBD activation function 2AF-2 E/F helix Two-hybrid GAL4 -helix12 DNA L/IXXI/VI GAL4DNA LXXLL

3 41 Biacore CoA-BAP 2 Two-hybrid SPR RI RI SPR Surface Plasmon ResonanceSPR SPR CoA-BAP ELISA 2 ( ) SPR

4 42 PEPCK 6 GLUT4 100nm LXR LXR A B 2 A B A B SPR Biacore A B B 1 A B 2 Biacore LXR Biacore LXR Biacore LXR reverse cholesterol transport ABCA1 ABCG1 ApoE HDL ABC

5 43 SA Steroid Receptor Coactivator 1 (SRC-1) LXXLL hsrc-1, aa LXR-LBD LXR T SRC-1 LXR-LBD T LXXLL 3 4T LXR T T Biacore LXR 70 (1) (2)N hsrc-1, aa ) LXR (3) LXR(hLXR -LBD,aa ) (4) LXR LXR 100MLXR 100M 33M11M 2 SPR -

6 44 Delage-Mourroux R, Martini PG, Choi I, Kraichely DM, Hoeksema J, Katzenellenbogen BS Analysis of estrogen receptor interaction with a repressor of estrogen receptor activity (REA) and the regulation of estrogen receptor transcriptional activity by REA. J Biol Chem. Nov 17;275(46): GE healthcare, Biacore Biacore GE healthcare, BIA technology Handbook. Giguere V, Ong ES, Segui P, Evans RM Identification of a receptor for the morphogen retinoic acid. Nature. Dec 17-23;330(6149): Green S, Wahli W Peroxisome proliferator-activated receptors: finding the orphan a home. Mol Cell Endocrinol. Apr;100(1-2): Augereau P, Badia E, Balaguer P, Carascossa S, Castet A, Jalaguier S, Cavaillès V Negative regulation of hormone signaling by RIP140. J Steroid Biochem Mol. Biol. Dec;102(1-5):51-9. Epub 2006 Oct 23. Heery DM, Kalkhoven E, Hoare S, Parker MG A Baldán A, Tarr P, Lee R, Edwards PA ATP-binding signature motif in transcriptional co-activators cassette transporter G1 and lipid homeostasis. Curr mediates binding to nuclear receptors. Nature. Jun Opin Lipidol. Jun;17(3): ;387(6634): Benbrook D., Pfahl M A novel thyroid hormone Hollenberg SM, Weinberger C, Ong ES, Cerelli G, Oro A, receptor encoded by a cdna clone from a human Lebo R, Thompson EB, Rosenfeld MG, Evans RM. testis library. Science. Nov 6;238(4828): Primary structure and expression of a functional human glucocorticoid receptor cdna. Nature. Dec Bruce A, Alexander J, Julian L, Martin R, Keith R, Peter W, Jan 1;318(6047): , Newton Press. Hu X, Lazar MA The CoRNR motif controls the recruitment of corepressors by nuclear hormone Chawla A, Repa JJ, Evans RM, Mangelsdorf DJ receptors. Nature. Nov 4;402(6757):93-6. Nuclear receptors and lipid physiology: opening the X-files. Science. Nov 30;294(5548): Janowski BA, Willy PJ, Devi TR, Falck JR, Mangelsdorf DJ An oxysterol signalling pathway mediated

7 45 by the nuclear receptor LXR alpha. Nature. Oct 24;383(6602): and adipose tissue. Proc Natl Acad Sci U S A. Apr 29;100(9): Joseph SB, Bradley MN, Castrillo A, Bruhn KW, Mak PA, Pei L, Hogenesch J, O'connell RM, Cheng G, Saez E, Miller JF, Tontonoz P LXR-dependent gene expression is important for macrophage survival and Laffitte BA, Joseph SB, Walczak R, Pei L, Wilpitz DC, Collins JL, Tontonoz P Autoregulation of the human liver X receptor alpha promoter. Mol Cell Biol. Nov;21(22): the innate immune response. Cell. Oct 15;119(2): Lubahn DB, Joseph DR, Sullivan PM, Willard HF, French FS, Wilson EM Cloning of human androgen Kanayama T, Mamiya S, Nishihara T, Nishikawa J Basis of a high-throughput method for nuclear receptor receptor complementary DNA and localization to the X chromosome. Science. Apr 15;240(4850): ligands. J Biochem. Jun;133(6): Makishima M, Okamoto AY, Repa JJ, Tu H, Learned RM,, Luk A, Hull MV, Lustig KD, Mangelsdorf DJ, Shan B.,, Vol. 119 No. 4: Identification of a nuclear receptor for bile acids. Science. May 21;284(5418): Kaneko E, Matsuda M, Yamada Y, Tachibana Y, Shimomura I, Makishima M Induction of Mangelsdorf DJ, Evans RM The RXR heterodimers and orphan receptors. Cell. Dec 15;83(6): intestinal ATP-binding cassette transporters by a phytosterol-derived liver X receptor agonist. J Biol McDonnell DP, Mangelsdorf DJ, Pike JW, Haussler MR, Chem. Sep 19;278(38): O'Malley BW Molecular cloning of complementary DNA encoding the avian receptor for : vitamin D. Science. Mar 6;235(4793): Kressler D, Hock MB, Kralli A Coactivators PGC-1beta and SRC-1 interact functionally to promote McKenna NJ, Lanz RB, O'Malley BW Nuclear receptor coregulators: cellular and molecular biology. Endocr Rev. Jun;20(3): the agonist activity of the selective estrogen receptor modulator tamoxifen. J Biol Chem. Sep, ;282(37): BIACORE.. Laffitte BA, Chao LC, Li J, Walczak R, Hummasti S, Joseph SB, Castrillo A, Wilpitz DC, Mangelsdorf DJ, Collins JL, Saez E, Tontonoz P Activation of liver X receptor improves glucose tolerance through coordinate regulation of glucose metabolism in liver Repa JJ, Mangelsdorf DJ The liver X receptor gene team: potential new players in atherosclerosis. Nat Med. Nov;8(11): Spencer TA, Li D, Russel JS, Collins JL, Bledsoe RK,

8 46 Consler TG, Moore LB, Galardi CM, McKee DD, Moore JT, Watson MA, Parks DJ, Lambert MH, Willson TM Pharmacophore analysis of the nuclear oxysterol receptor LXRalpha. J Med Chem. Mar 15;44(6): Tontonoz P, Mangelsdorf DJ Liver X receptor signaling pathways in cardiovascular disease. Mol Endocrinol. Jun;17(6): Tsai MJ, O'Malley BW Molecular mechanisms of action of steroid/thyroid receptor superfamily members. Annu Rev Biochem. 63: Zelcer N, Khanlou N, Clare R, Jiang Q, Reed-Geaghan EG, Landreth GE, Vinters HV, Tontonoz P Attenuation of neuroinflammation and Alzheimer's disease pathology by liver x receptors. Proc Natl Acad Sci U S A. Jun 19;104(25): Title : Screening of nuclear receptor ligand Authors :Masanori Nagao 1), Takayuki YONEZAWA 2), Byung-Yoon CHA 2), Toshiaki TERUYA 2), Kazuo NAGAI 1,2), Woo Je-Tae 1,2) Addresses : 1) College of Bioscience and Biotechnology, Chubu University. 2) Research Institute for Biological Function, Chubu University. Keywords : Nuclear Receptor, Ligand Screening, Liver X Receptor, Surface Plasmon Resonance, Biacore

第124回日本医学会シンポジウム

第124回日本医学会シンポジウム III γ γ γ α γ Molecular Mechanism of Insulin Resistance by Adipocytes TAKASHI KADOWAKI Department of Metabolic Diseases, Graduate School of Medicine, University of Tokyo Key words γ 110 124 TNFα FFA 1,2