The impact of altered O-GlcNAcylation on fructose-derived metabolic derangements due to deletion of O-GlcNAc transferase in the hepatocytes.

• Project/Area Number: 24591350
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Metabolomics
• Research Institution: Shiga University of Medical Science
• Principal Investigator: SEKINE Osamu 滋賀医科大学, 医学部, 助教 (00402719)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000); Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2013: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2012: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: O-GlcNAc修飾 / 肝臓 / 果糖 / 糖・脂質代謝異常 / O-結合型糖修飾 / 肝蔵 / マイクロアレイ

Outline of Final Research Achievements

O-GlcNAcylation is characterized by the addition of O-linked β-N-acetylglucosamine to proteins and serves as an intracellular nutrient sensor for modulating cell functions. O-GlcNAc transferase (OGT) is a critical enzyme for O-GlcNAcylation. We found out that protein O-GlcNAcylation and expression of OGT was increased in the liver fed a high-fructose diet compared to a control diet related to elevation of the lipogenesis and metabolic disorders, associating to the susceptibility to high-fructose diet.
To examine the physiological role of O-GlcNAcylation in hepatocyte biology, hepatocyte-specific OGT-deleted mice (Ogt-KO) were generated by crossbreeding Ogt-flox mice with Albumin-Cre mice. Ogt-KO showed severe hepatocellular damage, proliferation of bile ducts and fibrosis.
Our results suggest that protein O-GlcNAcylation is a key modulator for nutrient-derived metabolism in the liver, and tuning of OGT-mediated protein O-GlcNAcylation is essential to maintain hepatocyte homeostasis.

Research Products

• [Journal Article] A high-fiber, low-fat diet improves periodontal disease markers in high-risk subjects: a pilot study. (2014)
  • Author(s): Kondo K, Ishikado A, Morino K, Nishio Y, Ugi S, Kajiwara S, Kurihara M, Iwakawa H, Nakao K, Uesaki S, Shigeta Y, Imanaka H, Yoshizaki T, Sekine O, Makino T, Maegawa H, King GL, Kashiwagi A.
  • Journal Title: Nutr Res. Volume: 34(6) Issue: 6 Pages: 491-498
  • DOI: 10.1016/j.nutres.2014.06.001
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] A fish-based diet intervention improves endothelial function in postmenopausal women with type 2 diabetes mellitus: a randomized crossover trial. (2014)
  • Author(s): Kondo K, Morino K, Nishio Y, Kondo M, Nakao K, Nakagawa F, Ishikado A, Sekine O, Yoshizaki T, Kashiwagi A, Ugi S, Maegawa H.
  • Journal Title: Metabolism. Volume: 63(7) Issue: 7 Pages: 930-940
  • DOI: 10.1016/j.metabol.2014.04.005
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] 4-Hydroxy hexenal derived from dietary n-3 polyunsaturated fatty acids induces anti-oxidative enzyme heme oxygenase-1 in multiple organs. (2014)
  • Author(s): Nakagawa F, Morino K, Ugi S, Ishikado A, Kondo K, Sato D, Konno S, Nemoto K, Kusunoki C, Sekine O, Sunagawa A, Kawamura M, Inoue N, Nishio Y, Maegawa H.
  • Journal Title: Biochem Biophys Res Commun. Volume: 443 Issue: 3 Pages: 991-996
  • DOI: 10.1016/j.bbrc.2013.12.085
  • Peer Reviewed
• [Journal Article] CCDC3 is specifically upregulated in omental adipose tissue in subjects with abdominal obesity. (2014)
  • Author(s): Satoshi Ugi, Shiro Maeda, Yoshihiro Kawamura, Masa-aki Kobayashi, Minako Imamura, Takeshi Yoshizaki, Katsutaro Morino, Osamu Sekine, Hiroshi Yamamoto, Toru Tani, Masatomo Rokushima, Atsunori Kashiwagi, Hiroshi Maegawa
  • Journal Title: Obesity Volume: 22 Issue: 4 Pages: 1070-1077
  • DOI: 10.1002/oby.20645
  • Peer Reviewed
• [Journal Article] 4-Hydroxy hexenal derived from docosahexaenoic acid protects endothelial cells via Nrf2 activation (2013)
  • Author(s): Ishikado A, Morino K, Nishio Y, Nakagawa F, Mukose A, Sono Y, Yoshioka N, Kondo K, Sekine O, Yoshizaki T, Ugi S, Uzu T, Kawai H, Makino T, Okamura T, Yamamoto M, Kashiwagi A, Maegawa H
  • Journal Title: PLoS One Volume: 8 Issue: 7 Pages: e69415-e69415
  • DOI: 10.1371/journal.pone.0069415
  • Peer Reviewed
• [Journal Article] Ezetimibe prevents hepatic steatosis induced by a high-fat but not a high-fructose diet. (2013)
  • Author(s): Ushio M, Nishio Y, Sekine O, Nagai Y, Maeno Y, Ugi S, Yoshizaki T, Morino K, Kume S, Kashiwagi A, Maegawa H.
  • Journal Title: Am J Physiol Endocrinol Metab. Volume: 305 Issue: 2 Pages: E293-E304
  • DOI: 10.1152/ajpendo.00442.2012
  • Peer Reviewed
• [Journal Article] Omega-3 polyunsaturated fatty acid has an anti-oxidant effect via the Nrf-2/HO-1 pathway in 3T3-L1 adipocytes. (2012)
  • Author(s): Kusunoki C, Yang L, Yoshizaki T, Nakagawa F, Ishikado A, Kondo M, Morino K, Sekine O, Ugi S, Nishio Y, Kashiwagi A, Maegawa H.
  • Journal Title: Biochem Biophys Res Commun. Volume: 430 Issue: 1 Pages: 225-230
  • DOI: 10.1016/j.bbrc.2012.10.115
  • Peer Reviewed
• [Journal Article] Autophagy regulates inflammation in adipocytes (2012)
  • Author(s): Yoshizaki T, Maegawa H., et al
  • Journal Title: Biochem Biophys Res Commun Volume: 417 Issue: 1 Pages: 352-357
  • DOI: 10.1016/j.bbrc.2011.11.114
  • Peer Reviewed
• [Presentation] ２型糖尿病患者におけるDUALSCANを用いた内臓脂肪面積測定の有用性 (2014)
  • Author(s): 関根 理、近藤 慶子、根本 憲一、楠 知里、森野 勝太郎、卯木 智、前川 聡
  • Organizer: 第46回日本動脈硬化学会
  • Place of Presentation: 東京
  • Year and Date: 2014-07-10
• [Presentation] 当院外来患者におけるエゼチミブ投与の効果の検証－スタチン系薬剤との比較-
  • Author(s): 関根 理、他
  • Organizer: 第56回日本糖尿病学会年次学術集会
  • Place of Presentation: 熊本
• [Presentation] Docosahexaenoic acidの血管平滑筋細胞への作用
  • Author(s): 関根 理、他
  • Organizer: 第45回日本動脈硬化学会
  • Place of Presentation: 東京
• [Presentation] マウス系統間で、果糖摂取による肝臓内核蛋白のO-結合型糖修飾の機構に差異を認める
  • Author(s): 関根 理、他
  • Organizer: 第55回日本糖尿病学会年次学術集会
  • Place of Presentation: 横浜
• [Presentation] ω3多価不飽和脂肪酸の血管平滑筋細胞への作用
  • Author(s): 関根 理、他
  • Organizer: 第27回日本糖尿病合併症学会
  • Place of Presentation: 博多
• [Book] Modern Physician ３５巻１号 (2015)
  • Author(s): 関根 理、前川 聡
  • Total Pages: 5
  • Publisher: 新興医学出版社
• [Book] 糖尿病治療薬併用療法を究める インクレチン関連薬＋α (2013)
  • Author(s): 関根 理、前川 聡
  • Total Pages: 7
  • Publisher: 日本医事新報社