Identification of novel treatment and biomarkers based on pharmacokinetics in patients with hepatocellular carcinoma

2017 Fiscal Year Annual Research Report

• Project/Area Number: 15K08077
• Research Institution: Nara Medical University
• Principal Investigator: 浪崎 正 奈良県立医科大学, 医学部, 講師 (20526850)
• Co-Investigator(Kenkyū-buntansha): 野口 隆一 奈良県立医科大学, 医学部附属病院, 研究員 (30423908) ; 吉治 仁志 奈良県立医科大学, 医学部, 教授 (40336855) ; 北出 光輝 奈良県立医科大学, 医学部, 学内講師 (40526795)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Keywords: 肝線維化 / 胆汁酸

Outline of Annual Research Achievements

我々はこれまでにウルソデオキシコール酸のエンドトキシン制御による肝TLR4細胞内シグナル伝達経路阻害およびアンジオテンシンII受容体阻害薬(ARB)の活性化肝星細胞(Ac-HSC)に対する直接作用の協調効果により非アルコール性脂肪肝炎 (NASH)肝線維化進展を著明に抑制することを報告してきた Namisaki T et al. J Gastroenterol (2016)。近年NASHに対するFXR agonist(オベチコール酸:OCA)の臨床応用が進みつつあるが、単剤での抗線維化効果は限定的であることも指摘されている。今回、OCAおよびARB併用によるNASH肝線維化進展抑制効果をAc-HSCへの作用を中心に検討した。
肥満性2型糖尿病モデルラットにブタ血清(0.5ml/kg)を週2回、8週間腹腔内投与して実験的肝線維症を作成し、OCAおよびARBの影響を組織学的、および活性化肝星細胞(Ac-HSC)への作用をαSMA免疫染色で検討した。また、肝TGFβ1、Collagen-I、TLR4、LPS binding protein (LBP)、FXR、PPARγ、および小腸TLR4のmRNA発現をreal-time PCR法で比較検討した。OCA群およびARB群では対照群に比し、肝線維化およびAc-HSC数が有意に抑制され、併用群では顕著な抑制効果が認められた。肝TGFβ1、Collagen-IおよびTLR4発現は肝線維化とほぼ平行して抑制された。肝LBP発現はOCA群および併用群で有意に抑制され、肝FXRおよびPPARγ発現は両群で有意な上昇を認めた。
肝癌発症予防を含めたNASH病態進展抑制に対する治療法としてOCAとARBの併用療法が効果的である可能性が示唆された。以上を hepatology communication 2017年9月に報告した。

Research Products

• [Journal Article] Effect of combined farnesoid X receptor agonist and angiotensin II type 1 receptor blocker on hepatic fibrosis (2017)
  • Author(s): Namisaki T, Moriya K, Kitade M, Takeda K, Kaji K, Okura Y, Shimozato N, Sato S, Nishimura N, Seki K, Kawaratani H, Takaya H, Sawada Y, Akahane T, Saikawa S, Nakanishi K, Kubo T, Furukawa M, Noguchi R, Asada K, Kitagawa K, Ozutsumi T, Tsuji Y, Kaya D, Fujinaga Y, Yoshiji H.
  • Journal Title: Hepatology Communications Volume: 1 Pages: 928～945
  • DOI: 10.1002/hep4.1104
  • Peer Reviewed / Open Access
• [Journal Article] Genome-Wide Association Study Identifies TLL1 Variant Associated With Development of Hepatocellular Carcinoma After Eradication of Hepatitis C Virus Infection. (2017)
  • Author(s): Matsuura K, Ogawa S, Iio E, Isogawa M, Shimada N
  • Journal Title: Gastroenterology Volume: 152 Pages: 1383～1394
  • DOI: 10.1053/j.gastro.2017.01.041
  • Peer Reviewed
• [Journal Article] Clinical significance of the Scheuer histological staging system for primary biliary cholangitis in Japanese patients. (2017)
  • Author(s): Namisaki T, Moriya K, Kitade M, Kawaratani H, Takeda K, Okura Y, Takaya H, Nishimura N, Seki K, Kaji K, Sato S, Sawada Y, Yamao J, Mitoro A, Uejima M, Mashitani T, Shimozato N, Nakanishi K, Furukawa M, Saikawa S, Kubo T, Yoshiji H.
  • Journal Title: Eur J Gastroenterol Hepatol. Volume: 29 Pages: 23-30
  • Peer Reviewed
• [Journal Article] Combined treatment with dipeptidyl peptidase-4 inhibitor (sitagliptin) and angiotensin-II type 1 receptor blocker (losartan) suppresses progression in a non-diabetic rat model of steatohepatitis. (2017)
  • Author(s): Okura Y, Namisaki T, Moriya K, Kitade M, Takeda K, Kaji K, Noguchi R, Nishimura N, Seki K, Kawaratani H, Takaya H, Sato S, Sawada Y, Shimozato N, Furukawa M, Nakanishi K, Saikawa S, Kubo T, Asada K, Yoshiji H.
  • Journal Title: Hepatol Res Volume: 47 Pages: 1317-1328
  • DOI: doi: 10.1111/hepr.12860
  • Peer Reviewed
• [Journal Article] Sodium glucose cotransporter 2 inhibitor canagliflozin attenuates liver cancer cell growth and angiogenic activity by inhibiting glucose uptake (2017)
  • Author(s): Kaji K, Nishimura N, Seki K, Sato S, Saikawa S, Nakanishi K, Furukawa M, Kawaratani H, Kitade M, Moriya K, Namisaki T, Yoshiji H.
  • Journal Title: Int J Cancer Volume: 142 Pages: 1712-1722
  • DOI: doi: 10.1007/s00535-015-1104-x
  • Peer Reviewed
• [Presentation] Effect of nalfurafine hydrochloride for refractory pruritus in patients with primary biliary cholangitis: a multicenter, postmarketing single-arm, prospective study (2018)
  • Author(s): Yagi M, Tanaka A, Namisaki T, Abe M, Takahashi A, Honda A, Matsuzaki Y, Ohira H, Yoshiji H, Takikawa H
  • Organizer: EASL
  • Int'l Joint Research
• [Presentation] Biochemical response to ursodeoxycholic acid predicts histologic primary ciliary cholangitis progression (2018)
  • Author(s): Namisaki T, Fujinaga Y, Moriya K, Kitade M, Kaji K, Kawaratani H, Seki K, Takaya H, Sato S, Sawada Y, Akahane T, Yoshji H
  • Organizer: EASL
  • Int'l Joint Research
• [Presentation] Are the Globe and UK-PBC scrore also effective for predicting risk in patients treated with bezafibrate in addition to ursodeoxycholic acid?:A validation study in Japan (2018)
  • Author(s): Tanaka A, Komori A, Abe M, Inao M, Namisaki T, Hashimoto N, Kawata K, Takahashi A, Ninomiya M, Honda A, Hong-Hon K, Arakawa M, Yamagiwa S, Joshita S, Sato K, Kaneko A, Kikuchi K, Itakura J, Nomura T, Kakisaka K, Yoshji H, and et al.
  • Organizer: EASL
  • Int'l Joint Research
• [Presentation] Biochemical response to ursodeoxycholic acid predicts histologic primary biliary cholangitis progression (2018)
  • Author(s): Fujinaga Y, Namisaki T, Moriya K, Kitade M, Kawaratani H, Kaji K, Okura Y, Seki K, Takaya H, Sawada Y, Akahane T, Nishimura N, Sato S, Shimozato N, Saikawa S, Nakanishi K, Kubo T, Furukawa M, Yoshiji H
  • Organizer: AASLD
  • Int'l Joint Research
• [Presentation] Beneficial effects of combined farnesoid X receptor agonist(INT747) and dipeptidyl peptidase-4 inhibitor(sitagliptin) on hepatic fibrogenesis in a rat model of nonalcoholic steatohepatitis (2017)
  • Author(s): Shimozato N, Namisaki T, Moriya K, Kitade M, Takeda K, Kawaratani H, Kaji K, Okura Y, Takaya H, Sawada Y, Nishimura N, Sato S, Saikawa S, Seki K, Furukawa M, Nakanishi K, Kubo T, Yoshiji H
  • Organizer: AASLD
  • Int'l Joint Research
• [Presentation] Bezafibrate improves GLOBE and UK-PBC scores and long-term outcomes in patients with primary biliary cholangitis (2017)
  • Author(s): Honda A, Tanak A, Komori A, Abe M, Inao M, Moshida S, Namisaki T, Yoshiji H, Hashimoto N, Kawata K, Takahashi A, Ohira H, and et al.
  • Organizer: AASLD
  • Int'l Joint Research
• [Presentation] Pruritus, dryness, fatigue and health-related quality of life in Japanese patients with primaty biliaty cholangitis (2017)
  • Author(s): Yagi M, Tanaka A, Abe M, Namisaki T, Yoshiji H, Takahashi A, Ohira H, Komori A, Yamagiwa S, and et al.
  • Organizer: AASLD
  • Int'l Joint Research
• [Patent(Industrial Property Rights)] FXRアゴニストとARBの組み合わせ医薬 (2017)
  • Inventor(s): 浪崎正
  • Industrial Property Rights Holder: 浪崎正
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: PCT/JP2017/012448
  • Overseas
• [Patent(Industrial Property Rights)] FXRアゴニストとARBの組み合わせ医薬 (2017)
  • Inventor(s): 浪崎正
  • Industrial Property Rights Holder: 浪崎正
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 106110180
  • Overseas