2021/10/21 更新

写真a

シラカワ イブキ
白川 伊吹
SHIRAKAWA Ibuki
所属
環境医学研究所 ストレス受容・応答研究部門 特任助教
職名
特任助教

学位 1

  1. 博士(医学) ( 2001年6月   帝京大学 ) 

研究キーワード 3

  1. マクロファージ

  2. 生活習慣病

  3. 炎症

研究分野 2

  1. ライフサイエンス / 病態医化学

  2. ライフサイエンス / 機能生物化学

経歴 2

  1. 東京医科歯科大学   医歯学総合研究科 臓器代謝ネットワーク講座   特任助教

    2015年4月 - 2019年3月

      詳細を見る

    国名:日本国

  2. 帝京大学   医学部第2生理学講座   助手

    1991年7月 - 2004年3月

      詳細を見る

    国名:日本国

学歴 1

  1. 筑波大学   第二学群   生物学類

    1984年4月 - 1988年3月

      詳細を見る

    国名: 日本国

 

論文 8

  1. Dietary Supplementation With Eicosapentaenoic Acid Inhibits Plasma Cell Differentiation and Attenuates Lupus Autoimmunity 査読有り

    Kobayashi Azusa, Ito Ayaka, Shirakawa Ibuki, Tamura Atsushi, Tomono Susumu, Shindou Hideo, Hedde Per Niklas, Tanaka Miyako, Tsuboi Naotake, Ishimoto Takuji, Akashi-Takamura Sachiko, Maruyama Shoichi, Suganami Takayoshi

    FRONTIERS IN IMMUNOLOGY   12 巻   頁: 650856   2021年6月

     詳細を見る

    記述言語:日本語   出版者・発行元:Frontiers in Immunology  

    Accumulating evidence suggests that cholesterol accumulation in leukocytes is causally associated with the development of autoimmune diseases. However, the mechanism by which fatty acid composition influences autoimmune responses remains unclear. To determine whether the fatty acid composition of diet modulates leukocyte function and the development of systemic lupus erythematosus, we examined the effect of eicosapentaenoic acid (EPA) on the pathology of lupus in drug-induced and spontaneous mouse models. We found that dietary EPA supplementation ameliorated representative lupus manifestations, including autoantibody production and immunocomplex deposition in the kidneys. A combination of lipidomic and membrane dynamics analyses revealed that EPA remodels the lipid composition and fluidity of B cell membranes, thereby preventing B cell differentiation into autoantibody-producing plasma cells. These results highlight a previously unrecognized mechanism by which fatty acid composition affects B cell differentiation into autoantibody-producing plasma cells during autoimmunity, and imply that EPA supplementation may be beneficial for therapy of lupus.

    DOI: 10.3389/fimmu.2021.650856

    Web of Science

    Scopus

    PubMed

  2. Macrophages rely on extracellular serine to suppress aberrant cytokine production 査読有り

    Kurita Kento, Ohta Hiroya, Shirakawa Ibuki, Tanaka Miyako, Kitaura Yasuyuki, Iwasaki Yorihiro, Matsuzaka Takashi, Shimano Hitoshi, Aoe Seiichiro, Arima Hiroshi, Ogawa Yoshihiro, Ito Ayaka, Suganami Takayoshi

    SCIENTIFIC REPORTS   11 巻 ( 1 ) 頁: 11137   2021年5月

     詳細を見る

    記述言語:日本語   出版者・発行元:Scientific Reports  

    A growing body of evidence indicates that cellular metabolism is involved in immune cell functions, including cytokine production. Serine is a nutritionally non-essential amino acid that can be generated by de novo synthesis and conversion from glycine. Serine contributes to various cellular responses, but the role in inflammatory responses remains poorly understood. Here, we show that macrophages rely on extracellular serine to suppress aberrant cytokine production. Depleting serine from the culture media reduced the cellular serine content in macrophages markedly, suggesting that macrophages depend largely on extracellular serine rather than cellular synthesis. Under serine deprivation, macrophages stimulated with lipopolysaccharide showed aberrant cytokine expression patterns, including a marked reduction of anti-inflammatory interleukin-10 expression and sustained expression of interleukine-6. Transcriptomic and metabolomics analyses revealed that serine deprivation causes mitochondrial dysfunction: reduction in the pyruvate content, the NADH/NAD+ ratio, the oxygen consumption rate, and the mitochondrial production of reactive oxygen species (ROS). We also found the role of mitochondrial ROS in appropriate cytokine production. Thus, our results indicate that cytokine production in macrophages is tightly regulated by the nutritional microenvironment.

    DOI: 10.1038/s41598-021-90086-w

    Web of Science

    Scopus

    PubMed

  3. Dipeptidyl peptidase-4 inhibition prevents nonalcoholic steatohepatitis-associated liver fibrosis and tumor development in mice independently of its anti-diabetic effects 査読有り

    Kawakubo Mitsuhiro, Tanaka Miyako, Ochi Kozue, Watanabe Akiko, Saka-Tanaka Marie, Kanamori Yohei, Yoshioka Naoki, Yamashita Satoko, Goto Moritaka, Itoh Michiko, Shirakawa Ibuki, Kanai Sayaka, Suzuki Hiromi, Sawada Makoto, Ito Ayaka, Ishigami Masatoshi, Fujishiro Mitsuhiro, Arima Hiroshi, Ogawa Yoshihiro, Suganami Takayoshi

    SCIENTIFIC REPORTS   10 巻 ( 1 ) 頁: 983   2020年1月

     詳細を見る

    記述言語:日本語   出版者・発行元:Scientific Reports  

    Nonalcoholic steatohepatitis (NASH) is a hepatic phenotype of the metabolic syndrome, and increases the risk of cirrhosis and hepatocellular carcinoma (HCC). Although increasing evidence points to the therapeutic implications of certain types of anti-diabetic agents in NASH, it remains to be elucidated whether their effects on NASH are independent of their effects on diabetes. Genetically obese melanocortin 4 receptor–deficient (MC4R-KO) mice fed Western diet are a murine model that sequentially develops hepatic steatosis, NASH, and HCC in the presence of obesity and insulin resistance. In this study, we investigated the effect of the dipeptidyl peptidase-4 (DPP-4) inhibitor anagliptin on NASH and HCC development in MC4R-KO mice. Anagliptin treatment effectively prevented inflammation, fibrosis, and carcinogenesis in the liver of MC4R-KO mice. Interestingly, anagliptin only marginally affected body weight, systemic glucose and lipid metabolism, and hepatic steatosis. Histological data and gene expression analysis suggest that anagliptin treatment targets macrophage activation in the liver during the progression from simple steatosis to NASH. As a molecular mechanism underlying anagliptin action, we showed that glucagon-like peptide-1 suppressed proinflammatory and profibrotic phenotypes of macrophages in vitro. This study highlights the glucose metabolism–independent effects of anagliptin on NASH and HCC development.

    DOI: 10.1038/s41598-020-57935-6

    Web of Science

    Scopus

    PubMed

  4. Upregulation of cancer-associated gene expression in activated fibroblasts in a mouse model of non-alcoholic steatohepatitis 査読有り

    Asakawa Masahiro, Itoh Michiko, Suganami Takayoshi, Sakai Takeru, Kanai Sayaka, Shirakawa Ibuki, Yuan Xunmei, Hatayama Tomomi, Shimada Shu, Akiyama Yoshimitsu, Fujiu Katsuhito, Inagaki Yutaka, Manabe Ichiro, Yamaoka Shoji, Yamada Tetsuya, Tanaka Shinji, Ogawa Yoshihiro

    SCIENTIFIC REPORTS   9 巻 ( 1 ) 頁: 19601   2019年12月

     詳細を見る

    記述言語:日本語   出版者・発行元:Scientific Reports  

    Non-alcoholic steatohepatitis (NASH), characterized by chronic inflammation and fibrosis, is predicted to be the leading cause of cirrhosis and hepatocellular carcinoma (HCC) in the next decade. Although recent evidence suggests the importance of fibrosis as the strongest determinant of HCC development, the molecular mechanisms underlying NASH-induced carcinogenesis still remain unclear. Here we performed RNA sequencing analysis to compare gene expression profiles of activated fibroblasts prepared from two distinct liver fibrosis models: carbon tetrachloride–induced fibrosis as a model without obesity and HCC and genetically obese melanocortin 4 receptor–deficient (MC4R-KO) mice fed Western diet, which develop steatosis, NASH, and eventually HCC. Our data showed that activated fibroblasts exhibited distinct gene expression patterns in each etiology, and that the ‘pathways in cancer’ were selectively upregulated in the activated fibroblasts from MC4R-KO mice. The most upregulated gene in these pathways was fibroblast growth factor 9 (FGF9), which was induced by metabolic stress such as palmitate. FGF9 exerted anti-apoptotic and pro-migratory effects in fibroblasts and hepatoma cells in vitro and accelerated tumor growth in a subcutaneous xenograft model. This study reveals upregulation of cancer-associated gene expression in activated fibroblasts in NASH, which would contribute to the progression from NASH to HCC.

    DOI: 10.1038/s41598-019-56039-0

    Web of Science

    Scopus

    PubMed

  5. Obeticholic acid protects against hepatocyte death and liver fibrosis in a murine model of nonalcoholic steatohepatitis 査読有り

    Goto Toshihiro, Itoh Michiko, Suganami Takayoshi, Kanai Sayaka, Shirakawa Ibuki, Sakai Takeru, Asakawa Masahiro, Yoneyama Toshihiro, Kai Toshihiro, Ogawa Yoshihiro

    SCIENTIFIC REPORTS   8 巻 ( 1 ) 頁: 8157   2018年5月

     詳細を見る

    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Scientific Reports  

    Accumulating evidence has suggested that farnesoid X receptor (FXR) agonists, such as obeticholic acid (OCA) are therapeutically useful for non-Alcoholic steatohepatitis (NASH). However, it is still unclear how FXR agonists protect against NASH and which cell type is the main target of FXR agonists. In this study, we examined the effects of OCA on the development of NASH using melanocortin 4 receptor-deficient (MC4R-KO) mice that progressively developed hepatic steatosis and NASH on Western diet (WD). Treatment with OCA effectively prevented chronic inflammation and liver fibrosis in WD-fed MC4R-KO mice with only marginal effect on body weight and hepatic steatosis. Hepatic crown-like structure (hCLS) is a unique histological structure characteristic of NASH, which triggers hepatocyte death-induced interstitial fibrosis. Intriguingly, treatment with OCA markedly reduced hCLS formation even after MC4R-KO mice developed NASH, thereby inhibiting the progression of liver fibrosis. As its mechanism of action, OCA suppressed metabolic stress-induced p53 activation and cell death in hepatocytes. Our findings in this study highlight the role of FXR in hepatocytes in the pathogenesis of NASH. Collectively, this study demonstrates the anti-fibrotic effect of OCA in a murine model of NASH with obesity and insulin resistance, which suggests the clinical implication for human NASH.

    DOI: 10.1038/s41598-018-26383-8

    Web of Science

    Scopus

    PubMed

  6. CD11c(+) resident macrophages drive hepatocyte death-triggered liver fibrosis in a murine model of nonalcoholic steatohepatitis 査読有り

    Itoh Michiko, Suganami Takayoshi, Kato Hideaki, Kanai Sayaka, Shirakawa Ibuki, Sakai Takeru, Goto Toshihiro, Asakawa Masahiro, Hidaka Isao, Sakugawa Hiroshi, Ohnishi Koji, Komohara Yoshihiro, Asano Kenichi, Sakaida Isao, Tanaka Masato, Ogawa Yoshihiro

    JCI INSIGHT   2 巻 ( 22 )   2017年11月

     詳細を見る

    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:JCI insight  

    Although recent evidence has pointed to the role of organ- and pathogenesis-specific macrophage subsets, it is still unclear which subsets are critically involved in the pathogenesis of nonalcoholic steatohepatitis (NASH). Using melanocortin-4 receptor-deficient (MC4R-KO) mice fed Western diet (WD), which exhibit liver phenotypes similar to those of human NASH, we found a histological structure, termed hepatic crown-like structure (hCLS), in which CD11c+ macrophages surround dead/dying hepatocytes, a prominent feature of NASH. Here, we demonstrate that hCLS-constituting macrophages could be a novel macrophage subset that drives hepatocyte death-triggered liver fibrosis. In an "inducible NASH model," hepatocyte death induces hCLS formation and liver fibrosis sequentially in the short term. In combination with the long-term WD feeding model, we also showed that resident macrophages are a major cellular source of CD11c+ macrophages constituting hCLS, which exhibited gene expression profiles distinct from CD11c- macrophages scattered in the liver. Moreover, depletion of CD11c+ macrophages abolished hCLS formation and fibrogenesis in NASH. Our clinical data suggest the role of CD11c+ macrophages in the disease progression from simple steatosis to NASH. This study sheds light on the role of resident macrophages, in addition to recruited macrophages, in the pathogenesis of NASH.

    DOI: 10.1172/jci.insight.92902

    Web of Science

    Scopus

    PubMed

  7. Synthetic "smart gel" provides glucose-responsive insulin delivery in diabetic mice 査読有り

    Matsumoto Akira, Tanaka Miyako, Matsumoto Hiroko, Ochi Kozue, Moro-oka Yuki, Kuwata Hirohito, Yamada Hironori, Shirakawa Ibuki, Miyazawa Taiki, Ishii Hitoshi, Kataoka Kazunori, Ogawa Yoshihiro, Miyahara Yuji, Suganami Takayoshi

    SCIENCE ADVANCES   3 巻 ( 11 ) 頁: eaaq0723   2017年11月

     詳細を見る

    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Science Advances  

    Although previous studies have attempted to create "electronics-free" insulin delivery systemsusing glucose oxidase and sugar-binding lectins as a glucose-sensingmechanism, no successful clinical translation has hitherto beenmade. These protein-based materials are intolerant of long-term use and storage because of their denaturing and/or cytotoxic properties. We provide a solution by designing a protein-free and totally synthetic material-based approach. Capitalizing on the sugar-responsive properties of boronic acid, we have established a synthetic polymer gel-based insulin delivery device confined within a single catheter, which exhibits an artificial pancreas-like function in vivo. Subcutaneous implantation of the device in healthy and diabetic mice establishes a closed-loop systemcomposed of "continuous glucose sensing" and "skin layer"-regulated insulin release. As a result, glucose metabolism was controlled in response to interstitial glucose fluctuation under both insulin-deficient and insulin-resistant conditions with at least 3-week durability. Our "smart gel" technology could offer a user-friendly and remarkably economic (disposable) alternative to the current state of the art, thereby facilitating availability of effective insulin treatment not only to diabetic patients in developing countries but also to those patients who otherwise may not be strongly motivated, such as the elderly, infants, and patients in need of nursing care.

    DOI: 10.1126/sciadv.aaq0723

    Web of Science

    Scopus

    PubMed

  8. Hepatocyte death-triggered CD11c-positive macrophage accumulation induces liver fibrosis in a murine model of non-alcoholic steatohepatitis

    Itoh Michiko, Suganami Takayoshi, Kanai Sayaka, Shirakawa Ibuki, Sakai Takeru, Goto Toshihiro, Asakawa Masahiro, Hidaka Isao, Sakaida Isao, Ogawa Yoshihiro

    HEPATOLOGY   66 巻   頁: 1052A-1052A   2017年10月

     詳細を見る

    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Web of Science

▼全件表示

MISC 5

  1. The H3K9 methyltransferase Setdb1 regulates TLR4-mediated inflammatory responses in macrophages. 査読有り

    Hachiya R, Shiihashi T, Shirakawa I, Iwasaki Y, Matsumura Y, Oishi Y, Nakayama Y, Miyamoto Y, Manabe I, Ochi K, Tanaka M, Goda N, Sakai J, Suganami T, Ogawa Y  

    Scientific reports6 巻   頁: 28845   2016年6月

     詳細を見る

    記述言語:英語  

    DOI: 10.1038/srep28845

    PubMed

  2. Macrophage-inducible C-type lectin underlies obesity-induced adipose tissue fibrosis. 査読有り

    Tanaka M, Ikeda K, Suganami T, Komiya C, Ochi K, Shirakawa I, Hamaguchi M, Nishimura S, Manabe I, Matsuda T, Kimura K, Inoue H, Inagaki Y, Aoe S, Yamasaki S, Ogawa Y  

    Nature communications5 巻   頁: 4982   2014年9月

     詳細を見る

    記述言語:英語  

    DOI: 10.1038/ncomms5982

    PubMed

  3. Activating transcription factor 4 links metabolic stress to interleukin-6 expression in macrophages. 査読有り

    Iwasaki Y, Suganami T, Hachiya R, Shirakawa I, Kim-Saijo M, Tanaka M, Hamaguchi M, Takai-Igarashi T, Nakai M, Miyamoto Y, Ogawa Y  

    Diabetes63 巻 ( 1 ) 頁: 152-61   2014年1月

     詳細を見る

    記述言語:英語  

    DOI: 10.2337/db13-0757

    PubMed

  4. Increased expression of macrophage-inducible C-type lectin in adipose tissue of obese mice and humans. 査読有り

    Ichioka M, Suganami T, Tsuda N, Shirakawa I, Hirata Y, Satoh-Asahara N, Shimoda Y, Tanaka M, Kim-Saijo M, Miyamoto Y, Kamei Y, Sata M, Ogawa Y  

    Diabetes60 巻 ( 3 ) 頁: 819-26   2011年3月

     詳細を見る

    記述言語:英語  

    DOI: 10.2337/db10-0864

    PubMed

  5. Activating transcription factor 3 constitutes a negative feedback mechanism that attenuates saturated Fatty acid/toll-like receptor 4 signaling and macrophage activation in obese adipose tissue. 査読有り

    Suganami T, Yuan X, Shimoda Y, Uchio-Yamada K, Nakagawa N, Shirakawa I, Usami T, Tsukahara T, Nakayama K, Miyamoto Y, Yasuda K, Matsuda J, Kamei Y, Kitajima S, Ogawa Y  

    Circulation research105 巻 ( 1 ) 頁: 25-32   2009年7月

     詳細を見る

    記述言語:英語  

    DOI: 10.1161/CIRCRESAHA.109.196261

    PubMed