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Bile Acids and Their Derivatives As Vitamin D Receptor Agonists:Molecular Mechanism and Biological Actions

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Bile Acids and Their Derivatives As Vitamin D Receptor Agonists:Molecular Mechanism and Biological Actions View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Tsukuba Repository Bile Acids and Their Derivatives as Vitamin D Receptor Agonists:Molecular Mechanism and Biological Actions 著者 Adachi Ryutaro year 2018 その他のタイトル ビタミンD受容体アゴニストとしての胆汁酸および その誘導体：分子メカニズムと生物学的作用 学位授与大学 筑波大学 (University of Tsukuba) 学位授与年度 2017 報告番号 12102甲第8562号 URL http://doi.org/10.15068/00152262 Bile Acids and Their Derivatives as Vitamin D Receptor Agonists: Molecular Mechanism and Biological Actions January 2018 Ryutaro ADACHI Bile Acids and Their Derivatives as Vitamin D Receptor Agonists: Molecular Mechanism and Biological Actions A Dissertation Submitted to the Graduate School of Life and Environmental Sciences, the University of Tsukuba in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy in Biological Science (Doctoral Program in Biological Sciences) Ryutaro ADACHI Table of Contents Abstract ......................................................................................................................................... 1 Abbreviations ................................................................................................................................ 4 General Introduction ..................................................................................................................... 7 Structure and function of nuclear receptors .............................................................................. 8 NR family as drug target ......................................................................................................... 10 NR modulators ........................................................................................................................ 11 Vitamin D receptor ................................................................................................................. 12 Development of VDR agonists ............................................................................................... 15 VDR as a bile acid sensor ....................................................................................................... 17 Objectives of this research ...................................................................................................... 20 Part 1 ........................................................................................................................................... 21 ABSTRACT............................................................................................................................ 22 INTRODUCTION .................................................................................................................. 23 MATERIALS AND METHODS ............................................................................................ 25 Chemical compounds ......................................................................................................... 25 Graphical manipulation and docking .................................................................................. 25 Plasmids .............................................................................................................................. 25 Cell culture and cotransfection assay ................................................................................. 26 Ligand binding assay .......................................................................................................... 27 RESULTS ............................................................................................................................... 28 Comparison of LBDs of VDR and PXR ............................................................................ 28 Functional analysis of VDR mutants .................................................................................. 29 Docking models of VDR interacting with LCA ................................................................. 35 DISCUSSION ......................................................................................................................... 38 Part 2 ........................................................................................................................................... 42 ABSTRACT............................................................................................................................ 43 INTRODUCTION .................................................................................................................. 44 MATERIALS AND METHODS ............................................................................................ 45 Chemical compounds ......................................................................................................... 45 Plasmids .............................................................................................................................. 45 Cell lines and cell culture ................................................................................................... 47 Cotransfection assay ........................................................................................................... 47 i Competitive ligand binding assay ....................................................................................... 47 Graphical manipulation and docking .................................................................................. 48 Animal studies .................................................................................................................... 48 Quantitative real time reverse transcription (RT)-polymerase chain reaction (PCR) analysis ............................................................................................................................................ 49 Growth and differentiation of myeloid leukemia cells ....................................................... 50 RESULTS ............................................................................................................................... 52 Transactivation of VDR by LCA derivatives ..................................................................... 52 LCA acetate is a potent agonist for VDR ........................................................................... 53 LCA acetate is not a potent agonist for other bile acid receptors ....................................... 55 Effect of VDR mutation on LCA acetate response ............................................................ 57 Induction of VDR target genes by LCA acetate in intestinal cells ..................................... 59 LCA acetate induces the differentiation of monoblastic leukemia cells ............................ 61 DISCUSSION ......................................................................................................................... 62 General Discussion ...................................................................................................................... 68 Structural determinants for VDR responses to its ligands ...................................................... 69 LCA acetate acted as a VDR modulator ................................................................................. 71 Possible molecular mechanism of VDR modulator ................................................................ 72 Development of better bile acid derived VDR modulators ..................................................... 73 Application to studies on the biological function of VDR ...................................................... 74 Future directions for the study of NR modulators .................................................................. 75 Acknowledgements ..................................................................................................................... 77 References ................................................................................................................................... 79 ii Abstract 1 The vitamin D receptor (VDR), a member of the nuclear receptor superfamily, mediates the biological actions of the active form of vitamin D, 1,25-dihydroxyvitamin D3 (1, 25(OH)2D3). It regulates calcium homeostasis, immunity, cellular differentiation, and other physiological processes. Secondary bile acids such as lithocholic acid (LCA) were identified as endogenous VDR agonists. The LCA binds to VDR and induces expression of an enzyme that metabolizes itself and reduces its toxicity. I determined amino acid residues of VDR required for its activation by 1, 25(OH)2D3 and LCA by generating VDR mutants predicted to modulate ligand response based on sequence homology to pregnane X receptor, another bile acid-responsive nuclear receptor. In both vitamin D response element activation and mammalian two-hybrid assays, I clarified molecular mechanisms underlying VDR activation mediated by 1, 25(OH)2D3 and LCA. To elucidate the relationship between chemical structures of bile acids and their agonistic activities for VDR, I examined the effect of several LCA derivatives on VDR activation. I determined structural elements required for potent activation of VDR and identified compounds with more potent activity than LCA. LCA acetate is the most potent of these VDR agonists with selectivity. LCA acetate induced VDR target genes in intestinal cells. Unlike LCA, LCA acetate inhibited the proliferation of human monoblastic leukemia cells and induced their 2 differentiation. These results clearly demonstrated LCA acetate exhibits more potent efficacies in cancer cells relative to LCA. Molecular and biological analyses on bile acids
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