2024/09/27 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. 生活習慣病

  2. 炎症

  3. マクロファージ

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

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    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

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    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

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    国名: 日本国

 

論文 9

  1. Lysosomal cholesterol overload in macrophages promotes liver fibrosis in a mouse model of NASH 査読有り 国際誌

    Itoh, M; Tamura, A; Kanai, S; Tanaka, M; Kanamori, Y; Shirakawa, I; Ito, A; Oka, Y; Hidaka, I; Takami, T; Honda, Y; Maeda, M; Saito, Y; Murata, Y; Matozaki, T; Nakajima, A; Kataoka, Y; Ogi, T; Ogawa, Y; Suganami, T

    JOURNAL OF EXPERIMENTAL MEDICINE   220 巻 ( 11 )   2023年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Journal of Experimental Medicine  

    Accumulation of lipotoxic lipids, such as free cholesterol, induces hepatocyte death and subsequent inflammation and fibrosis in the pathogenesis of nonalcoholic steatohepatitis (NASH). However, the underlying mechanisms remain unclear. We have previously reported that hepatocyte death locally induces phenotypic changes in the macrophages surrounding the corpse and remnant lipids, thereby promoting liver fibrosis in a murine model of NASH. Here, we demonstrated that lysosomal cholesterol overload triggers lysosomal dysfunction and profibrotic activation of macrophages during the development of NASH. β-cyclodextrin polyrotaxane (βCD-PRX), a unique supramolecule, is designed to elicit free cholesterol from lysosomes. Treatment with βCD-PRX ameliorated cholesterol accumulation and profibrotic activation of macrophages surrounding dead hepatocytes with cholesterol crystals, thereby suppressing liver fibrosis in a NASH model, without affecting the hepatic cholesterol levels. In vitro experiments revealed that cholesterol-induced lysosomal stress triggered profibrotic activation in macrophages predisposed to the steatotic microenvironment. This study provides evidence that dysregulated cholesterol metabolism in macrophages would be a novel mechanism of NASH.

    DOI: 10.1084/jem.20220681

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  2. 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

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    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

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  3. 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

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    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

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  4. 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

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    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

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  5. 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

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    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

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▼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

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    記述言語:英語  

    DOI: 10.1038/srep28845

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  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

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    記述言語:英語  

    DOI: 10.1038/ncomms5982

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  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

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    記述言語:英語  

    DOI: 10.2337/db13-0757

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  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

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    記述言語:英語  

    DOI: 10.2337/db10-0864

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  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

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    記述言語:英語  

    DOI: 10.1161/CIRCRESAHA.109.196261

    PubMed