⣽ ⬊ ෆ ࢚ ࢿ ࣝ ࢠ ࣮ ௦ ㅰ ⏕ ⌮ ᶵ ⬟
ᚋ⸨ோᚿ࣭㔝ᮧ┿࣭ᑠ㔝ᙪ
ி 㒔 ᗓ ❧ ་ ⛉ Ꮫ ་ Ꮫ ⛉ ᩍ 㣴 ⏕ ≀ Ꮫ ᗎㄽ ከ⣽⬊⏕≀ࡣᵝࠎ࡞ᰤ㣴ࢆᦤྲྀࡋࠊࡑࢀࡽࢆ௦ㅰࡍࡿࡇࡼࡗ࡚⏕άືࢆ⥔ᣢ ࡋ࡚࠸ࡿࠋࡇࡢ࠺ࡕ⢾㉁࣭⬡㉁࣭ࢱࣥࣃࢡ㉁ࡣศゎࡉࢀ࡚࢚ࢿࣝࢠ࣮ࢆ⏕ࡌࠊࢹࣀ ࢩࣥ୕ࣜࣥ㓟(ATP)࠸࠺ࡓࡕ࢚ࢿࣝࢠ࣮ࢆྲྀࡾฟࡍࠋ⣽⬊ෆ࢚ࢿࣝࢠ࣮௦ㅰࡣࠊ ⣽⬊ࡀྲྀࡾ㎸ࢇࡔศᏊࡀᵝࠎ࡞㓝⣲ᛂࡼࡗ࡚ศゎࡉࢀ࡚࢚ࢿࣝࢠ࣮ࡀྲྀࡾฟࡉࢀ ࡿ㐣⛬࠾ࡼࡧࠊ᰾㓟ࡸ⬡㉁ྜᡂࡢࡓࡵࡢ୰㛫௦ㅰ⏘≀ࢆ౪⤥ࡍࡿ㐣⛬ࡢࡇࢆ♧ࡋࠊ ࡑࡢࢥࡢ࡞ࡿ㐣⛬ࡣࠊከࡃࡢ⏕≀࡛㧗ᗘಖᏑࡉࢀ࡚࠸ࡿࠋ≉ࠊࢢࣝࢥ࣮ࢫࡀ ศゎࡉࢀ࡚ࠊH2O CO2ኚࡉࢀࡿ㐣⛬ࡣ㧗ᰯࣞ࣋ࣝࡢ⏕≀Ꮫᩍ⛉᭩࡛ࡶヲ⣽ ⤂ࡉࢀࠊ⏕άືࢆ⌮ゎࡍࡿୖ࡛᭱ࡶᇶ♏ⓗ࡞▱㆑ࡢ୍ࡘ࡛࠶ࡿࠋࡇࡢࡼ࠺ྂ ⓗ࡞࢚ࢿࣝࢠ࣮௦ㅰࡢศ㔝࡛࠶ࡿࡀࠊ㏆ᖺࡢゎᯒᢏ⾡ࡢᨵⰋࡼࡗ࡚ࠊ᪂ࡓ࡞Ⓨぢࡀ ┦ḟ࠸࡛࠸ࡿࠋᮏㄽᩥ࡛ࡣࠊ࢚ࢿࣝࢠ࣮௦ㅰ⤒㊰⣽⬊ᶵ⬟ࡘ࠸࡚㏙ࠊ㏆ᖺ᫂ࡽ ࡞ࡗ࡚ࡁࡓ࢚ࢿࣝࢠ࣮௦ㅰ㑇ఏᏊⓎ⌧ㄪ⠇ࡢ㛵ಀࢆ⤂ࡋࠊ᭦ࡣ➹⪅ࡓࡕࡢ ࢢ࣮ࣝࣉ࡛◊✲ࢆ࠾ࡇ࡞ࡗ࡚࠸ࡿ࢚ࢿࣝࢠ࣮※࡛࠶ࡿࢢࣜࢥ࣮ࢤࣥࡘ࠸࡚㏙ࠊ࢚ ࢿࣝࢠ࣮௦ㅰ◊✲ࡢ㐍ᒎࡘ࠸࡚㆟ㄽࡋࡓ࠸ࠋ 㸯㸬⣽⬊ෆ࢚ࢿࣝࢠ࣮௦ㅰ⤒㊰⣽⬊ᶵ⬟ ࢢࣝࢥ࣮ࢫ࡞ࡢ⢾㉁ࡣࠊ⣽⬊ෆྲྀࡾ㎸ࡲࢀࡿ࣊࢟ࢯ࢟ࢼ࣮ࢮࡼࡗ࡚ࣜࣥ㓟 ࡉࢀ࡚ࢢࣝࢥ࣮ࢫ6 ࣜࣥ㓟(G6P)࡞ࡿࠋG6P ࡣࠊ࣌ࣥࢺ࣮ࢫࣜࣥ㓟ᅇ㊰ࡼࡗ࡚ ᰾㓟ࡢྜᡂ࡞⏝࠸ࡽࢀࡿࠊ10 ✀௨ୖࡢ㓝⣲ࡀ㛵ࡍࡿ㐣⛬ࡼࡗ࡚ ATPࠊ nicotineamide adenine dinucleotide(NAD)ࠊࣆࣝࣅࣥ㓟ኚࡉࢀࡿ(ᅗ 1)ࠋᚋ⪅ࡢ ୍㐃ࡢᛂࡣࠊ1900 ᖺ௦๓༙ⓎぢࡉࢀࠊⓎぢ⪅㐩ࡢྡ๓ࢆࡾ࢚࣒ࢹࣥ-࣐࣮ࣖ ࣍ࣇ⤒㊰ࠊ࠶ࡿ࠸ࡣゎ⢾⣔ࡤࢀ࡚࠸ࡿࠋゎ⢾⣔࠾ࡅࡿ㔜せ࡞ㄪ⠇ᶵᵓࡢ୍ࡘ ࡋ࡚࣍ࢫ࣍ࣇࣝࢡࢺ࢟ࢼ࣮ࢮ1(PFK1)ࡢάᛶไᚚࡀ࠶ࡆࡽࢀࡿࠋPFK1 ࡣࠊゎ⢾⣔࠾࠸࡚ࣇࣝࢡࢺ࣮ࢫ-6-ࣜࣥ㓟స⏝ࡋ࡚ࠊࣇࣝࢡࢺ࣮ࢫ-1,6-ࣅࢫࣜࣥ㓟ࢆ⏕ᡂࡍࡿ㓝 ⣲࡛࠶ࡿࠋPFK1 ࡢ㢮ఝ㓝⣲࡛࠶ࡿ PFK2 ࡣࠊྠࡌࣇࣝࢡࢺ࣮ࢫ-6-ࣜࣥ㓟(Fru6P) స⏝ࡋ࡚ࣇࣝࢡࢺ࣮ࢫ-2,6-ࣅࢫࣜࣥ㓟(Fru2,6BP)ࢆ⏕ᡂࡍࡿࠋࡇࡢ Fru2,6BP ࡣゎ⢾ ⣔࠾ࡅࡿ⏘≀࡛࠶ࡿࡀࠊPFK1 ࡢάᛶࢆࣟࢫࢸࣜࢵࢡㄪ⠇ࡍࡿ㔜せ࡞ᅉᏊ࡛ ࠶ࡿࠋPFK2 ᒓࡍࡿᅄࡘࡢศᏊࡢ୍ࡘ࡛࠶ࡿ PFKFB3 ࡣࠊFru2,6BP ࢆ⏕ᡂࡍࡿ㔜 せ࡞㓝⣲࡛࠶ࡿࡇࡀ▱ࡽࢀ࡚࠸ࡿࠋ ゎ⢾⣔ࡢ᭱⤊⏘≀࡛࠶ࡿࣆࣝࣅࣥ㓟ࡣࠊ࣑ࢺࢥࣥࢻࣜ㍺㏦ࡉࢀ࡚ࢭࢳࣝCoA ኚࡉࢀࠊTCA ࢧࢡࣝ㓟ⓗࣜࣥ㓟ࡢ㐣⛬ࢆ⤒࡚ ATP ࡀྜᡂࡉࢀࡿ(ᅗ㸯)ࠋ ࡇࢀࡽࡢ࣑ࢺࢥࣥࢻࣜ࠾ࡅࡿᛂࡣࠊ㓟⣲ࢆᚲせࡋࠊ㓟⣲ࡀ↓࠸᎘Ẽⓗ࡞᮲௳ ୗ࡛ࡣࠊࣆࣝࣅࣥ㓟ࡣࢭࢳࣝCoA ࡛ࡣ࡞ࡃங㓟ኚࡉࢀࡿࠋࡋࡋࠊ࢞ࣥ⣽⬊ ࡛ࡣࠊ㓟⣲Ꮡᅾୗ࡛ࡶゎ⢾⣔ࡼࡗ࡚ATP ྜᡂࢆ⾜࠸ࠊࡇࡢ⌧㇟ࢆ Warburg ຠ ᯝࡪ(Warburg, 1956)ࠋ࢞ࣥ⣽⬊ࡣࠊ㏻ᖖ⣽⬊ࡣ␗࡞ࡿࣆࣝࣅࣥ㓟࢟ࢼ࣮ࢮ ࢯࣇ࢛࣮࣒M2(PKM2)ࢆⓎ⌧ࡋࠊࡇࢀࡀ TCA ᅇ㊰ᑟධࡉࢀࡿࡣࡎࡢࣆࣝࣅࣥ㓟 ࢆங㓟ኚࡋࠊWarburg ຠᯝᐤࡋ࡚࠸ࡿࡇࡀ᫂ࡽ࡞ࡗࡓࠋ(Christofk et al., 2008)ࠋ᭱㏆ࡢ◊✲࡛ࡣࠊṇᖖ࡞㦵⣽⬊ࡢศࡸ⾑⟶⣽⬊ࡢศዲẼⓗ࡞ゎ⢾⣔ ࢚ࢿࣝࢠ࣮௦ㅰࢆ⾜࠺ࡇࡀᚲせ࡛࠶ࡾࠊゎ⢾⣔ࢆ㜼ᐖࡍࡿ⣽⬊ศࡀᢚไࡉࢀࡿ ࡇࡀሗ࿌ࡉࢀ࡚࠸ࡿ(De Bock et al., 2013; Esen et al., 2013)ࠋ≉ De Bock ࡽࡢሗ ࿌࡛ࡣࠊ࢚ࢿࣝࢠ࣮௦ㅰࡢ㜼ᐖࡣ㑇ఏᏊⓎ⌧ࡢኚࢆకࢃࡎⓎ⏕␗ᖖࢆᘬࡁ㉳ࡇࡍࡓ ࡵࠊゎ⢾⣔ࢆࡋࡓ㎿㏿࡞࢚ࢿࣝࢠ࣮౪⤥ࡀ㑇ఏᏊࡼࡗ࡚ࣉࣟࢢ࣒ࣛࡉࢀࡓⓎ⏕ ㇟ࢆࢱ࣒ࢫࢣࢪ࣮ࣗࣝ㏻ࡾ㐍ࡵࡿࡓࡵྍḞ࡛࠶ࡿࡇࢆ♧၀ࡋ࡚࠸ࡿࠋ᭦ࠊ ⬻ࡢⓎ⏕ᮇ࠾࠸࡚ࡶ⚄⤒⣽⬊㛫ࡢࢩࢼࣉࢫࡀ┒ࢇᙧᡂࡉࢀࡿᮇࠊዲẼⓗ࡞ゎ ⢾⣔ࡀ┒ࢇ࡛࠶ࡿࡇࡀሗ࿌ࡉࢀ࡚࠸ࡿ(Goyal et al., 2014)ࠋࡇࢀࡽࡢࡇࡽࠊ⣽ ⬊ෆ࢚ࢿࣝࢠ࣮௦ㅰࠊ≉ゎ⢾⣔ࡣࠊⓎ⏕ࡸศࢆㄪ⠇ࡍࡿ㔜せ࡞ࣇࢡࢱ࣮࡛࠶ࡿ ࡇࡀ♧၀ࡉࢀࡿࠋ
㸰㸬⣽⬊ෆ࢚ࢿࣝࢠ࣮௦ㅰ⣽⬊࿘ᮇ࣭⣽⬊Ṛࡢㄪ⠇ ⣽⬊ෆ࢚ࢿࣝࢠ࣮௦ㅰࡣࡢࡼ࠺࡞࣓࢝ࢽࢬ࣒ࡼࡗ࡚Ⓨ⏕࣭ศࢆไᚚࡋ࡚࠸ࡿ ࡢࡔࢁ࠺㸽⣽⬊ෆ௦ㅰࡣࠊ⣽⬊ቑṪࡸ⣽⬊Ṛ῝ࡃ㛵ࡋ࡚࠸ࡿࡇࡀሗ࿌ࡉࢀ࡚ ࠸ࡿࠋ࠼ࡤࠊ⣽⬊እᰤ㣴⣲ࡢᯤῬࡼࡗ࡚⣽⬊࿘ᮇࡀṆࡍࡿࠋ⣽⬊እࡢᰤ㣴⣲ࡢ ᯤῬࡣࢹࣀࢩ୍ࣥࣜࣥ㓟(Adenosine Mono-Phosphate)ࡢ⣽⬊ෆ⃰ᗘࡢୖ᪼ࢆࡦࡁ ࠾ࡇࡋࠊࢹࣀࢩ୍ࣥࣜࣥ㓟౫Ꮡᛶ࢟ࢼ࣮ࢮ(AMPK)ࡀάᛶࡉࢀࠊᶆⓗࢱࣥࣃࢡ㉁ ࡢ୍ࡘ࡛࠶ࡿ㌿ᅉᏊp53 ࢆࣜࣥ㓟ࡍࡿࠋࣜࣥ㓟 p53 ࡣ p21 㑇ఏᏊࡢ㌿ࢆಁ 㐍ࡋࠊⓎ⌧ࡋࡓp21 ࡣࠊࢧࢡࣜࣥ౫Ꮡᛶ࢟ࢼ࣮ࢮ(Cdk)ࡢάᛶࢆᢚไࡍࡿࡇ࡛⣽ ⬊࿘ᮇࢆṆࡉࡏࡿ(Jones et al., 2005)ࠋ㏆ᖺࠊPFKFB3 ࢆ⣽⬊㐣Ⓨ⌧ࡉࡏࡿࠊ ᅗ㸯 ⣽⬊ෆ࢚ࢿࣝࢠ࣮௦ㅰࡢᴫせࠋ⣽⬊እࡽྲྀࡾ㎸ࢇࡔࢢࣝࢥ࣮ࢫࡣࠊゎ⢾⣔ࠊ TCA ᅇ㊰ࠊ㟁Ꮚఏ㐩⣔ࢆ⤒࡚ ATP ྜᡂ⏝ࡉࢀࡿࠋࡲࡓࠊࢢࣝࢥ࣮ࢫࡀ࣌ࣥࢺ ࣮ࢫࣜࣥ㓟ᅇ㊰ࡼࡗ࡚௦ㅰࡉࢀࡿࠊ᰾㓟ࡢྜᡂ⏝ࡉࢀࡿࠋࢢࣝࢱ࣑ࣥ࡞ ࡢ࣑ࣀ㓟࡞ࡣTCA ᅇ㊰ࡢ୰㛫௦ㅰ⏘≀࡞ࡗ࡚౪⤥ࡉࢀࡿࡇ࡛ࠊ࢚ࢿࣝࢠ ࣮౪⤥⏝࠸ࡽࢀࡿࠋ
⣽⬊ቑṪࡀಁ㐍ࡉࢀࡿࡇࡀሗ࿌ࡉࢀ࡚࠸ࡿ(Yalcin et al., 2009)ࠋࡇࡢሗ࿌ࡼࡿࠊ PFKFB3 ࡣ⣽⬊㉁ࡢࡳ࡞ࡽࡎࠊ᰾ࡶᏑᅾࡋ࡚᰾ࡢ Fru2,6BP ࡢୖ᪼ࢆᘬࡁ㉳ࡇࡍࠋ ࡇࡢ᰾ෆFru2,6BP ࡢ⃰ᗘୖ᪼ࡀ cyclin D3 ࡸࠊcdc25c ࡞ࡢ⣽⬊࿘ᮇ㔜せ࡞ᅉᏊ ࡢⓎ⌧ࢆㄪ⠇ࡍࡿࡇࡀሗ࿌ࡉࢀ࡚࠸ࡿࠋࡇࢀࡽࡢ⤖ᯝࡽࠊ⣽⬊ෆ௦ㅰ⤒㊰࠾ࡅ ࡿ୰㛫௦ㅰ⏘≀ࡣ⣽⬊࿘ᮇㄪ⠇⣔ᐦ᥋㛵㐃ࡋ࡚࠸ࡿࡇࡀ♧၀ࡉࢀ࡚࠸ࡿࠋ ⣽⬊ࡀᴟᗘࡢᰤ㣴㣚㣹ࡸ㛗ᮇ㛫ࡢᰤ㣴㣚㣹ࡉࡽࡉࢀࠊ㛗ᮇ㛫p53 ࡢࣜࣥ㓟ࡀ⥔ ᣢࡉࢀࡿࠊ⣽⬊ࡣ࣏ࢺ࣮ࢩࢫࢆㄏᑟࡍࡿࡇࡀሗ࿌ࡉࢀ࡚࠸ࡿࠋp53 ࡣࠊDNA ᦆയ࡞࠾ࡅࡿ࣏ࢺ࣮ࢩࢫಁ㐍ᅉᏊࡋ࡚ࡢᙺࡀࡼࡃ▱ࡽࢀ࡚࠾ࡾࠊୗὶࡢᅉ Ꮚࡋ࡚PUMAࠊBAX ࠸ࡗࡓ࣏ࢺ࣮ࢩࢫಁ㐍ᅉᏊࡢⓎ⌧ࢆಁ㐍ࡍࡿ(Miyashita and Reed, 1995; Nakano and Vousden, 2001; Zhao et al., 2008)ࠋ㏫ࠊp53 ࡣ⣽⬊ ෆ௦ㅰ㛵㐃ࡍࡿᅉᏊࡢⓎ⌧ㄏᑟࢆ⾜࠺ࡇࡼࡗ࡚ᢠ࣏ࢺ࣮ࢩࢫస⏝ࡶ♧ࡍࠋࢢ ࣝࢥ࣮ࢫ㣚㣹࠾ࡅࡿ p53 ࡢୗὶᅉᏊࡋ࡚ࠊ࣍ࢫ࣍ࢢࣜࢭࣜࣥ㓟࣒ࢱ࣮ࢮ(PGM) ࡢⓎ⌧ࡀᢚไࡉࢀࠊTP53-induced glycolysis and apoptosis regulator (TIGAR)ࡸ glutaminase2 ࡢⓎ⌧ࡀㄏᑟࡉࢀࡿ(Bensaad et al., 2006; Hu et al., 2010; Kondoh et al., 2005; Matoba et al., 2006)ࠋPGM ࡣゎ⢾⣔ࡢ㓝⣲࡛࠶ࡾࠊPGM ࡢⓎ⌧ᢚไࡣゎ ⢾⣔ࡢ㜼ᐖࡘ࡞ࡀࡿࠋࡲࡓࠊTIGAR ࡣ Fru2,6BP ࢆ Fru6P ㌿ࡍࡿ㓝⣲࡛࠶ࡾࠊ TIGAR ࡢⓎ⌧ㄏᑟࡣ PFK1 ࡢάᛶࢆᢚไࡍࡿࡇ࡛ゎ⢾⣔㜼ᐖࡘ࡞ࡀࡿࠋࡇࢀࡽ ࡢస⏝ࡼࡾࠊp53 ࡢάᛶࡣゎ⢾⣔ࡢ㜼ᐖࢆᘬࡁ㉳ࡇࡋࠊࢢࣝࢥ࣮ࢫࡣ㏻ᖖࡼࡾࡶ ࣌ࣥࢺ࣮ࢫࣜࣥ㓟⤒㊰ࡼࡗ࡚ᾘ㈝ࡉࢀࡿࠋ࣌ࣥࢺ࣮ࢫࣜࣥ㓟⤒㊰ࡼࡗ࡚⏕ᡂࡉࢀ ࡿศᏊࡢ୍ࡘ࡛࠶ࡿNADPH ࡣࠊ⣽⬊ෆࡢ㑏ඖᆺࢢࣝࢱࢳ࢜ࣥࡢ⥔ᣢࢆࡋ࡚ᢠ㓟 స⏝ࢆ♧ࡍࠋࡲࡓࠊglutaminase2 ࡣࠊࢢࣝࢱ࣑ࣥࢆࢢࣝࢱ࣑ࣥ㓟㌿ࡍࡿ㓝⣲࡛ ࠶ࡾࠊ⏕ᡂࡉࢀࡓࢢࣝࢱ࣑ࣥ㓟ࡣࠊTCA ᅇ㊰ᑟධࡉࢀ࡚࣑ࢺࢥࣥࢻ࡛ࣜࡢ྾ࢆ ᥎㐍ࡋࡓࡾࠊࢢࣝࢱࢳ࢜ࣥྜᡂ㛵ࡍࡿࡇࡼࡗ࡚ᢠ㓟స⏝ࢆ♧ࡍࠋࡇࢀࡽࡢ ࡇࡽࠊp53 ࡢάᛶࡣ⣽⬊ࡢᰤ㣴≧ែ࠾ࡅࡿ⣽⬊ෆ࡛ࡢᵝࠎ࡞ࣂࣛࣥࢫࢆㄪ⠇ ࡋ࡚࠾ࡾࠊࡑࡢᖹ⾮≧ែࡀࢀࡿ⣽⬊Ṛ⮳ࡿ⪃࠼ࡽࢀࡿࠋ 㸱㸬⣽⬊ෆ࢚ࢿࣝࢠ࣮௦ㅰ࢚ࣆࢪ࢙ࢿࢸࢡࢫ ࢥ⣽⬊ෆ࢚ࢿࣝࢠ࣮௦ㅰ⤒㊰࠾ࡅࡿ୰㛫⏘≀ࡣࠊ࢚ࣆࢪ࢙ࢿࢸࢡࢫࡢᶵᵓࢆ ࡋ࡚㑇ఏᏊⓎ⌧㛵ࡍࡿࡇ࡛⣽⬊ᶵ⬟ࢆไᚚࡍࡿࡇࡀ᫂ࡽ࡞ࡗ࡚ࡁࡓࠋ ࢚ࢿࣝࢠ࣮௦ㅰ⤒㊰࠾ࡅࡿ㟁Ꮚఏ㐩య࡛࠶ࡿNAD ࡢ㓟ᆺ(NAD+)ࡣࠊࣄࢫࢺࣥ⬺
ࢭࢳࣝ㓝⣲࡛࠶ࡿSirtuin ࣇ࣑࣮ࣜࢆάᛶࡍࡿࡇࡼࡗ࡚㑇ఏᏊⓎ⌧ࢆไ ᚚࡍࡿࡇࡀ▱ࡽࢀ࡚࠸ࡿ(Chang and Guarente, 2014)ࠋࡲࡓࠊࢭࢳࣝ CoA ࡣࠊ ࣄࢫࢺࣥࢱࣥࣃࢡ㉁ࡢࢭࢳࣝࡢࢻࢼ࣮࡞ࡿࡇ࡛㑇ఏᏊⓎ⌧ࢆㄪ⠇ࡍࡿࡇࡀ ▱ࡽࢀ࡚࠸ࡿࠋ㑇ఏᏊⓎ⌧㛵ࡍࡿࢭࢳࣝCoA ࡣࠊ့ங㢮࡛ࡣ⌧ᅾࡢࡇࢁࡘ ࡢ౪⤥⤒㊰ࡼࡗ࡚⏘⏕ࡉࢀࡿ⪃࠼ࡽࢀ࡚࠸ࡿࠋ୍ࡘࡵࡣࠊTCA ࢧࢡࣝࡢ୰㛫௦ ㅰ⏘≀࡛࠶ࡿࢡ࢚ࣥ㓟ࡀࠊ࣑ࢺࢥࣥࢻࣜࡽ⣽⬊㉁㍺㏦ࡉࢀࠊATP-citrate lyase(ACL)ࡢస⏝ࡼࡗ࡚ࢭࢳࣝ CoA ㌿ࡉࢀࡿ⤒㊰࡛࠶ࡿࠋ(Wellen et al., 2009)ࠋࡘ┠ࡣࠊ᰾Ꮡᅾࡍࡿࣆࣝࣅࣥ㓟⬺Ỉ⣲㓝⣲」ྜయࡀࠊ᰾ෆ࡛ࣆࣝࣅࣥ㓟 ࢆࢭࢳࣝCoA ኚࡍࡿ⤒㊰࡛࠶ࡿ(Sutendra et al., 2014)ࠋ࠸ࡎࢀࡏࡼࠊࣄࢫ ࢺࣥࢭࢳࣝࡢ⣽⬊ෆ࢚ࢿࣝࢠ࣮௦ㅰࡀᐦ᥋㛵ಀࡋ࡚࠸ࡿࡇࡀ♧၀ࡉࢀࡿࠋ ࡇࢀࡽࡢไᚚࡣ≉ᐃࡢ㑇ఏᏊࡢⓎ⌧ࢆไᚚࡋ࡚࠸ࡿࡢ࡛࠶ࢁ࠺㸽ࡇࢀࡲ࡛ࡢሗ࿌࡛ ࡣࠊᇵ㣴⣽⬊࡛ ACL ࡢⓎ⌧ᢚไࢆ⾜࠺ࠊࢢ࣮ࣟࣂࣝ࡞ࣄࢫࢺࣥࡢࢭࢳࣝࡢῶ ᑡࡢࡳ࡞ࡽࡎࠊPFK1 ࡸங㓟⬺Ỉ⣲㓝⣲ A(LDHA)ࡢⓎ⌧㜼ᐖࢆᘬࡁ㉳ࡇࡍࡇࡀሗ ࿌ࡉࢀ࡚࠸ࡿࠋࡇࡢࡇࡽࠊࢭࢳࣝCoA ࡢ⣽⬊ෆ⃰ᗘࡣࣇ࣮ࢻࣂࢵࢡⓗ⣽⬊ ෆ௦ㅰᙳ㡪ࡍࡿࡇࡀ⪃࠼ࡽࢀࡿࠋ᭦ࠊ⬇ᛶᖿ⣽⬊࡛ࡣ TCA ࢧࢡࣝࡢ୰㛫௦ ㅰ⏘≀࡛࠶ࡿȘ-ࢣࢺࢢࣝࢱࣝ㓟ࡀࠊ⬺࣓ࢳࣝ㓝⣲࡛࠶ࡿ Tet ࣇ࣑࣮ࣜࡢάᛶࢆไ ᚚࡍࡿࡇࡼࡾࣄࢫࢺࣥࡢ࣓ࢳࣝࢆㄪ⠇ࡋ࡚࠸ࡿࡇࡀሗ࿌ࡉࢀࡓ(Carey et al., 2014)ࠋࡇࡢࡇࡣࠊⓎ⏕ᮇࡢࡢᮇࡸ⤌⧊࠾࠸࡚ࡶྠᵝࡢ࣓࢝ࢽࢬ࣒ࡀ㛵 ࡋ࡚࠸ࡿࡇࢆ♧ࡋ࡚࠸ࡿࠋࡇࢀࡽࡢ▱ぢࡣ࠸ࡎࢀࡶࠊ⣽⬊ෆ௦ㅰ࢚ࣆࢪ࢙ࢿࢸ ࢡࢫࡢ㛵㐃ࡢ㔜せᛶࢆ♧၀ࡋ࡚࠸ࡿ⪃࠼ࡽࢀࠊ᭦⣽⬊ෆ௦ㅰ⤒㊰ࡀ୍ⓗ␗ᖖ ࠾ࡕ࠸ࡿࠊ࢚ࣆࢪ࢙ࢿࢸࢵࢡ࡞ᶵᵓࡼࡗ࡚ᚋࠎࡢ⾲⌧⣔ᙳ㡪ࢆཬࡰࡍࡇ ࡶ⪃࠼࠺ࡿࠋ 㸲㸬ࢢࣜࢥ࣮ࢤࣥ⏕⌮ᶵ⬟ไᚚ ࢢࣜࢥ࣮ࢤࣥࡣࠊ1800 ᖺ௦ࢡ࣮ࣟࢻ࣭࣋ࣝࢼ࣮ࣝࡽࡼࡗ࡚ぢฟࡉࢀࡓࢢࣝࢥ࣮ ࢫࡀከᩘ㔜ྜࡋࡓከ⢾㢮࡛࠶ࡿࠋࢢࣝࢥ࣮ࢫࡣȘ1,4 ⤖ྜࡼࡗ࡚┤㙐≧ࡢࢢࣝࢥ࣮ ࢫ࣏࣐࣮ࣜࢆᙧᡂࡋࠊȘ1,6 ⤖ྜࡼࡗ࡚ศᒱࢆసࡿࠋࢢࣜࢥ࣮ࢤࣥࢆ࠼ࡿせ࡞ ⤌⧊ࡣࠊ⫢⮚ࠊ➽⫗࠾ࡼࡧ⬻࡛࠶ࡿࠋࢢࣜࢥ࣮ࢤࣥࡣࠊࢢࣝࢥ࣮ࢫࡽࢢࣜࢥ࣮ ࢤࣥࢩࣥࢱ࣮ࢮࡼࡗ࡚ྜᡂࡉࢀࠊ⏝ࡣࠊࢢࣜࢥ࣮ࢤࣥ࣍ࢫ࣮࣍ࣜࣛࢮࡼࡗ࡚ ࢢࣝࢥ࣮ࢫ-1-ࣜࣥ㓟ኚࡉࢀࡿࠋ⏕ᡂࡉࢀࡓࢢࣝࢥ࣮ࢫ-1-ࣜࣥ㓟ࡣࠊ࣍ࢫ࣍ࢢࣝࢥ
࣒ࢱ࣮ࢮࡢస⏝ࡼࡗ࡚ࢢࣝࢥ࣮ࢫ-6-ࣜࣥ㓟(G6P)㌿ࡉࢀࠊゎ⢾⣔౪ࡉࢀ࡚࢚ ࢿࣝࢠ࣮ࡢ⏘⏕ࡀ⾜ࢃࢀࡿࠋࢢࣜࢥ࣮ࢤࣥ࣍ࢫ࣮࣍ࣜࣛࢮࡣࠊࣜࣥ㓟ࡸ⣽⬊ෆ࢚ࢿ ࣝࢠ࣮ࡢᣦᶆ࡞ࡿAMP ࡼࡗ࡚ࣟࢫࢸࣜࢵࢡṇࡢάᛶㄪ⠇ࢆཷࡅࡿࠋࢢࣜࢥ ࣮ࢤࣥࡣࠊ➽⫗࡛ࡣ㐠ື↓㓟⣲ⓗゎ⢾⣔ࢆ㥑ືࡉࡏࡿᰤ㣴㈓ⶶ≀㉁ࡋ࡚ാ࠸ ࡚࠸ࡿࡇࡽࠊ࢚ࢿࣝࢠ࣮Ḟஈࢢࣝࢥ࣮ࢫࡢ௦᭰ࡋ࡚༶ⓗ⏝࠸ࡽࢀࡿᰤ 㣴㈓ⶶ≀㉁ࡋ࡚ാ࠸࡚࠸ࡿ⪃࠼ࡽࢀ࡚࠸ࡿࠋࡋࡋࠊ㏆ᖺ࡛ࡣࢢࣜࢥ࣮ࢤࣥࡣࡼ ࡾືⓗ⏝࠸ࡽࢀࡿᰤ㣴⣲࡛࠶ࡿࡇࡀᥦၐࡉࢀ࡚࠸ࡿࠋࡍ࡞ࢃࡕࠊ⣽⬊ෆྲྀࡾ㎸ ࡲࢀࡓࢢࣝࢥ࣮ࢫࡣ༶ᗙゎ⢾⣔౪ࡉࢀࡿࡢ࡛ࡣ࡞ࡃࠊ୍᪦ࢢࣜࢥ࣮ࢤࣥྲྀࡾ ㎸ࡲࢀࠊ࢚ࢿࣝࢠ࣮せồᛂࡌ࡚ࢢࣜࢥ࣮ࢤࣥࡀศゎࡉࢀࠊG6P ㌿ࡉࢀ࡚ゎ⢾⣔ ౪ࡉࢀࡿ࠸࠺௦ㅰ⤒㊰࡛࠶ࡿࠋࢢࣝࢥ࣮ࢫࡀ┤᥋ゎ⢾⣔ࡼࡗ࡚௦ㅰࡉࢀࡿሙ ྜࡣ2 ศᏊࡢ ATP ࡀ⏝ࡉࢀࠊ4 ศᏊࡢ ATP ࡀ⏕ᡂࡉࢀࡿࡀࠊࢢࣜࢥ࣮ࢤࣥࢆࡍ ࡿሙྜࡣ3 ศᏊࡢ ATP ࡀ⏝ࡉࢀࡿࡓࡵࠊ᭱⤊ⓗ 1 ศᏊࡢ ATP ࡀ⏕ࡳฟࡉࢀࡿ(ᅗ 2Aձ㹼նࡢ㡰␒ᛂࡀ㐍ࡴ)ࠋࡇࡢࡼ࠺┤᥋ⓗ࡞ゎ⢾⣔ࡼࡾࡶ࢚ࢿࣝࢠ࣮ᨭୖ ࡣ࡛࠶ࡿࡀࠊࢢࣜࢥ࣮ࢤࣥࢆᰤ㣴౪⤥※ࡋ࡚⏝ࡍࡿࡇࡼࡾࠊゎ⢾⣔ࡢᚊ ㏿ᛂࡢ୍ࡘ࡛࠶ࡿࢢࣝࢥ࣮ࢫЍG6P ࡢᛂࢆࢫ࢟ࢵࣉࡍࡿࡇࡀ࡛ࡁࡿࡓࡵࠊ▷ᮇ 㛫ࡲࡲࡗࡓ࢚ࢿࣝࢠ࣮ࢆ౪⤥ࡍࡿࡢ㒔ྜࡀࡼ࠸⪃࠼ࡽࢀࡿࠋ➽⫗࡞࡛ࡣ ⦰ࡢྜ㛫ࠊ⏝ࡉࢀࡓࢢࣜࢥ࣮ࢤࣥࡀࢢࣝࢥ࣮ࢫࡽྜᡂࡉࢀḟࡢ⦰ࡢ࢚ࢿࣝ ࢠ࣮࡞ࡿࠋࡇࡢࡇࡣ’Glycogen shunt’ࡤࢀ࡚࠸ࡿ(Shulman and Rothman, 2001)ࠋGlycogen shunt ࡣࠊ⚄⤒⣔ࡢ࢚ࢿࣝࢠ࣮௦ㅰ⤒㊰ࡶ㔜せ࡛࠶ࡿࡇࡀሗ࿌ ࡉࢀ࡚࠸ࡿࠋ⾑⟶ࡽ౪⤥ࡉࢀࡓࢢࣝࢥ࣮ࢫࡣ┤᥋⚄⤒⣽⬊౪⤥ࡉࢀࡿࡢ࡛ࡣ࡞ࡃࠊ ࢢࣜ⣽⬊ࡢ୍✀࡛࠶ࡿࢫࢺࣟࢧࢺࡢࢢࣜࢥ࣮ࢤࣥ㈓ⶶࡉࢀࠊ⏝ࡉࢀࡿࠋ⚄ ⤒⣔࠾࠸࡚ࡣࠊ⯆ዧᛶࢩࢼࣉࢫ࠾ࡅࡿ⚄⤒ఏ㐩≀㉁࡛࠶ࡿࢢࣝࢱ࣑ࣥ㓟ࢆᨺฟᚋ ┤ࡕᅇࡋࠊ⏝ࡍࡿࡇࡀሗఏ㐩㔜せ࡛࠶ࡿࡀࠊࡇࡢࡢ ATP ⏘⏕ Glycogen shunt ࡢ࣓࢝ࢽࢬ࣒ࡀ⏝ࡉࢀ࡚࠸ࡿࡇࡀሗ࿌ࡉࢀ࡚࠸ࡿ(Shulman et al., 2001)ࠋࢢࣜࢥ࣮ࢤࣥ⏝㔜せ࡞㓝⣲࡛࠶ࡿࢢࣜࢥ࣮ࢤࣥ࣍ࢫ࣮࣍ࣜࣛࢮࡢ㜼ᐖ ࢆᾏ㤿ᢞࡍࡿࠊᾏ㤿⚄⤒⣽⬊ࡢࢩࢼࣉࢫఏ㐩ࡀ㜼ᐖࡉࢀࠊࡑࡢ⤖ᯝࡋ࡚グ ᠈ᙧᡂ␗ᖖࡀㄆࡵࡽࢀࡿࡇࡀࢽ࣡ࢺࣜࡸ࣐࢘ࢫࢆ⏝࠸ࡓᐇ㦂ࡼࡗ࡚ド᫂ࡉࢀ࡚ ࠸ࡿ(Gibbs et al., 2006; Suzuki et al., 2011)ࠋ➹⪅㐩ࡢචᰁⰍࢆ⏝࠸ࡓ⤌⧊Ꮫⓗゎ ᯒࡼࡗ࡚ࡶࠊglutamine synthase 㝧ᛶࡢࢫࢺࣟࢧࢺ㸦ᅗ 2B ୖẁ▮㢌ࠊ▮༳ࡣ ᰾ࢆ♧ࡋ࡚࠸ࡿ㸧࠾࠸࡚ࠊࢢࣜࢥ࣮ࢤࣥࡣࢩࢼࣉࢫ㛫㝽ࢆ⿕そࡋ࡚࠸ࡿࢫࢺࣟࢧ
ࢺࡢ✺㉳㇏ᐩᏑᅾࡍࡿࡇࡀ᫂ࡽ࡞ࡗ࡚࠾ࡾ(ᅗ 2B ୗẁ▮㢌)ࠊࢢࣜࢥ࣮ࢤ ࣥࡀࢩࢼࣉࢫ㏆ഐ࡛ࡢ࢚ࢿࣝࢠ࣮౪⤥㔜せ࡞ࡇࡀ♧၀ࡉࢀࡿࠋࡇࢀࡽࡢሗ࿌ࡽࠊ Glycogen shunt ࡣ▷ᮇ㛫ከ㔞ࡢ࢚ࢿࣝࢠ࣮ࢆ౪⤥ࡍࡿᇶ♏ⓗ࡞࣓࢝ࢽࢬ࣒࡛࠶ࡿ ࡇྍ⬟ᛶࡀ♧၀ࡉࢀࡿࠋ ㏆ᖺࠊࢢࣜࢥ࣮ࢤࣥࡣ࢞ࣥ⣽⬊ࡀGlycogen shunt ࡢ࣓࢝ࢽࢬ࣒ࡼࡗ࡚࢚ࢿࣝࢠ ࣮ࢆ౪⤥ࡋࠊศ࣭ቑṪࡍࡿ㝿ᚲせ࡞࢚ࢿࣝࢠ࣮※࡛࠶ࡿࡇࡀሗ࿌ࡉࢀࡓ(Favaro et al., 2012)ࠋࡇࡢࡇࡽࠊࢢࣜࢥ࣮ࢤࣥࡣ༢࡞ࡿ㈓ⶶ≀㉁࡛ࡣ࡞ࡃࠊ⣽⬊ࡢᇶᮏⓗ ᶵ⬟ࢆ⾜࠺ࡓࡵࢲࢼ࣑ࢵࢡ⏝ࡉࢀࡿ࢚ࢿࣝࢠ࣮※࡛࠶ࡿࡇࡀ♧၀ࡉࢀࡿࠋ ಶయࡢⓎ⏕࣭ศࡣ▷ᮇ㛫ከ㔞ࡢ࢚ࢿࣝࢠ࣮ࢆᚲせࡍࡿ⏕≀ࡢ㇟࡛࠶ࡿࡀࠊⓎ ⏕࣭ศ࠾ࡅࡿࢢࣜࢥ࣮ࢤࣥࡢ⏕⌮ⓗព⩏ࡣ࠶ࡲࡾሗ࿌ࡉࢀ࡚࠸࡞࠸ࠋࡋࡋ࡞ࡀ ࡽࠊୖ㏙ࡢࡼ࠺࡞⣽⬊࿘ᮇࡸ࢚ࣆࢪ࢙ࢿࢸࢡࢫࡢᶵᵓࢆ㏻ࡌ࡚ࠊࢢࣜࢥ࣮ࢤࣥࡣⓎ ⏕ศࢆไᚚࡋ࡚࠸ࡿࡇࡀணࡉࢀࡿࠋᚋࠊ➹⪅㐩ࡢ◊✲ࡢ㐍ᒎࡼࡾࡇࢀࡽࡢ ㇟ࡀ᫂ࡽ࡞ࡿࡇࢆᮇᚅࡋࡓ࠸ࠋ
ᅗ2A Glycogen shunt ࡼࡿ࢚ࢿࣝࢠ࣮ྜᡂ⤒㊰ࠊձ㹼նࡢ㡰␒ᛂࡀ㐍 ࡴࠋ࢚ࢿࣝࢠ࣮ࢆ౪⤥ࡍࡿ㝿ࡣմЍյЍն࢚ࢿࣝࢠ࣮ྜᡂࡀ㐍ࡴࠋձЍն ࡢሙྜẚࠊ࢚ࢿࣝࢠ࣮ᨭࡣᝏ࠸ࡀࠊ࢚ࢿࣝࢠ࣮౪⤥ձࡢࢫࢸࢵࣉࡀ ┬␎࡛ࡁࡿࠋ ᅗ2B ୖẁ㸸ࢫࢺࣟࢧࢺࡢ࣐࣮࣮࡛࢝࠶ࡿ glutamine synthase(▮㢌)ࡣࠊ ᰾(▮༳)࿘ᅖࡢ⣽⬊㉁Ꮡᅾࡍࡿࠋୗẁ㸸ࢢࣜࢥ࣮ࢤࣥࡣࢫࢺࣟࢧࢺࡢ௬ ㊊ከࡃᏑᅾࡍࡿ(▮㢌)ࠋࣂ࣮ࡣ 10ȣmࠋ
㸳㸬ᚋࡢᒎᮃ ࡇࢀࡲ࡛ࡣࠊ⣽⬊ෆ࢚ࢿࣝࢠ࣮௦ㅰࡢ◊✲ࡣࠊ⏕Ꮫⓗᡭἲࡸᇵ㣴⣽⬊ࢆ⏝࠸ࡓᐇ 㦂࡞ẚ㍑ⓗᆒ୍࡞᮲௳ୗ࡛⾜ࢃࢀ࡚ࡁࡓࠋᚋࡣࠊ⣽⬊ෆ࢚ࢿࣝࢠ࣮௦ㅰࡢ⏕≀Ꮫ ⓗ㔜せᛶࢆ⤌⧊ࠊಶయ࡛ࣞ࣋ࣝ᫂ࡽࡍࡿᚲせࡀ࠶ࡿࠋ㏆ᖺ㛤Ⓨࡉࢀࡓ㉁㔞㢧ᚤ㙾 ࡣࠊ⤌⧊ࣞ࣋ࣝࡢᚤᑠ࡞௦ㅰኚࢆࡽ࠼ࡿࡢ㠀ᖖᙉຊ࡞ࢶ࣮࡛ࣝ࠶ࡿࠋ⤌⧊ࡢ ᅛᐃἲࡼࡗ࡚⣽⬊ෆ࢚ࢿࣝࢠ࣮௦ㅰࡢ୰㛫⏘≀㔞ࡀኚࡍࡿࡇࡀᮍࡔၥ㢟࡛࠶ࡿ ⪃࠼ࡽࢀࡿࡀ(Sugiura et al., 2014)ࠊ࢟ࣕࣆ࣮ࣛࣜ㟁ẼὋືᆺ㉁㔞ศᯒィ(CE-MS) ࡞⏕Ꮫⓗᡭἲ⤌ࡳྜࢃࡏࡿࡇࡼࡗ࡚ࠊᚤᑠ㡿ᇦ࡛ࡢ⣽⬊ෆ࢚ࢿࣝࢠ࣮௦ㅰ ࢆ᳨ฟࡍࡿࡇࡀྍ⬟࡛࠶ࡿ⪃࠼ࡽࢀࡿࠋࡇࢀࡽࡢᡭἲࢆ⏝࠸࡚ࠊ➹⪅㐩ࡢ◊✲ᐊ ࡛ゎᯒࡋ࡚࠸ࡿࡼ࠺࡞Ⓨ⏕ࡢࡼ࠺࡞ẚ㍑ⓗᑠࡉ࡞⤌⧊ࢆᑐ㇟ࡍࡿ⏕≀Ꮫⓗ㇟ࡶ᫂ ࡽ࡞ࡿ⪃࠼ࡽࢀࡿࠋ 㸳㸬ㅰ㎡ ࢢࣜࢥ࣮ࢤࣥᑐࡍࡿࣔࣀࢡ࣮ࣟࢼࣝᢠయࢆ౪㡬࠸ࡓዟ⩚Ꮫ 㤿ሙ㯞ேᩍᤵឤ ㅰ⏦ࡋୖࡆࡲࡍࠋࡲࡓࠊ◊✲⯡ࡢ㐙⾜ᚚ༠ຊ࠸ࡓࡔ࠸ࡓி㒔ᗓ❧་⏕≀Ꮫᩍᐊ ࡢ᭷ᮧᘯẶࠊᕝぢ⨾㔛Ặឤㅰ⏦ࡋୖࡆࡲࡍࠋ
ཧ⪃ᩥ⊩
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