Role of membrane lipid-modulated signal transductions in endotoxin hyperresponse of fatty livers

• Project/Area Number: 20K07349
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 49010:Pathological biochemistry-related
• Research Institution: Institute of Physical and Chemical Research
• Principal Investigator: Qin Xian-Yang 国立研究開発法人理化学研究所, 生命医科学研究センター, 研究員 (60756815)
• Project Period (FY): 2020-04-01 – 2024-03-31
• Project Status: Completed (Fiscal Year 2023)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2022: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 非アルコール性脂肪性肝炎 / 脂肪肝 / トランスグルタミナーゼ / エンドトキシン / 微小環境 / マルチオミクス解析 / 酸化ストレス / コーンオリゴペプチド / ホスファチジルエタノールアミン / LIMK1 / in situイメージング / NASH / 膜脂質 / 膜タンパク質

Outline of Research at the Start

脂肪肝において腸管に由来する細菌性のエンドトキシンの過剰反応が亢進し、非アルコール性脂肪性肝炎の病態を進展させる。炎症刺激に応じて細胞膜脂質の飽和度が増加し、集合状態を変化させ、その中に硬くパッキングされた膜タンパク質を介してシングル伝達を調節し細胞機能を維持する。本申請では、分子間接着因子トランスグルタミナーゼTG2活性化のin vivoイメージング技術とMALDI-TOFMSを用いた脂質in vivoイメージングを活用し、脂肪肝を背景にしたエンドトキシンの過剰反応における膜脂質によるシグナル伝達経路の役割の解明を目的とする。

Outline of Final Research Achievements

Nonalcoholic steatohepatitis (NASH), characterized by accumulation of lipids and oxidative stress in the hepatocytes and continual liver damage, is believed will soon be the leading etiology of liver fibrosis and HCC. Hyperresponsivity to lipopolysaccharide (LPS) in fatty liver indicated to contribute to the progression of NASH, including hepatic inflammation and fibrosis, was observed in high-fat diet (HFD) mice compared with chow-fed mice. Transglutaminase (TG2) is a crosslinking enzyme that forms a covalent bond between lysine and glutamine. In this study, enhanced TG2 activation was selectively observed in liver macrophages in LPS-induced liver injury mouse models. By integrating lipidome, proteome and transcriptome analyses, a hepatic phosphatidylethanolamine-related membrane signaling network was established in NASH mouse models. Finally, liver protective functions were observed with TG2 activity inhibitors in sepsis-related liver injury and obesity and NASH mouse models.

Academic Significance and Societal Importance of the Research Achievements

正常肝組織では、TG2の発現が観察されたが、顕著なTG2の活性化は見られなかった。それに対して、敗血症関連肝障害やNASHマウスにおいて、肝マクロファージに特異的にTG2の活性化が観察された。TG2は特定の組織環境において異なる機能を持つことが示唆された。TG2活性化を指標としたマクロファージの追跡は、敗血症性や脂肪性肝炎の発症機序の解明並びに新規治療法の開発に繋がると期待される。

Research Products

• [Journal Article] Serum MYCN as a predictive biomarker of prognosis and therapeutic response in the prevention of hepatocellular carcinoma recurrence (2024)
  • Author(s): Qin XY, Shirakami Y, Honda M, Yeh SH, Numata K, Lai YY, Li CL, Wei F, Xu Y, Imai K, Takai K, Chuma M, Komatsu N, Furutani Y, Gailhouste L, Aikata H, Chayama K, Enomoto M, Tateishi R, Kawaguchi K, Yamashita T, Kaneko S, Nagaoka K, Tanaka M, Sasaki Y, Tanaka Y, Baba H, Miura K, Ochi S, Masaki T, et al
  • Journal Title: International Journal of Cancer Volume: － Issue: 3 Pages: 582-594
  • DOI: 10.1002/ijc.34893
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Corn Oligopeptide Alleviates Nonalcoholic Fatty Liver Disease by Regulating the Sirtuin Signaling Pathway (2024)
  • Author(s): Xu Yali、Su Ting、Mishra Hricha、Ando Reiko、Furutani Yutaka、Lu Jun、Cai Muyi、Suzuki Harukazu、Yu Wenkui、Qin Xian-Yang
  • Journal Title: Journal of Agricultural and Food Chemistry Volume: 72 Issue: 12 Pages: 6360-6371
  • DOI: 10.1021/acs.jafc.3c09058
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Transcriptome analysis of long non-coding RNAs in Mycobacterium avium complex?infected macrophages (2024)
  • Author(s): Yoshida Mitsunori、Kwon Andrew Taejun、Qin Xian-Yang、Nishimura Hajime、Maeda Shiori、Miyamoto Yuji、Yoshida Yasuhiro、Hoshino Yoshihiko、Suzuki Harukazu
  • Journal Title: Frontiers in Immunology Volume: 15 Pages: 1374437-1374437
  • DOI: 10.3389/fimmu.2024.1374437
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Targeting transglutaminase 2 mediated exostosin glycosyltransferase 1 signaling in liver cancer stem cells with acyclic retinoid (2023)
  • Author(s): Qin XY, Furutani Y, Yonezawa K, Shimizu N, Kato-Murayama M, Shirouzu M, Xu Y, Yamano Y, Wada A, Gailhouste L, Shrestha R, Takahashi M, Keillor JW, Su T, Yu W, Fujii S, Kagechika H, Dohmae N, Shirakami Y, Shimizu M, Masaki T, Matsuura T, Suzuki H, Kojima S
  • Journal Title: Cell Death & Disease Volume: 14 Issue: 6 Pages: 358-358
  • DOI: 10.1038/s41419-023-05847-4
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A small molecule iCDM-34 identified by in silico screening suppresses HBV DNA through activation of aryl hydrocarbon receptor (2023)
  • Author(s): Furutani Y, Hirano Y, Toguchi M, Higuchi S, Qin XY, Yanaka K, Sato-Shiozaki Y, Takahashi N, Sakai M, Kongpracha P, Suzuki T, Dohmae N, Kukimoto-Niino M, Shirouzu M, Nagamori S, Suzuki H, Kobayashi K, Masaki T, Koyama H, Sekiba K, Otsuka M, Koike K, Kohara M, Kojima S, Kakeya H, Matsuura T
  • Journal Title: Cell Death Discovery Volume: 9 Issue: 1 Pages: 467-467
  • DOI: 10.1038/s41420-023-01755-w
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Akkermansia muciniphila Alleviates Persistent Inflammation, Immunosuppression, and Catabolism Syndrome in Mice (2023)
  • Author(s): Xu Yali、Duan Jianfeng、Wang Dacheng、Liu Jiali、Chen Xiancheng、Qin Xian-Yang、Yu Wenkui
  • Journal Title: Metabolites Volume: 13 Issue: 2 Pages: 194-194
  • DOI: 10.3390/metabo13020194
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] iGEM as a human iPS cell-based global epigenetic modulation detection assay provides throughput characterization of chemicals affecting DNA methylation (2023)
  • Author(s): Otsuka Satoshi、Qin Xian-Yang、Wang Wenlong、Ito Tomohiro、Nansai Hiroko、Abe Kuniya、Fujibuchi Wataru、Nakao Yoichi、Sone Hideko
  • Journal Title: Scientific Reports Volume: 13 Issue: 1 Pages: 6663-6663
  • DOI: 10.1038/s41598-023-33729-4
  • Peer Reviewed / Open Access
• [Journal Article] Editorial: Cancer and nutrients: new chemicals, signals, and biomarker-based therapy (2023)
  • Author(s): Qin Xian-Yang、Mendoza-Parra Marco Antonio、Shirakami Yohei
  • Journal Title: Frontiers in Oncology Volume: 13 Pages: 190065-190065
  • DOI: 10.3389/fonc.2023.1190065
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Integrative Approaches of Bioassay and Computational Analysis for Discovering Potential Bioactive Compounds and Predictive Toxicity (2022)
  • Author(s): SONE Hideko、QIN Xian-Yang、HAYAMIZU Kohsuke、FUJIBUCHI Wataru、NAKAO Yoichi
  • Journal Title: Journal of Nutritional Science and Vitaminology Volume: 68 Issue: Supplement Pages: S131-S133
  • DOI: 10.3177/jnsv.68.S131
  • ISSN: 0301-4800, 1881-7742
  • Year and Date: 2022-11-30
• [Journal Article] Design, synthesis and antitumor activity of phthalazine-1,4-dione-based menaquinone analogs (2021)
  • Author(s): Fujii Shinya、Miura Takahiro、Oikawa Tsuyoshi、Qin Xian-Yang、Kojima Soichi、Kagechika Hiroyuki
  • Journal Title: Bioorganic and Medicinal Chemistry Letters Volume: 43 Pages: 128065-128065
  • DOI: 10.1016/j.bmcl.2021.128065
  • Peer Reviewed
• [Journal Article] Epigenetic reprogramming promotes the antiviral action of IFNα in HBV-infected cells (2021)
  • Author(s): Gailhouste Luc、Sudoh Masayuki、Qin Xian-Yang、Watashi Koichi、Wakita Takaji、Ochiya Takahiro、Matsuura Tomokazu、Kojima Soichi、Furutani Yutaka
  • Journal Title: Cell Death Discovery Volume: 7 Issue: 1 Pages: 130-130
  • DOI: 10.1038/s41420-021-00515-y
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Latency-associated Peptide Degradation Fragments Produced in Stellate Cells and Phagocytosed by Macrophages in Bile Duct-ligated Mouse Liver (2021)
  • Author(s): Inoue Ikuyo、Qin Xian-Yang、Masaki Takahiro、Mezaki Yoshihiro、Matsuura Tomokazu、Kojima Soichi、Furutani Yutaka
  • Journal Title: Journal of Histochemistry & Cytochemistry Volume: 69 Issue: 11 Pages: 723-730
  • DOI: 10.1369/00221554211053665
  • Peer Reviewed / Open Access
• [Journal Article] Establishment of a Rapid Detection System for ISG20-Dependent SARS-CoV-2 Subreplicon RNA Degradation Induced by Interferon-α (2021)
  • Author(s): Furutani Yutaka、Toguchi Mariko、Higuchi Shoko、Yanaka Kaori、Gailhouste Luc、Qin Xian-Yang、Masaki Takahiro、Ochi Sae、Matsuura Tomokazu
  • Journal Title: International Journal of Molecular Sciences Volume: 22 Issue: 21 Pages: 11641-11641
  • DOI: 10.3390/ijms222111641
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Transglutaminase 2 as a Marker for Inflammation and Therapeutic Target in Sepsis (2021)
  • Author(s): Su Ting、Qin Xian-Yang、Furutani Yutaka
  • Journal Title: International Journal of Molecular Sciences Volume: 22 Issue: 4 Pages: 1897-1897
  • DOI: 10.3390/ijms22041897
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Inhibition of Ganglioside Synthesis Suppressed Liver Cancer Cell Proliferation through Targeting Kinetochore Metaphase Signaling (2021)
  • Author(s): Su Ting、Qin Xian-Yang、Dohmae Naoshi、Wei Feifei、Furutani Yutaka、Kojima Soichi、Yu Wenkui
  • Journal Title: Metabolites Volume: 11 Issue: 3 Pages: 167-167
  • DOI: 10.3390/metabo11030167
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Non-Genomic Control of Dynamic MYCN Gene Expression in Liver Cancer (2021)
  • Author(s): Qin Xian-Yang、Gailhouste Luc
  • Journal Title: Frontiers in Oncology Volume: 10 Pages: 618515-618515
  • DOI: 10.3389/fonc.2020.618515
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Early Transcriptomic Changes upon Thalidomide Exposure Influence the Later Neuronal Development in Human Embryonic Stem Cell-Derived Spheres (2020)
  • Author(s): Kikegawa Mami、Qin Xian-Yang、Ito Tomohiro、Nishikawa Hiromi、Nansai Hiroko、Sone Hideko
  • Journal Title: International Journal of Molecular Sciences Volume: 21 Issue: 15 Pages: 5564-5564
  • DOI: 10.3390/ijms21155564
  • Peer Reviewed / Open Access
• [Presentation] 肝がんの治療と予後予測における血中MYCN測定の臨床的意義 (2023)
  • Author(s): 秦咸陽
  • Organizer: 第63回日本臨床化学会
  • Invited
• [Presentation] 空間オミクス解析を用いた脂肪性肝炎による肝発がん微小環境の解明とレチノイン酸シグナルの追跡 (2023)
  • Author(s): 秦咸陽、古谷裕、松浦知和、鈴木治和
  • Organizer: 第377回脂溶性ビタミン総合研究委員会
• [Presentation] 肝がん幹細胞マーカーMYCNの発見から創薬へ (2023)
  • Author(s): 秦咸陽
  • Organizer: 第887回千葉県がんセンター研究所集談会
• [Presentation] ガングリオシド合成を標的とした肝がん細胞増殖の抑制 (2023)
  • Author(s): 秦咸陽
  • Organizer: 日本がん分子標的治療学会第27回学術集会
• [Presentation] Chemoprevention by vitamin A and its derivatives (2022)
  • Author(s): Xian-Yang Qin
  • Organizer: 22nd IUNS-International Congress of Nutrition (22nd IUNS-ICN)
  • Int'l Joint Research / Invited
• [Presentation] トランスグルタミナーゼ2を標的とする肝がん幹細胞の増殖制御と分子機構解明 (2021)
  • Author(s): 秦咸陽，小嶋聡一
  • Organizer: 第25回日本がん分子標的治療学会学術集会
• [Presentation] 血中MYCNを指標として非環式レチノイドによる肝がん再発予防予測の後ろ向き試験 (2021)
  • Author(s): 秦咸陽，白上洋平，清水雅仁，古谷裕，政木隆博，松浦知和，小嶋聡一
  • Organizer: 日本レチノイド研究会第32回学術集会
• [Presentation] トランスグルタミナーゼを標的とした敗血症治療への応用と分子基盤の理解 (2021)
  • Author(s): 秦咸陽，Ting Su，古谷裕，小嶋聡一
  • Organizer: 第23回トランスグルタミナーゼ研究会
• [Presentation] Serum MYCN as a predictive biomarker of prognosis and therapeutic response in the prevention of hepatocellular carcinoma (2021)
  • Author(s): Xian-Yang Qin
  • Organizer: JDDW 2021 KOBE
• [Presentation] 分子間接着因子活性化のin vivoイメージングによるエンドトキシン刺激肝臓の微小環境解析 (2020)
  • Author(s): 秦咸陽、古谷裕
  • Organizer: 第56回日本肝臓学会総会
• [Presentation] 肝がんの診断と予後予測における組織中・血中MYCN発現の臨床的意義 (2020)
  • Author(s): 秦咸陽、小嶋聡一
  • Organizer: 日本がん分子標的治療学会第24回学術集会
• [Presentation] 非環式レチノイドによる肝癌幹細胞排除における細胞内局在に依存したトランスグルタミナーゼ2の活性制御 (2020)
  • Author(s): 秦咸陽、古谷裕、小嶋聡一
  • Organizer: 日本レチノイド研究会第31回学術集会
• [Remarks] 肝がん予防のための患者層別化マーカーを発見
  • URL: https://www.riken.jp/press/2024/20240228_2/index.html
• [Remarks] トウモロコシ由来化合物で肥満や脂肪肝を改善
  • URL: https://www.riken.jp/press/2024/20240325_1/index.html
• [Remarks] MAC感染で働くロングノンコーディングRNA
  • URL: https://www.riken.jp/press/2024/20240425_1/index.html
• [Remarks] 肝がん再発予防薬の標的タンパク質を同定
  • URL: https://www.riken.jp/press/2023/20230613_1/index.html