The molecular mechanism that CREBH activation by nutrition improves metabolic syndrome

• Project/Area Number: 22300234
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Applied health science
• Research Institution: University of Tsukuba
• Principal Investigator: NAKAGAWA Yoshimi 筑波大学, 医学医療系, 講師 (80361351)
• Co-Investigator(Kenkyū-buntansha): SHIMANO Hitoshi 筑波大学, 医学医療系, 教授 (20251241) ; MATSUZAKA Takashi 筑波大学, 医学医療系, 准教授 (70400679) ; ISHII Kiyoaki 筑波大学, 医学医療系, 助教 (80419150)
• Project Period (FY): 2010 – 2012
• Project Status: Completed (Fiscal Year 2012)
• Budget Amount: ¥18,200,000 (Direct Cost: ¥14,000,000、Indirect Cost: ¥4,200,000); Fiscal Year 2012: ¥6,110,000 (Direct Cost: ¥4,700,000、Indirect Cost: ¥1,410,000); Fiscal Year 2011: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2010: ¥6,890,000 (Direct Cost: ¥5,300,000、Indirect Cost: ¥1,590,000)
• Keywords: 生活習慣病 / エネルギー代謝 / 転写調節 / 遺伝子発現 / 転写因子 / 糖代謝 / 脂質代謝 / CREBH / FGF21 / PPARα / 栄養代謝

Research Abstract

Transcriptional regulation of metabolic genes in the liver is the key to maintaining systemic energy homeostasis. Here we demonstrate that a membrane-bound transcription factor, cAMP responsive element binding protein-H (CREBH), is activated during fasting, which mediates a wide spectrum of metabolic responses to starvation. Adenoviral and transgenic overexpression of CREBH reduces plasma lipid and glucose levels and body weight in both normal and diabetic obese mice. CREBH directly transactivates fibroblast growth factor 21 and its plasma level, which is at least partially attributed to these effects of CREBH on the systemic energy homeostasis.

Research Products

• [Journal Article] TFE3 inhibits myoblast differentiation in C2C12 cells via down-regulating gene expression of myogenin. (2013)
  • Author(s): Naka A, Iida K, Nakagawa Y, Iwasaki H, Takeuchi Y, Satoh A, Matsuzaka T, Ishii KA, Kobayashi K, Yatoh S, Shimada M, Yahagi N, Suzuki H, Sone H, Yamada N, Shimano H.
  • Journal Title: Biochem Biophys Res Commun. Volume: (in press)
  • Peer Reviewed
• [Journal Article] Elovl6 promotes nonalcoholic steatohepatitis in mice and humans. (2013)
  • Author(s): Matsuzaka T, Atsumi A, Matsumori R, Nie T, Shinozaki H, Suzuki-Kemuriyama N, Kuba M, Nakagawa Y, Ishii K, Shimada M, Kobayashi K, Yatoh S, Takahashi A, Takekoshi K, Sone H, Yahagi N, Suzuki H, Murata S, Nakamuta M, Yamada N, Shimano H.
  • Journal Title: Hepatology Volume: (in press)
  • Peer Reviewed
• [Journal Article] Dicer has a crucial role in the early stage of adipocyte differentiation, but not in lipid synthesis, in 3T3-L1 cells. (2012)
  • Author(s): Fujimoto Y, Nakagawa Y, Shingyouchi A, Tokushige N, Nakanishi N, Satoh A, Matsuzaka T, Ishii KA, Iwasaki H, Kobayashi K, Yatoh S, Suzuki H, Yahagi N, Urayama O, Yamada N, Shimano H.
  • Journal Title: Biochem Biophys Res Commun. Volume: 420(4) Pages: 931-6
  • Peer Reviewed
• [Journal Article] TFE3 Regulates Muscle Metabolic Gene Expression, Increases Glycogen Stores, and Enhances Insulin Sensitivity in Mice. (2012)
  • Author(s): Iwasaki H, Naka A, Iida K, Nakagawa Y, Matsuzaka T, Ishii KA, Kobayashi K, Takahashi A, Yatoh S, Yahagi N, Sone H, Suzuki H, Yamada N, Shimano H.
  • Journal Title: Am J Physiol Endocrinol Metab. Volume: 302(7)
  • Peer Reviewed
• [Journal Article] TFE3 regulates muscle metabolic gene expression, increases glycogen stores, and enhances insulin sensitivity in mice (2012)
  • Author(s): Iwasaki H, et al.
  • Journal Title: Am J Physiol Endocrinol Metab Volume: 302
  • Peer Reviewed
• [Journal Article] Inhibition of ubiquitin ligase F-box and WD repeat domain-containing 7α (Fbw7α) causes hepatosteatosis through Kruppel-like factor 5 (KLF5)/peroxisome proliferator-activated receptor γ2 (PPARγ2) pathway but not SREBP-1c protein in mice. (2011)
  • Author(s): Kumadaki S, Karasawa T, Matsuzaka T, Ema M, Nakagawa Y, Nakakuki M, Saito R, Yahagi N, Iwasaki H, Sone H, Takekoshi K, Yatoh S, Kobayashi K, Takahashi A, Suzuki H, Takahashi S, Yamada N, Shimano H.
  • Journal Title: J Biol Chem. Volume: 286(47)
  • Peer Reviewed
• [Journal Article] Macrophage Elovl6 deficiency ameliorates foam cell formation and reduces atherosclerosis in low-density lipoprotein receptor-deficient mice. (2011)
  • Author(s): Saito R, Matsuzaka T, Karasawa T, Sekiya M, Okada N, Igarashi M, Matsumori R, Ishii K, Nakagawa Y, Iwasaki H, Kobayashi K, Yatoh S, Takahashi A, Sone H, Suzuki H, Yahagi N, Yamada N, Shimano H.
  • Journal Title: Arterioscler Thromb Vasc Biol. Volume: 31(9) Pages: 1973-9
  • Peer Reviewed
• [Journal Article] Sterol regulatory element-binding protein-1 determines plasma remnant lipoproteins and accelerates atherosclerosis in low-density lipoprotein receptor-deficient mice. (2011)
  • Author(s): Karasawa T, Takahashi A, Saito R, Sekiya M, Igarashi M, Iwasaki H, Miyahara S, Koyasu S, Nakagawa Y, Ishii K, Matsuzaka T, Kobayashi K, Yahagi N, Takekoshi K, Sone H, Yatoh S, Suzuki H, Yamada N, Shimano H.
  • Journal Title: Arterioscler Thromb Vasc Biol. Volume: 31(8) Pages: 1788-95
  • Peer Reviewed
• [Journal Article] Inhibition of ubiquitin ligase F-box and WD repeat domain-containing 7α (Fbw7α) causes hepatosteatosis through Kruppel-like factor 5 (KLF5)/peroxisome proliferator-activated receptor γ2 (PPARγ2) pathway but not SREBP-1c protein in mice (2011)
  • Author(s): Kumadaki S, et al.
  • Journal Title: J Biol Chem Volume: 286 Pages: 40835-46
  • Peer Reviewed
• [Journal Article] Macrophage Elovl6 deficiency ameliorates foam cell formation and reduces atherosclerosis in low-density lipoprotein receptor-deficient mice (2011)
  • Author(s): Saito R, et al.
  • Journal Title: Arterioscler Thromb Vase Biol Volume: 31 Pages: 1973-9
  • Peer Reviewed
• [Journal Article] Sterol regulatory element-binding protein-1 determines plasma remnant lipoproteins and accelerates atherosclerosis in low-density lipoprotein receptor-deficient mice (2011)
  • Author(s): Karasawa T, et al.
  • Journal Title: Arterioscler Thromb Vase Biol Volume: 31 Pages: 1788-95
  • Peer Reviewed
• [Journal Article] Protein kinase Cbeta mediates hepatic induction of sterol regulatory element-binding protein-1c by insulin. (2010)
  • Author(s): Yamamoto T, Watanabe K, Inoue N, Nakagawa Y, Ishigaki N, Matsuzaka T, Takeuchi Y, Kobayashi K, Yatoh S, Takahashi A, Suzuki H, Yahagi N, Gotoda T, Yamada N, Shimano H.
  • Journal Title: J Lipid Res. Volume: 51(7) Pages: 1859-70
  • Peer Reviewed
• [Journal Article] Polyunsaturated fatty acids selectively suppress sterol regulatory element-binding protein-1 through proteolytic processing and autoloop regulatory circuit. (2010)
  • Author(s): Takeuchi Y, Yahagi N, Izumida Y, Nishi M, Kubota M, Teraoka Y, Yamamoto T, Matsuzaka T, Nakagawa Y, Sekiya M, Iizuka Y, Ohashi K, Osuga JI, Gotoda T, Ishibashi S, Itaka K, Kataoka K, Nagai R, Yamada N, Kadowaki T, Shimano H.
  • Journal Title: J Biol Chem. Volume: 285(15) Pages: 11681-91
  • Peer Reviewed
• [Journal Article] The liver-enriched transcription factor CREBH is nutritionally regulated and activated by fatty acids and PPARalpha. (2010)
  • Author(s): Danno H, Ishii KA, Nakagawa Y, Mikami M, Yamamoto T, Yabe S, Furusawa M, Kumadaki S, Watanabe K, Shimizu H, Matsuzaka T, Kobayashi K, Takahashi A, Yatoh S, Suzuki H, Yamada N, Shimano H.
  • Journal Title: Biochem Biophys Res Commun. Volume: 391(2) Pages: 1222-7
  • Peer Reviewed
• [Journal Article] Theliver-enriched transcription factor CREBH is nutritionally regulated and activated by fatty acids and PPARalpha. (2010)
  • Author(s): Danno H, etal
  • Journal Title: Biochem Biophys Res Commun. Volume: 391(2) Pages: 1222-1227
  • Peer Reviewed
• [Presentation] 糖・脂質代謝調節における絶食応答転写因子CREBHの機能 (2013)
  • Author(s): 中川 嘉、島野 仁
  • Organizer: 第56回日本糖尿病学会
  • Place of Presentation: 熊本 シンポジウム
  • Year and Date: 2013-05-17
• [Presentation] 糖・脂質代謝調節におけるCREBH-PPARa相互作用の解明 (2013)
  • Author(s): 中川 嘉、佐 藤 葵、松坂 賢、岩崎 仁、小林 和人、矢藤 繁、嶋田 昌子、矢作 直也、山田 信博、鈴木 浩明、島野 仁
  • Place of Presentation: 熊本
  • Year and Date: 2013-05-16
• [Presentation] CREBH によるエネルギー代謝調節機構と生活習慣病に対する機能の解明 (2011)
  • Author(s): 中川 嘉、山田 信博
  • Organizer: 第32回日本肥満学会
  • Place of Presentation: 淡路島
  • Year and Date: 2011-09-23
• [Presentation] 生活習慣病における脂質代謝制御因子CREBH の機能解析 (2010)
  • Author(s): 徳重 直子,中川 嘉,三上 素樹,新行内晶子,藤本 ゆり,木綿 梢里,佐藤 葵,松坂 賢,石井 清朗、山田 信博,島野 仁
  • Organizer: BMB2010第33回日本分子生物学会年会第83回日本生化学会大会合同大会
  • Place of Presentation: 神戸
  • Year and Date: 2010-12-10
• [Presentation] 肥満病態モデルマウスにおける糖・脂質代謝制御因子CREBH の影響 (2010)
  • Author(s): 藤本 ゆり,中川 嘉,徳重 直子,三上 素樹,新行内 晶子,木綿 梢里,佐藤 葵,松坂 賢,石井 清朗,山田 信博,島野 仁
  • Organizer: BMB2010 第33回日本分子生物学会年会第83回日本生化学会大会合同大会
  • Place of Presentation: 神戸
  • Year and Date: 2010-12-10
• [Presentation] The liver-enriched transcriptionfactor CREBH is nutritionally regulated and activated by fatty acids and PPARa in vitro and in vivo. (2010)
  • Author(s): 三上 素樹,中川 嘉,徳重 直子,新行内晶子,木綿 梢里,藤本 ゆり,佐藤 葵,松坂 賢,石井 清朗,山 田 信博,島野 仁
  • Organizer: BMB2010第33回日本分子生物学会年会第83回日本生化学会大会合同大会
  • Place of Presentation: 神戸
  • Year and Date: 2010-12-09
• [Presentation] CREBH is the new regulator of hepatic gene expression in fasted state (2010)
  • Author(s): Yoshimi Nakagawa, Motoki Mikami, Akiko Shingyouuchi,Naoko Tokushige, Nobuhiro Yamada, Hitoshi Shimano
  • Organizer: 第42回日本動脈硬化学会総会・学術集会
  • Place of Presentation: 岐阜
  • Year and Date: 2010-07-15
• [Presentation] 糖・脂質代謝調節におけるCREBH-PPARa相互作用の解明
  • Author(s): 中川 嘉
  • Organizer: 日本糖尿病学会
  • Place of Presentation: 熊本
• [Presentation] 糖・脂質代謝調節における絶食応答転写因子CREBHの機能
  • Author(s): 中川 嘉
  • Organizer: 日本糖尿病学会
  • Place of Presentation: 熊本
  • Invited
• [Book] FGF21と糖代謝 Annual Review 糖尿病・代謝・内分泌2013 (2013)
  • Author(s): 中川 嘉、菊池 琢哉、島野 仁
  • Publisher: 中外医学社
• [Book] 絶食時の肝における遺伝子発現応答 (第1土曜特集 エネルギー代謝転写因子ネットワークと生活習慣病) -- (臓器・疾患別にみた転写因子の展開)The hepatic homeostasis by transcription factors in fasted condition 医学のあゆみ237(6) (2011)
  • Author(s): 中川 嘉、島野 仁
  • Publisher: 医歯薬出版
• [Remarks] 筑波大学 医学医療系 内分泌代謝・糖尿病内科
  • URL: http://www.u-tsukuba-endocrinology.jp/
• [Remarks] 筑波大学 内分泌代謝・糖尿病内科
  • URL: http://www.u-tsukuba-endocrinology.jp/
• [Remarks]
  • URL: http://www.u-tsukuba-endocrinology.jp/index.html
• [Remarks]
  • URL: http://www.md.tsukuba.ac.jp/clinical-med/endocrinology/research/