Glycan Modification Analysis as a Novel Diagnostic Marker and Therapeutic Target for Non-Alcoholic Fatty Liver Disease

• Project/Area Number: 20K08298
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 53010:Gastroenterology-related
• Research Institution: Hokkaido University
• Principal Investigator: Ogawa Koji 北海道大学, 大学病院, 助教 (20735188)
• Co-Investigator(Kenkyū-buntansha): 坂本 直哉 北海道大学, 医学研究院, 教授 (10334418) ; 須田 剛生 北海道大学, 大学病院, 特任助教 (20447460)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2022: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2021: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2020: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: NASH / 糖鎖 / 肝線維化 / 糖鎖マーカー / NAFLD / バイオマーカー

Outline of Research at the Start

申請者らはNASH新規診断マーカーとして、網羅的な複合糖質糖鎖解析から肝逸脱酵素と関連のなく肝における炎症を鋭敏に反映する血清糖鎖マーカーAAT-A3Fを見出した。本研究では、１）NASH 診断、病態反映マーカーであるAATA3Fの診断マーカー、病態進展予測マーカ―としての検討、2) AAT-A3F上昇に関与する因子の検討、3）NAFLD/NASH症例において特異的に上昇する糖化蛋白の網羅的な解析により同定したNASH症例のみにおいてのみ上昇する複数の糖化蛋白のNASH病態進展への影響の検討、を行い精度の高いNASH診断、病態進展マーカーの確立とNASH治療の新規治療標的の萌芽となる検討を行う

Outline of Final Research Achievements

The development of non-invasive diagnostic methods is urgently needed for the diagnosis and understanding of non-alcoholic steatohepatitis (NASH), as liver biopsy remains the only available diagnostic method. In this study, we performed comprehensive glycomic analysis (integrated glycomics) of serum samples from patients diagnosed with NAFL (non-alcoholic fatty liver) and NASH using a unique approach that goes beyond liver enzyme analysis. As a result, we discovered a novel serum glycan marker, AAT-A3F, which reflects liver inflammation sensitively without being correlated with liver enzyme levels. We further demonstrated that the serum AAT-A3F level correlates with the expression of inflammatory cytokines in liver cells and liver tissue inflammation, enabling the diagnosis of early-stage NASH. Our findings confirm that AAT-A3F, as a novel diagnostic and pathophysiological marker for NASH, can detect early-stage pathological changes associated with NASH progression.

Academic Significance and Societal Importance of the Research Achievements

非アルコール性脂肪性肝疾患は、肥満人口の増加に伴い世界的な公衆衛生上の問題となる。NAFLDは、非アルコール性脂肪肝（NAFL）と非アルコール性脂肪性肝（NASH）に分類されNAFLDの一部は、NASH、肝硬変、肝細胞癌へと進展する予後不良な病態をたどるため、早期に高リスク症例の囲い込みが必須である。この血清AAT-A3F値と既存の、診断マーカー統合し解析する事により、非侵襲的なNASH診断への開発の萌芽となりうる。

Research Products

• [Journal Article] Hepatitis C virus eradication by direct‐acting antivirals causes a simultaneous increase in the prevalence of fatty liver and hyper low‐density lipoprotein cholesterolemia without an increase in body weight (2023)
  • Author(s): Tokuchi Yoshimasa、Sho Takuya et al.,
  • Journal Title: Hepatology Research Volume: in press Issue: 7 Pages: 595-606
  • DOI: 10.1111/hepr.13899
  • Peer Reviewed
• [Journal Article] Changes in Serum Growth Factors during Resistance to Atezolizumab Plus Bevacizumab Treatment in Patients with Unresectable Hepatocellular Carcinoma (2023)
  • Author(s): Yang Zijian、Suda Goki、Maehara Osamu、Ohara Masatsugu、Yoda Tomoka、Sasaki Takashi、Kohya Risako、Yoshida Sonoe、Hosoda Shunichi、Tokuchi Yoshimasa、Kitagataya Takashi、Suzuki Kazuharu、Kawagishi Naoki、Nakai Masato、Sho Takuya、Natsuizaka Mitsuteru、Ogawa Koji、Ohnishi Shunsuke、Sakamoto Naoya
  • Journal Title: Cancers Volume: 15 Issue: 3 Pages: 593-593
  • DOI: 10.3390/cancers15030593
  • Peer Reviewed / Open Access
• [Journal Article] Serum Angiopoietin-2 Predicts the Occurrence and Recurrence of Hepatocellular Carcinoma after Direct-Acting Antiviral Therapy for Hepatitis C (2023)
  • Author(s): Kawagishi Naoki、Suda Goki、Yamamoto Yoshiya、Baba Masaru、Furuya Ken、Maehara Osamu、Ohnishi Shunsuke、Yoshida Sonoe、Fu Qingjie、Yang Zijian、Hosoda Shunichi、Tokuchi Yoshimasa、Kitagataya Takashi、Ohara Masatsugu、Suzuki Kazuharu、Nakai Masato、Sho Takuya、Natsuizaka Mitsuteru、Ogawa Koji、Sakamoto Naoya
  • Journal Title: Viruses Volume: 15 Issue: 1 Pages: 181-181
  • DOI: 10.3390/v15010181
  • Peer Reviewed / Open Access
• [Journal Article] Prophylactic tenofovir alafenamide for hepatitis B virus reactivation and reactivation‐related hepatitis (2023)
  • Author(s): Suda Goki、et al.,
  • Journal Title: Journal of Medical Virology Volume: 95 Issue: 2
  • DOI: 10.1002/jmv.28452
  • Peer Reviewed
• [Journal Article] Serum IL-1β predicts de novo hepatitis B virus reactivation during direct-acting antiviral therapy for hepatitis C, not during anti-cancer/immunosuppressive therapy (2022)
  • Author(s): Kawagishi Naoki、Suda Goki et al.,
  • Journal Title: Scientific Reports Volume: 12 Issue: 1
  • DOI: 10.1038/s41598-022-21315-z
  • Peer Reviewed / Open Access
• [Journal Article] Serum fatty acid-binding protein 5 is a significant factor in hepatocellular carcinoma progression independent of tissue expression level (2021)
  • Author(s): Ohira Masafumi、Yokoo Hideki、Ogawa Koji、Fukai Moto、Kamiyama Toshiya、Sakamoto Naoya、Taketomi Akinobu
  • Journal Title: Carcinogenesis Volume: 42 Issue: 6 Pages: 794-803
  • DOI: 10.1093/carcin/bgab025
  • Peer Reviewed
• [Journal Article] Baseline elevated serum angiopoietin-2 predicts long-term non-regression of liver fibrosis after direct-acting antiviral therapy for hepatitis C (2021)
  • Author(s): Kawagishi Naoki、Suda Goki、Kimura Megumi、Maehara Osamu、Yamada Ren、Tokuchi Yoshimasa、Kubo Akinori、Kitagataya Takashi、Shigesawa Taku、Suzuki Kazuharu、Ohara Masatsugu、Nakai Masato、Sho Takuya、Natsuizaka Mitsuteru、Morikawa Kenichi、Ogawa Koji、Kudo Yusuke、Nishida Mutsumi、Sakamoto Naoya
  • Journal Title: Scientific Reports Volume: 11 Issue: 1 Pages: 9207-9207
  • DOI: 10.1038/s41598-021-88632-7
  • Peer Reviewed / Open Access
• [Journal Article] Characteristics and Lenvatinib Treatment Response of Unresectable Hepatocellular Carcinoma with Iso-High Intensity in the Hepatobiliary Phase of EOB-MRI (2021)
  • Author(s): Kubo Akinori、Suda Goki、Kimura Megumi、Maehara Osamu、Tokuchi Yoshimasa、Kitagataya Takashi、Ohara Masatsugu、Yamada Ren、Shigesawa Taku、Suzuki Kazuharu、Kawagishi Naoki、Nakai Masato、Sho Takuya、Natsuizaka Mitsuteru、Morikawa Kenichi、Ogawa Koji、Ohnishi Shunsuke、Sakamoto Naoya
  • Journal Title: Cancers Volume: 13 Issue: 14 Pages: 3633-3633
  • DOI: 10.3390/cancers13143633
  • Peer Reviewed / Open Access
• [Journal Article] Possible correlation between increased serum free carnitine levels and increased skeletal muscle mass following HCV eradication by direct acting antivirals (2021)
  • Author(s): Tokuchi Yoshimasa、Suda Goki、et al.,
  • Journal Title: Scientific Reports Volume: 11 Issue: 1 Pages: 16616-16616
  • DOI: 10.1038/s41598-021-96203-z
  • Peer Reviewed / Open Access
• [Journal Article] Changes in the estimated renal function after hepatitis C virus eradication with direct-acting antiviral agents: Impact of changes in skeletal muscle mass (2021)
  • Author(s): Tokuchi Y, Suda G, Kimura M, Maehara O, Kitagataya T, Ohara M, Yamada R, Shigesawa T, Suzuki K, Kawagishi N, Nakai M, Sho T, Natsuizaka M, Morikawa K, Ogawa K, Sakamoto N.
  • Journal Title: J Viral Hepat. Volume: in press Issue: 5 Pages: 755-763
  • DOI: 10.1111/jvh.13484
  • Peer Reviewed
• [Journal Article] Durable response without recurrence to Tolvaptan improves long-term survival (2020)
  • Author(s): Nakai M, Suda G, Kubo A, Tokuchi Y, Kitagataya T, Yamada R, Shigesawa T, Suzuki K, Nakamura A, Kawagishi N, Ohara M, Umemura M, Sho T, Morikawa K, Ogawa K, Sakamoto N.
  • Journal Title: J Gastroenterol. Volume: 55 Issue: 12 Pages: 1150-1161
  • DOI: 10.1007/s00535-020-01721-8
  • Peer Reviewed
• [Journal Article] Time-dependent changes in the seroprevalence of COVID-19 in asymptomatic liver disease outpatients in an area in Japan undergoing a second wave of COVID-19 (2020)
  • Author(s): Suda G, Ogawa K, Kimura M, Maehara O, Kitagataya T, Ohara M, Tokuchi Y, Kubo A, Yamada R, Shigesawa T, Suzuki K, Kawagishi N, Nakai M, Sho T, Natsuizaka M, Morikawa K, Sakamoto N.
  • Journal Title: Hepatol Res. Volume: 5- Issue: 10 Pages: 1196-1200
  • DOI: 10.1111/hepr.13551
  • Peer Reviewed
• [Journal Article] Analysis of the optimal psoas muscle mass index cut-off values, as measured by computed tomography, for the diagnosis of loss of skeletal muscle mass in Japanese people. (2020)
  • Author(s): Ohara M, Suda G, Kimura M, Maehara O, Shimazaki T, Shigesawa T, Suzuki K, Nakamura A, Kawagishi N, Nakai M, Sho T, Natsuizaka M, Morikawa K, Ogawa K, Kobayashi T, Uebayashi M, Takagi R, Yokota I, Shimamura T, Sakamoto N.
  • Journal Title: Hepatol Res Volume: in press Issue: 6 Pages: 715-725
  • DOI: 10.1111/hepr.13499
  • Peer Reviewed
• [Journal Article] Prevalence, clinical course, and predictive factors of immune checkpoint inhibitor monotherapy-associated hepatitis in Japan. (2020)
  • Author(s): Kitagataya T, Suda G, Nagashima K, Katsurada T, Yamamoto K, Kimura M, Maehara O, Yamada R, Shigesawa T, Suzuki K, Nakamura A, Ohara M, Umemura M, Kawagishi N, Nakai M, Sho T, Natsuizaka M, Morikawa K, Ogawa K, Ohnishi S, Komatsu Y, Hata H, Takeuchi S, Abe T, Sakakibara-Konishi J, Teshima T, Homma A, Sakamoto N.
  • Journal Title: J Gastroenterol Hepatol Volume: in press Issue: 10 Pages: 1782-1788
  • DOI: 10.1111/jgh.15041
  • NAID: 120007160309
  • Peer Reviewed