Name

GODA, Nobuhito

Official Title

Professor

Affiliation

(School of Advanced Science and Engineering)

Contact Information

Mail Address

Mail Address
goda@waseda.jp

Address・Phone Number・Fax Number

Address
TWIns Room02C218, 2-2 Wakamatsu-cho, Shinjuku-ku, Tokyo 162-8480, Japan

URL

Web Page URL

http://www.waseda.jp/sem-godalab/

Pure
Scival
Grant-in-aids for Scientific Researcher Number
00245549
ORCID ID
0000-0003-0295-4257

Sub-affiliation

Sub-affiliation

Faculty of Science and Engineering(Graduate School of Advanced Science and Engineering)

Research Council (Research Organization)/Affiliated organization(Global Education Center)

Affiliated Institutes

欧州バイオメディカルサイエンス研究所

研究所員 2009-2011

欧州バイオメディカルサイエンス研究所

研究所員 2011-2012

欧州バイオメディカルグリーンサイエンス研究所

研究所員 2012-2014

ライフサポートイノベーション研究所

研究所員 2014-2014

ライフサポートイノベーション研究所

研究所員 2015-2017

欧州バイオメディカルグリーンサイエンス研究所

研究所員 2015-2016

グローバルバイオメディカルグリーンサイエンス研究所

研究所員 2016-2017

グローバルバイオメディカルグリーンサイエンス研究所

研究所員 2017-2018

アクティヴ・エイジング研究所

研究所員 2013-2017

理工学術院総合研究所(理工学研究所)

兼任研究員 2009-2018

理工学術院総合研究所(理工学研究所)

兼任研究員 2018-

Educational background・Degree

Educational background

-1990 Keio University Faculty of Medicine
-1997 Keio University Graduate School, Division of Medicine

Research Field

Keywords

oxygen, hypoxic response, energy metabolism, liver biology and pathobiology

Grants-in-Aid for Scientific Research classification

Medicine, dentistry, and pharmacy / Basic medicine / Pathological medical chemistry

Medicine, dentistry, and pharmacy / Basic medicine / General medical chemistry

Medicine, dentistry, and pharmacy / Basic medicine / Environmental physiology (including physical medicine and nutritional physiology)

Paper

Adipose Tissue Hypoxia Induces Inflammatory M1 Polarity of Macrophages in HIF-1a-Dependent and HIF-1a-Independent Manners in Obese Mice.

Fujisaka S, Usui I, Ikutani M, Aminuddin A, Takikawa A, Tsuneyama K, Mahmood A, Goda N, Nagai Y, Takatsu K, Tobe K.

Diabetologia 56(6) p.1403 - 14122013-

DOI

Application of nanosheets as an anti-adhesion barrier in partial hepatectomy.

Niwa D, Koide M, Fujie T, Goda N, Takeoka S

J Biomed Mater Res 2013-

Hypoxia-inducible factor-1 is a determinant of lobular structure and oxygen consumption in the liver.

Tsukada K, Tajima T, Hori S, Matsuura T, Johnson RS, Goda N, Suematsu M

Microcirculation 2012-

DOI

Regulation of Glycolysis by Pdk Functions as a Metabolic Checkpoint for Cell Cycle Quiescence in Hematopoietic Stem Cells.

Takubo K, Nagamatsu G, Kobayashi CI, Nakamura-Ishizu A, Kobayashi H, Ikeda E, Goda N, Rahimi Y, Johnson RS, Soga T, Hirao A, Suematsu M, Suda T

Cell Stem Cell 12(1) p.49 - 612013-

DOI

Hypoxia biology in health and disease

Goda N

Int J Hematol 95p.455 - 4562012-

DOI

Hypoxia-inducible factors and their roles in energy metabolism

Goda N, Kanai M

Int J Hematol 95p.457 - 4632012-

DOI

HIF-1 in T cells ameliorated dextran sodium sulfate-induced murine colitis.

Higashiyama M, Hokari R, Hozumi H, Kurihara C, Ueda T, Watanabe C, Tomita K, Nakamura M, Komoto S, Okada Y, Kawaguchi A, Nagao S, Suematsu M, Goda N, Miura S

J Leukoc Biol 91(6) p.901 - 9092012-

DOI

A role for endothelial cells in promoting the maturation of astrocytes through the apelin/APJ system in mice.

Sakimoto S, Kidoya H, Naito H, Kamei M, Sakaguchi H, Goda N, Fukamizu A, Nishida K, Takakura N

Development 139(7) p.1327 - 13352012-

DOI

The formation of an angiogenic astrocyte template is regulated by the neuroretina in a HIF-1-dependent manner.

Nakamura-Ishizu A, Kurihara T, Okuno Y, Ozawa Y, Kishi K, Goda N, Tsubota K, Okano H, Suda T, Kubota Y

Dev Biol 363(1) p.106 - 1142012-

DOI

Dynamic regulation of Th17 differentiation by oxygen concentrations.

Ikejiri A, Nagai S, Goda N, Kurebayashi Y, Osada-Oka M, Takubo K, Suda T, Koyasu S.

Int Immunol 24(3) p.137 - 1462012-

DOI

HIF-1a induction suppresses excessive lipid accumulation in alcoholic fatty liver in mice.

Nishiyama Y, Goda N, Kanai M, Niwa D, Osanai K, Yamamoto Y, Senoo-Matsuda N, Johnson RS, Miura S, Kabe Y, Suematsu M.

J Hepatol 56(2) p.441 - 4472012-

DOI

Disruption of HIF-1a in hepatocytes impairs glucose metabolism in diet-induced obesity mice.

Ochiai D, Goda N, Hishiki T, Kanai M, Senoo-Matsuda N, Soga T, Johnson RS, Yoshimura Y, Suematsu M.

Biochem Biophys Res Commun 415(3) p.445 - 4492011-

DOI

Heterofunctional nanosheet controlling cell adhesion properties by collagen coating.

Niwa D, Fujie T, Lang T, Goda N, Takeoka S.

J Biomater Appl 27(2) p.131 - 1422012-

Fenofibrate, a peroxisome proliferator-activated receptor alpha agonist, improves hepatic microcirculatory patency and oxygen availability in a high-fat-diet-induced fatty liver in mice.

Kazunari Kondo, Tadao Sugioka, Kosuke Tsukada, Michiyoshi Aizawa, Masayuki Takizawa, Kenji Shimizu, Masaya Morimoto, Makoto Suematsu, and Nobuhito Goda

Adv Exp Med Biol 662p.77 - 822010-

DOI

Regulation of the HIF-1alpha level is essential for hematopoietic stem cells.

Keiyo Takubo, Nobuhito Goda, Wakako Yamada, Hirono Iriuchishima, Eiji Ikeda, Yoshiaki Kubota, Haruko Shima, Randall S. Johnson, Atsushi Hirao, Makoto Suematsu, and Toshio Suda.

Cell Stem Cell 7p.391 - 4022010-

DOI

von Hippel-Lindau protein regulates transition from the fetal to the adult circulatory system in retina.

Toshihide Kurihara, Yoshiaki Kubota, Yoko Ozawa, Keiyo Takubo, Kousuke Noda, M Celeste Simon, Randall S Johnson, Makoto Suematsu, Kazuo Tsubota, Susumu Ishida, Nobuhito Goda, Toshio Suda, and Hideyuki Okano.

Development 137p.1563 - 15712010-

DOI

Cystathionine beta-synthase as a carbon monoxide-sensitive regulator of bile excretion

Tsunehiro Shintani, Takuya Iwabuchi, Tomoyoshi Soga, Yuichiro Kato, Takehiro Yamamoto, Naoharu Takano, Takako Hishiki, Yuki Ueno, Satsuki Ikeda, Tadayuki Sakuragawa, Kazuo Ishikawa, Nobuhito Goda, Yuko Kitagawa, Mayumi Kajimura, Kenji Matsumoto, and Makoto Suematsu

Hepatology 49p.141 - 1502009-

HIF-1alpha is necessary to support gluconeogenesis during liver regeneration.

Toshihide Tajima, Nobuhito Goda#, Natsuko Fujikia, Takako Hishikia, Yasumasa Nishiyama, Nanami Senoo-Matsuda, Motohide Shimazu, Tomoyoshi Soga, Yasunori Yoshimura, Randall S. Johnson, and Makoto Suematsu

Biochem Biophys Res Commun 387p.789 - 7942009-

Erythrocytes with T-state-stabilized hemoglobin as a therapeutic tool for postischemic liver dysfunction

Kazuhiro Suganuma, Kosuke Tsukada, Misato Kashiba, Antonio Tsuneshige, Toshiharu Furukawa, Tetsuro Kubota, Nobuhito Goda, Masaki Kitajima, Takashi Yonetan, and Makoto Suematsu

Antioxid Redox Signal 8p.1847 - 18552006-

Carbon monoxide as a guardian against hepatobiliary dysfunction.

Makoto Suematsu, Kosuke Tsukada, Toshihide Tajima, Takehiro Yamamoto, Daigo Ochiai, Hiroshi Watanabe, Yasunori Yoshimura, and Nobuhito Goda

Alcohol Clin Exp Res 29p.134S - 139S2005-

Carbon monoxide from heme oxygenase-2 Is a tonic regulator against NO-dependent vasodilatation in the adult rat cerebral microcirculation

Mami Ishikawa, Mayumi Kajimura, Takeshi Adachi, Kayo Maruyama, Nobuya Makino, Nobuhito Goda, Tokio Yamaguchi, Eiichi Sekizuka, and Makoto Suemats

Circ Res 97p.e104 - e1142005-

Hydrogen sulfide as an endogenous modulator of biliary bicarbonate excretion in the rat liver

Kimihito Fujii, Tadayuki Sakuragawa, Misato Kashiba, Yasoo Sugiura, Mieko Kondo, Kayo Maruyama, Nobuhito Goda, Yuji Nimura, and Makoto Suemats

Antioxid Redox Signal 7p.788 - 7942005-

HIF-1 in cell cycle regulation, apoptosis, and tumor progression

Nobuhito Goda, Sara J. Dozier, and Randall S. Johnson

Antioxid Redox Signal 5p.467 - 4732003-

Hypoxia-inducible factor 1alpha is essential for cell cycle arrest during hypoxia

Nobuhito Goda, Heather E. Ryan, Bahram Khadivi, Wayne McNulty, Robert C. Rickert, and Randall S. Johnson

Mol Cell Biol 23p.359 - 3692003-

Analysis of the interaction between cells and the different types of nanosheets

Niwa, Daisuke;Fujie, Toshinobu;Lang, Thorsten;Goda, Nobuhito;Takeoka, Shinji

ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY 2392010-2010

WoS

Detail

ISSN:0065-7727

von Hippel-Lindau protein regulates transition from the fetal to the adult circulatory system in retina

Kurihara, Toshihide;Kubota, Yoshiaki;Ozawa, Yoko;Takubo, Keiyo;Noda, Kousuke;Simon, M. Celeste;Johnson, Randall S.;Suematsu, Makoto;Tsubota, Kazuo;Ishida, Susumu;Goda, Nobuhito;Suda, Toshio;Okano, Hideyuki

DEVELOPMENT 137(9) p.1563 - 15712010-2010

DOIWoS

Detail

ISSN:0950-1991

HIF-1 alpha induction suppresses excessive lipid accumulation in alcoholic fatty liver in mice

Nishiyama, Yasumasa;Goda, Nobuhito;Kanai, Mai;Niwa, Daisuke;Osanai, Kota;Yamamoto, Yu;Senoo-Matsuda, Nanami;Johnson, Randall S.;Miura, Soichiro;Kabe, Yasuaki;Suematsu, Makoto

JOURNAL OF HEPATOLOGY 56(2) p.441 - 4472012-2012

DOIWoS

Detail

ISSN:0168-8278

Guest editorial: hypoxia biology in health and disease

Goda, Nobuhito

INTERNATIONAL JOURNAL OF HEMATOLOGY 95(5) p.455 - 4562012-2012

DOIWoS

Detail

ISSN:0925-5710

The manner of metabolism is different between the atrium and the ventricle

Shimura, Daisukie;Jiao, Qibin;Kashikura, Kasumi;Endo, Keiko;Soga, Tomoyoshi;Goda, Nobuhito;Minamisawa, Susumu

FASEB JOURNAL 262012-2012

WoS

Detail

ISSN:0892-6638

Metabolomic profiling analysis reveals chamber-dependent metabolite patterns in the mouse heart

Shimura, Daisuke;Nakai, Gaku;Jiao, Qibin;Osanai, Kota;Kashikura, Kasumi;Endo, Keiko;Soga, Tomoyoshi;Goda, Nobuhito;Minamisawa, Susumu

AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY 305(4) p.H494 - H5052013-2013

DOIWoS

Detail

ISSN:0363-6135

Transcription Profiles of the Ductus Arteriosus in Brown-Norway Rats With Irregular Elastic Fiber Formation

Hsieh, Yi-Ting;Liu, Norika Mengchia;Ohmori, Eriko;Yokota, Tomohiro;Kajimura, Ichige;Akaike, Toru;Ohshima, Toshio;Goda, Nobuhito;Minamisawa, Susumu

CIRCULATION JOURNAL 78(5) p.1224 - U2522014-2014

DOIWoS

Detail

ISSN:1346-9843

Hypoxia and fatty liver

Suzuki, Tomohiro;Shinjo, Satoko;Arai, Takatomo;Kanai, Mai;Goda, Nobuhito

WORLD JOURNAL OF GASTROENTEROLOGY 20(41) p.15087 - 150972014-2014

DOIWoS

Detail

ISSN:1007-9327

Potential Biomarkers of Fatigue Identified by Plasma Metabolome Analysis in Rats

Kume, Satoshi;Yamato, Masanori;Tamura, Yasuhisa;Jin, Guanghua;Nakano, Masayuki;Miyashige, Yukiharu;Eguchi, Asami;Ogata, Yoshiyuki;Goda, Nobuhito;Iwai, Kazuhiro;Yamano, Emi;Watanabe, Yasuyoshi;Soga, Tomoyoshi;Kataoka, Yosky

PLOS ONE 10(3) 2015-2015

DOIWoS

Detail

ISSN:1932-6203

HIF-mediated regulation of carbohydrate and lipid metabolisms in the liver

GODA Nobuhito

84(11) p.942 - 9472012/11-2012/11

CiNii

Detail

ISSN:00371017

[HIF-mediated regulation of carbohydrate and lipid metabolisms in the liver].

Goda Nobuhito

[HIF-mediated regulation of carbohydrate and lipid metabolisms in the liver]. 84(11) 2012-2012

Detail

ISSN:0037-1017

Transcription profiles of the ductus arteriosus in Brown-Norway rats with irregular elastic fiber formation.

Hsieh Yi-Ting;Liu Norika Mengchia;Ohmori Eriko;Yokota Tomohiro;Kajimura Ichige;Akaike Toru;Ohshima Toshio;Goda Nobuhito;Minamisawa Susumu

Transcription profiles of the ductus arteriosus in Brown-Norway rats with irregular elastic fiber formation. 78(5) 2014-2014

Detail

ISSN:1347-4820

Outline:BACKGROUND:Patent ductus arteriosus (PDA) is one of the most common congenital cardiovascular defects in children. The Brown-Norway (BN) inbred rat presents a higher frequency of PDA. A previous study reported that 2 different quantitative trait loci on chromosomes 8 and 9 were significantly linked to PDA in this strain. Nevertheless, the genetic or molecular mechanisms underlying PDA phenotypes in BN rats have not been fully investigated yet.;METHODS AND RESULTS:It was found that the elastic fibers were abundant in the subendothelial area but scarce in the media even in the closed ductus arteriosus (DA) of full-term BN neonates. DNA microarray analysis identified 52 upregulated genes (fold difference >2.5) and 23 downregulated genes (fold difference <0.4) when compared with those of F344 control neonates. Among these genes, 8 (Tbx20, Scn3b, Stac, Sphkap, Trpm8, Rup2, Slc37a2, and RGD1561216) are located in chromosomes 8 and 9. Interestingly, it was also suggested that the significant decrease in the expression levels of the PGE2-specfic receptor, EP4, plays a critical role in elastogenesis in the DA.;CONCLUSIONS:BN rats exhibited dysregulation of elastogenesis in the DA. DNA microarray analysis identified the candidate genes including EP4 involved in the DNA phenotype. Further investigation of these newly identified genes will hopefully clarify the molecular mechanisms underlying the irregular formation of elastic fibers in PDA.

WITHDRAWN: Loss of hepatic HIF-1α accelerates lipid accumulation by inhibiting peroxisomal fatty acid oxidation in nonalcoholic fatty liver disease.

Arai Takatomo;Kato Yuki;Ishimoto Kenji;Kanai Mai;Shinjo Satoko;Sayama Keimon;Suzuki Tomohiro;Doi Takefumi;Johnson Randall S;Suematsu Makoto;Goda Nobuhito

Journal of hepatology 2015-2015

PubMedDOI

Detail

ISSN:1600-0641

Outline::This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy.

Innate Response to Human Cancer Cells with or without IL-2 Receptor Common γ-Chain Function in NOD Background Mice Lacking Adaptive Immunity.

Nishime Chiyoko;Kawai Kenji;Yamamoto Takehiro;Katano Ikumi;Monnai Makoto;Goda Nobuhito;Mizushima Tomoko;Suemizu Hiroshi;Nakamura Masato;Murata Mitsuru;Suematsu Makoto;Wakui Masatoshi

Journal of immunology (Baltimore, Md. : 1950) 195(4) 2015-2015

PubMedDOI

Detail

ISSN:1550-6606

Outline::Immunodeficient hosts exhibit high acceptance of xenogeneic or neoplastic cells mainly due to lack of adaptive immunity, although it still remains to be elucidated how innate response affects the engraftment. IL-2R common γ-chain (IL-2Rγc) signaling is required for development of NK cells and a subset of dendritic cells producing IFN-γ. To better understand innate response in the absence of adaptive immunity, we examined amounts of metastatic foci in the livers after intrasplenic transfer of human colon cancer HCT116 cells into NOD/SCID versus NOD/SCID/IL-2Rγc (null) (NOG) hosts. The intravital microscopic imaging of livers in the hosts depleted of NK cells and/or macrophages revealed that IL-2Rγc function critically contributes to elimination of cancer cells without the need for NK cells and macrophages. In the absence of IL-2Rγc, macrophages play a role in the defense against tumors despite the NOD Sirpa allele, which allows human CD47 to bind to the encoded signal regulatory protein α to inhibit macrophage phagocytosis of human cells. Analogous experiments using human pancreas cancer MIA PaCa-2 cells provided findings roughly similar to those from the experiments using HCT116 cells except for lack of suppression of metastases by macrophages in NOG hosts. Administration of mouse IFN-γ to NOG hosts appeared to partially compensate lack of IL-2Rγc-dependent elimination of transferred HCT116 cells. These results provide insights into the nature of innate response in the absence of adaptive immunity, aiding in developing tumor xenograft models in experimental oncology.

Heterozygous deletion of sarcolipin maintains normal cardiac function

Shimura, Daisuke; Kusakari, Yoichiro; Sasano, Tetsuo; Nakashima, Yasuhiro; Nakai, Gaku; Jiao, Qibin; Jin, Meihua; Yokota, Tomohiro; Ishikawa, Yoshihiro; Nakano, Atsushi; Nakano, Atsushi; Nakano, Atsushi; Nakano, Atsushi; Goda, Nobuhito; Minamisawa, Susumu; Minamisawa, Susumu

American Journal of Physiology - Heart and Circulatory Physiology 310(1) p.H92 - H1032016/01-2016/01

PubMedDOIScopus

Detail

ISSN:03636135

Outline:© 2016 the American Physiological Society.Sarcolipin (SLN) is a small proteolipid and a regulator of sarco(endo)plasmic reticulum Ca2+-ATPase. In heart tissue, SLN is exclusively expressed in the atrium. Previously, we inserted Cre recombinase into the endogenous SLN locus by homologous recombination and succeeded in generating SLN-Cre knockin (SlnCre/+) mice. This SlnCre/+ mouse can be used to generate an atrium-specific gene-targeting mutant, and it is based on the Cre-loxP system. In the present study, we used adult SlnCre/+ mice atria and analyzed the effects of heterozygous SLN deletion by Cre knockin before use as the gene targeting mouse. Both SLN mRNA and protein levels were decreased in SlnCre/+ mouse atria, but there were no morphological, physiological, or molecular biological abnormalities. The properties of contractility and Ca2+ handling were similar to wild-type (WT) mice, and expression levels of several stress markers and sarcoplasmic reticulum-related protein levels were not different between SlnCre/+ and WT mice. Moreover, there was no significant difference in sarco(endo)plasmic reticulum Ca2+-ATPase activity between the two groups. We showed that SlnCre/+ mice were not significantly different from WT mice in all aspects that were examined. The present study provides basic characteristics of SlnCre/+ mice and possibly information on the usefulness of SlnCre/+ mice as an atrium-specific gene-targeting model.

Low cardiac output leads hepatic fibrosis in right heart failure model rats

Fujimoto, Yoshitaka; Fujimoto, Yoshitaka; Urashima, Takashi; Shimura, Daisuke; Ito, Reiji; Kawachi, Sadataka; Kajimura, Ichige; Akaike, Toru; Kusakari, Yoichiro; Fujiwara, Masako; Ogawa, Kiyoshi; Goda, Nobuhito; Ida, Hiroyuki; Minamisawa, Susumu

PLoS ONE 11(2) 2016/02-2016/02

DOIScopus

Detail

Outline:© 2016 Fujimoto et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Background: Hepatic fibrosis progresses with right heart failure, and becomes cardiac cirrhosis in a severe case. Although its causal factor still remains unclear. Here we evaluated the progression of hepatic fibrosis using a pulmonary artery banding (PAB)-induced right heart failure model and investigated whether cardiac output (CO) is responsible for the progression of hepatic fibrosis. Methods and Results: Five-week-old Sprague-Dawley rats divided into the PAB and sham-operated control groups. After 4 weeks from operation, we measured CO by echocardiography, and hepatic fibrosis ratio by pathological examination using a color analyzer. In the PAB group, CO was significantly lower by 48% than that in the control group (78.2±27.6 and 150.1±31.2 ml/min, P<0.01). Hepatic fibrosis ratio and serum hyaluronic acid, an index of hepatic fibrosis, were significantly increased in the PAB group than those in the control group (7.8±1.7 and 1.0 ±0.2%, P<0.01, 76.2±27.5 and 32.7±7.5 ng/ml, P<0.01). Notably, the degree of hepatic fibrosis significantly correlated a decrease in CO. Immunohistological analysis revealed that hepatic stellate cells were markedly activated in hypoxic areas, and HIF-1α positive hepatic cells were increased in the PAB group. Furthermore, by real-time PCR analyses, transcripts of profibrotic and fibrotic factors (TGF-β1, CTGF, procollargen I, procollargen III, MMP 2, MMP 9, TIMP 1, TIMP 2) were significantly increased in the PAB group. In addition, western blot analyses revealed that the protein level of HIF-1α was significantly increased in the PAB group than that in the control group (2.31±0.84 and 1.0±0.18 arbitrary units, P<0.05). Conclusions: Our study demonstrated that low CO and tissue hypoxia were responsible for hepatic fibrosis in right failure heart model rats.

HIF-1α-PDK1 axis-induced active glycolysis plays an essential role in macrophage migratory capacity

Semba, Hiroaki; Semba, Hiroaki; Takeda, Norihiko; Takeda, Norihiko; Isagawa, Takayuki; Sugiura, Yuki; Sugiura, Yuki; Honda, Kurara; Wake, Masaki; Miyazawa, Hidenobu; Yamaguchi, Yoshifumi; Yamaguchi, Yoshifumi; Miura, Masayuki; Miura, Masayuki; Jenkins, Dana M R; Choi, Hyunsung; Kim, Jung Whan; Asagiri, Masataka; Cowburn, Andrew S.; Abe, Hajime; Soma, Katsura; Koyama, Katsuhiro; Katoh, Manami; Sayama, Keimon; Goda, Nobuhito; Johnson, Randall S.; Manabe, Ichiro; Nagai, Ryozo; Komuro, Issei

Nature Communications 72016/05-2016/05

DOIScopus

Detail

Outline:In severely hypoxic condition, HIF-1α-mediated induction of Pdk1 was found to regulate glucose oxidation by preventing the entry of pyruvate into the tricarboxylic cycle. Monocyte-derived macrophages, however, encounter a gradual decrease in oxygen availability during its migration process in inflammatory areas. Here we show that HIF-1α-PDK1-mediated metabolic changes occur in mild hypoxia, where mitochondrial cytochrome c oxidase activity is unimpaired, suggesting a mode of glycolytic reprogramming. In primary macrophages, PKM2, a glycolytic enzyme responsible for glycolytic ATP synthesis localizes in filopodia and lammelipodia, where ATP is rapidly consumed during actin remodelling processes. Remarkably, inhibition of glycolytic reprogramming with dichloroacetate significantly impairs macrophage migration in vitro and in vivo. Furthermore, inhibition of the macrophage HIF-1α-PDK1 axis suppresses systemic inflammation, suggesting a potential therapeutic approach for regulating inflammatory processes. Our findings thus demonstrate that adaptive responses in glucose metabolism contribute to macrophage migratory activity.

The H3K9 methyltransferase Setdb1 regulates TLR4-mediated inflammatory responses in macrophages

Hachiya, Rumi; Shiihashi, Takuya; Shiihashi, Takuya; Shirakawa, Ibuki; Iwasaki, Yorihiro; Matsumura, Yoshihiro; Oishi, Yumiko; Nakayama, Yukiteru; Miyamoto, Yoshihiro; Manabe, Ichiro; Ochi, Kozue; Tanaka, Miyako; Goda, Nobuhito; Sakai, Juro; Suganami, Takayoshi; Suganami, Takayoshi; Ogawa, Yoshihiro; Ogawa, Yoshihiro; Ogawa, Yoshihiro

Scientific Reports 62016/06-2016/06

DOIScopus

Detail

Outline:Proinflammatory cytokine production in macrophages involves multiple regulatory mechanisms, which are affected by environmental and intrinsic stress. In particular, accumulating evidence has suggested epigenetic control of macrophage differentiation and function mainly in vitro. SET domain, bifurcated 1 (Setdb1, also known as Eset) is a histone 3 lysine 9 (H3K9)-specific methyltransferase and is essential for early development of embryos. Here we demonstrate that Setdb1 in macrophages potently suppresses Toll-like receptor 4 (TLR4)-mediated expression of proinflammatory cytokines including interleukin-6 through its methyltransferase activity. As a molecular mechanism, Setdb1-deficiency decreases the basal H3K9 methylation levels and augments TLR4-mediated NF-κB recruitment on the proximal promoter region of interleukin-6, thereby accelerating interleukin-6 promoter activity. Moreover, macrophage-specific Setdb1-knockout mice exhibit higher serum interleukin-6 concentrations in response to lipopolysaccharide challenge and are more susceptible to endotoxin shock than wildtype mice. This study provides evidence that the H3K9 methyltransferase Setdb1 is a novel epigenetic regulator of proinflammatory cytokine expression in macrophages in vitro and in vivo. Our data will shed insight into the better understanding of how the immune system reacts to a variety of conditions.

Substrate limitation to soil microbial communities in a subalpine volcanic desert on Mount Fuji, Japan

Yoshitake, S.; Fujiyoshi, M.; Masuzawa, T.; Koizumi, H.

European Journal of Soil Biology 73p.34 - 452016/01-2016/01

DOIScopus

Detail

ISSN:11645563

Outline:© 2016 Elsevier Masson SASWe examined two hypotheses based on laboratory amendment experiments: (1) that development of the soil microbial community on volcanic deserts was regulated by substrate limitation; and (2) that the type and the extent of substrate limitation would change along the succession gradient. Soils were collected from the early (Stage B) and the late (Stage F) stages of primary succession of a subalpine volcanic desert on Mt. Fuji and they were amended with three carbon (C) sources (glucose, cellulose, or lignin), inorganic nitrogen (N), or phosphorus (P) sources alone or in a mixture. Respiration rates were monitored for 25 days and changes in microbial biomass and community structure were examined using the content and composition of phospholipid fatty acids. For both soils, the magnitude of the microbial response differed depending on the type of C source and it decreased in the following order reflecting the availability to microorganisms: glucose > cellulose > lignin. For Stage B soil, although any single amendment did not affect the microbial properties, combined amendment of C (glucose) and N increased microbial respiration and biomass and shifted the microbial community structure. In contrast, microbial properties in Stage F soils responded positively to single amendments of C source. Our results suggest that the microbial community in the early stage of succession is primarily limited by simultaneous shortage of C and N sources but the quality of the C source becomes more important in the late successional stages, which have large, but recalcitrant, organic matter pools in the soil.

p38α Activates Purine Metabolism to Initiate Hematopoietic Stem/Progenitor Cell Cycling in Response to Stress

Karigane, Daiki; Karigane, Daiki; Kobayashi, Hiroshi; Morikawa, Takayuki; Ootomo, Yukako; Ootomo, Yukako; Sakai, Mashito; Nagamatsu, Go; Kubota, Yoshiaki; Goda, Nobuhito; Matsumoto, Michihiro; Nishimura, Emi K.; Soga, Tomoyoshi; Otsu, Kinya; Suematsu, Makoto; Okamoto, Shinichiro; Suda, Toshio; Takubo, Keiyo

Cell Stem Cell 19(2) p.192 - 2042016/08-2016/08

DOIScopus

Detail

ISSN:19345909

Outline:© 2016 Elsevier Inc.Hematopoietic stem cells (HSCs) maintain quiescence by activating specific metabolic pathways, including glycolysis. We do not yet have a clear understanding of how this metabolic activity changes during stress hematopoiesis, such as bone marrow transplantation. Here, we report a critical role for the p38MAPK family isoform p38α in initiating hematopoietic stem and progenitor cell (HSPC) proliferation during stress hematopoiesis in mice. We found that p38MAPK is immediately phosphorylated in HSPCs after a hematological stress, preceding increased HSPC cycling. Conditional deletion of p38α led to defective recovery from hematological stress and a delay in initiation of HSPC proliferation. Mechanistically, p38α signaling increases expression of inosine-5′-monophosphate dehydrogenase 2 in HSPCs, leading to altered levels of amino acids and purine-related metabolites and changes in cell-cycle progression in vitro and in vivo. Our studies have therefore uncovered a p38α-mediated pathway that alters HSPC metabolism to respond to stress and promote recovery.

Index markers of chronic fatigue syndrome with dysfunction of TCA and urea cycles

Yamano, Emi; Sugimoto, Masahiro; Hirayama, Akiyoshi; Kume, Satoshi; Yamato, Masanori; Jin, Guanghua; Tajima, Seiki; Tajima, Seiki; Goda, Nobuhito; Iwai, Kazuhiro; Fukuda, Sanae; Fukuda, Sanae; Yamaguti, Kouzi; Yamaguti, Kouzi; Kuratsune, Hirohiko; Kuratsune, Hirohiko; Soga, Tomoyoshi; Watanabe, Yasuyoshi; Watanabe, Yasuyoshi; Kataoka, Yosky; Kataoka, Yosky

Scientific Reports 62016/10-2016/10

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Outline:© The Author(s) 2016.Chronic fatigue syndrome (CFS) is a persistent and unexplained pathological state characterized by exertional and severely debilitating fatigue, with/without infectious or neuropsychiatric symptoms, lasting at least 6 consecutive months. Its pathogenesis remains incompletely understood. Here, we performed comprehensive metabolomic analyses of 133 plasma samples obtained from CFS patients and healthy controls to establish an objective diagnosis of CFS. CFS patients exhibited significant differences in intermediate metabolite concentrations in the tricarboxylic acid (TCA) and urea cycles. The combination of ornithine/citrulline and pyruvate/isocitrate ratios discriminated CFS patients from healthy controls, yielding area under the receiver operating characteristic curve values of 0.801 (95% confidential interval [CI]: 0.711-0.890, P < 0.0001) and 0.750 (95% CI: 0.584-0.916, P = 0.0069) for training (n = 93) and validation (n = 40) datasets, respectively. These findings provide compelling evidence that a clinical diagnostic tool could be developed for CFS based on the ratios of metabolites in plasma.

Regulation of the HIF-1 alpha Level Is Essential for Hematopoietic Stem Cells

Takubo, Keiyo;Goda, Nobuhito;Yamada, Wakako;Iriuchishima, Hirono;Ikeda, Eiji;Kubota, Yoshiaki;Shima, Haruko;Johnson, Randall S.;Hirao, Atsushi;Suematsu, Makoto;Suda, Toshio

CELL STEM CELL 7(3) p.391 - 4022010-2010

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ISSN:1934-5909

Dynamic regulation of T(h)17 differentiation by oxygen concentrations

Ikejiri, Ai;Nagai, Shigenori;Goda, Nobuhito;Kurebayashi, Yutaka;Osada-Oka, Mayuko;Takubo, Keiyo;Suda, Toshio;Koyasu, Shigeo

INTERNATIONAL IMMUNOLOGY 24(3) p.137 - 1462012-2012

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ISSN:0953-8178

The formation of an angiogenic astrocyte template is regulated by the neuroretina in a HIF-1-dependent manner

Nakamura-Ishizu, Ayako;Kurihara, Toshihide;Okuno, Yuji;Ozawa, Yoko;Kishi, Kazuo;Goda, Nobuhito;Tsubota, Kazuo;Okano, Hideyuki;Suda, Toshio;Kubota, Yoshiaki

DEVELOPMENTAL BIOLOGY 363(1) p.106 - 1142012-2012

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ISSN:0012-1606

A role for endothelial cells in promoting the maturation of astrocytes through the apelin/APJ system in mice

Sakimoto, Susumu;Kidoya, Hiroyasu;Naito, Hisamichi;Kamei, Motohiro;Sakaguchi, Hirokazu;Goda, Nobuhito;Fukamizu, Akiyoshi;Nishida, Kohji;Takakura, Nobuyuki

DEVELOPMENT 139(7) p.1327 - 13352012-2012

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ISSN:0950-1991

Hypoxia-inducible factors and their roles in energy metabolism

Goda, Nobuhito;Kanai, Mai

INTERNATIONAL JOURNAL OF HEMATOLOGY 95(5) p.457 - 4632012-2012

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ISSN:0925-5710

HIF-1 in T cells ameliorated dextran sodium sulfate-induced murine colitis

Higashiyama, Masaaki;Hokari, Ryota;Hozumi, Hideaki;Kurihara, Chie;Ueda, Toshihide;Watanabe, Chikako;Tomita, Kengo;Nakamura, Mitsuyasu;Komoto, Shunsuke;Okada, Yoshikiyo;Kawaguchi, Atsushi;Nagao, Shigeaki;Suematsu, Makoto;Goda, Nobuhito;Miura, Soichiro

JOURNAL OF LEUKOCYTE BIOLOGY 91(6) p.901 - 9092012-2012

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ISSN:0741-5400

Heterofunctional nanosheet controlling cell adhesion properties by collagen coating

Niwa, Daisuke;Fujie, Toshinori;Lang, Thorsten;Goda, Nobuhito;Takeoka, Shinji

JOURNAL OF BIOMATERIALS APPLICATIONS 27(2) p.131 - 1412012-2012

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ISSN:0885-3282

Transcription Profiles of the Ductus Arteriosus in Brown-Norway Rats With Irregular Elastic Fiber Formation

Hsieh Yi-Ting;Liu Norika Mengchia;Ohmori Eriko;Yokota Tomohiro;Kajimura Ichige;Akaike Toru;Ohshima Toshio;Goda Nobuhito;Minamisawa Susumu

JAPANESE CIRCULATION JOURNAL 78(5) p.1224 - 12332014-2014

CiNii

Detail

ISSN:1346-9843

Outline:Background: Patent ductus arteriosus (PDA) is one of the most common congenital cardiovascular defects in children. The Brown-Norway (BN) inbred rat presents a higher frequency of PDA. A previous study reported that 2 different quantitative trait loci on chromosomes 8 and 9 were significantly linked to PDA in this strain. Nevertheless, the genetic or molecular mechanisms underlying PDA phenotypes in BN rats have not been fully investigated yet. Methods and Results: It was found that the elastic fibers were abundant in the subendothelial area but scarce in the media even in the closed ductus arteriosus (DA) of full-term BN neonates. DNA microarray analysis identified 52 upregulated genes (fold difference >2.5) and 23 downregulated genes (fold difference <0.4) when compared with those of F344 control neonates. Among these genes, 8 (Tbx20, Scn3b, Stac, Sphkap, Trpm8, Rup2, Slc37a2, and RGD1561216) are located in chromosomes 8 and 9. Interestingly, it was also suggested that the significant decrease in the expression levels of the PGE2-specfic receptor, EP4, plays a critical role in elastogenesis in the DA. Conclusions: BN rats exhibited dysregulation of elastogenesis in the DA. DNA microarray analysis identified the candidate genes including EP4 involved in the DNA phenotype. Further investigation of these newly identified genes will hopefully clarify the molecular mechanisms underlying the irregular formation of elastic fibers in PDA.  (Circ J 2014; 78: 1224–1233)

Heterofunctional nanosheet controlling cell adhesion properties by collagen coating.

Niwa Daisuke;Fujie Toshinori;Lang Thorsten;Goda Nobuhito;Takeoka Shinji

Heterofunctional nanosheet controlling cell adhesion properties by collagen coating. 27(2) 2012-2012

DOI

Detail

ISSN:1530-8022

Outline::Recently, biomaterials have been widely used in a variety of medical applications. We previously reported that a poly-l-lactic acid (PLLA) nanosheet shows anti-adhesive properties and constitutes a useful biomaterial for preventing unwanted wound adhesion in surgical operations. In this article, we examine whether the PLLA nanosheet can be specifically modified with biomacromolecules on one surface only. Such an approach would endow each side of the nanosheet with discrete functions, that is anti-adhesive and pro-healing properties. We fabricated two distinct PLLA nanosheets: (i) collagen cast on the surface of a PLLA nanosheet (Col-Cast-PLLA) and (ii) collagen spin-coated on the nanosheet (Col-Spin-PLLA). In the Col-Spin-PLLA nanosheet, the collagen layer had a thickness of 5-10 nm on the PLLA surface and displayed increased hydrophilicity compared to both PLLA and Col-Cast-PLLA nanosheets. In addition, atomic force microscopy showed disorganized collagen fibril formation on the PLLA layer when covered using the spin-coating method, while apparent bundle formations of collagen were formed in the Col-Cast-PLLA nanosheet. The Col-Spin-PLLA nanosheet provided a microenvironment for cells to adhere and spread. By contrast, the Col-Cast-PLLA nanosheet displayed reduced cell adhesion compared to the Col-Spin-PLLA nanosheet. Consistent with these findings, immunocytochemical analysis clearly showed fine networks of actin filaments in cells cultured on the Col-Spin-PLLA, but not the Col-Cast-PLLA nanosheet. Therefore, the Col-Spin-PLLA nanosheet was shown to be more suitable for acting as a scaffold. In conclusion, we have succeeded in developing a heterofunctional nanosheet comprising a collagen modified side, which has the ability to rapidly adhere cells, and an unmodified side, which acts as an adhesion barrier, by using a spin-coating technique.

Hypoxia-inducible factors and their roles in energy metabolism.

Goda Nobuhito;Kanai Mai

Hypoxia-inducible factors and their roles in energy metabolism. 95(5) 2012-2012

DOI

Detail

ISSN:1865-3774

Outline::Over the course of evolution, aerobic organisms have developed sophisticated systems for responding to alterations in oxygen concentration, as oxygen acts as a final electron acceptor in oxidative phosphorylation for energy production. Hypoxia-inducible factor (HIF) plays a central role in the adaptive regulation of energy metabolism, by triggering a switch from mitochondrial oxidative phosphorylation to anaerobic glycolysis in hypoxic conditions. HIF also reduces oxygen consumption in mitochondria by inhibiting conversion of pyruvate to acetyl CoA, suppressing mitochondrial biogenesis and activating autophagy of mitochondria concomitantly with reduction in reactive oxygen species production. In addition, metabolic reprogramming in response to hypoxia through HIF activation is not limited to the regulation of carbohydrate metabolism; it occurs in lipid metabolism as well. Recent studies using in vivo gene-targeting technique have revealed unexpected, but novel functions of HIF in energy metabolism in a context- and cell type-specific manner, and shed light on the possibility of pharmaceutical targeting HIF as a new therapy against many diseases, including cancer, diabetes, and fatty liver.

Application of nanosheets as an anti-adhesion barrier in partial hepatectomy.

Niwa Daisuke;Koide Masatsugu;Fujie Toshinori;Goda Nobuhito;Takeoka Shinji

Application of nanosheets as an anti-adhesion barrier in partial hepatectomy. 101(7) 2013-2013

DOI

Detail

ISSN:1552-4981

Outline::Postoperative adhesion often causes serious adverse effects such as bowl obstruction, chronic abdominal pain, pelvic pain, and infertility. We previously reported that a poly-L-lactic acid (PLLA) nanosheet can efficiently seal a surgical incision without scarring. In this report, we examined whether the PLLA nanosheet can form an effective anti-adhesion barrier in partial hepatectomy accompanied by severe hemorrhaging in rats. To evaluate the anti-adhesive property of the nanosheet, the liver wound surface was covered with TachoComb(®) , a well-known hemostat material used in clinical procedures, and then with the PLLA nanosheet. Dressing the wound surface with TachoComb(®) alone caused severe adhesion with omentum and/or residual parts of the liver. By contrast, combinational usage of TachoComb(®) and the PLLA nanosheet significantly reduced such adhesion, presumably by inhibiting the permeation of oozing blood cells and the infiltration of fibroblastic cells. Moreover, the nanosheet displayed low permeability against serum proteins as well as cells in vitro, supporting the notion that the PLLA nanosheet has anti-adhesive properties in vivo. These results strongly suggested that the PLLA nanosheet is a promising material for reducing unwanted postoperative adhesion.

Metabolomic profiling analysis reveals chamber-dependent metabolite patterns in the mouse heart.

Shimura Daisuke;Nakai Gaku;Jiao Qibin;Osanai Kota;Kashikura Kasumi;Endo Keiko;Soga Tomoyoshi;Goda Nobuhito;Minamisawa Susumu

Metabolomic profiling analysis reveals chamber-dependent metabolite patterns in the mouse heart. 305(4) 2013-2013

DOI

Detail

ISSN:1522-1539

Outline::Energy of the cardiac muscle largely depends on fatty acid oxidation. It is known that the atrium and ventricle have chamber-specific functions, structures, gene expressions, and pathologies. The left ventricle works as a high-pressure chamber to pump blood toward the body, and its muscle wall is thicker than those of the other chambers, suggesting that energy utilization in each of the chambers should be different. However, a chamber-specific pattern of metabolism remains incompletely understood. Recently, innovative techniques have enabled the comprehensive analysis of metabolites. Therefore, we aimed to clarify differences in metabolic patterns among the chambers. Male C57BL6 mice at 6 wk old were subject to a comprehensive measurement of metabolites in the atria and ventricles by capillary electrophoresis and mass spectrometry. We found that overall metabolic profiles, including nucleotides and amino acids, were similar between the right and left ventricles. On the other hand, the atria exhibited a distinct metabolic pattern from those of the ventricles. Importantly, the high-energy phosphate pool (the total concentration of ATP, ADP, and AMP) was higher in both ventricles. In addition, the levels of lactate, acetyl CoA, and tricarboxylic acid cycle contents were higher in the ventricles. Accordingly, the activities and/or expression levels of key enzymes were higher in the ventricles to produce more energy. The present study provides a basis for understanding the chamber-specific metabolism underlining pathophysiology in the heart.

Potential biomarkers of fatigue identified by plasma metabolome analysis in rats.

Kume Satoshi;Yamato Masanori;Tamura Yasuhisa;Jin Guanghua;Nakano Masayuki;Miyashige Yukiharu;Eguchi Asami;Ogata Yoshiyuki;Goda Nobuhito;Iwai Kazuhiro;Yamano Emi;Watanabe Yasuyoshi;Soga Tomoyoshi;Kataoka Yosky

PloS one 10(3) 2015-2015

PubMedDOI

Detail

ISSN:1932-6203

Outline::In the present study, prior to the establishment of a method for the clinical diagnosis of chronic fatigue in humans, we validated the utility of plasma metabolomic analysis in a rat model of fatigue using capillary electrophoresis-mass spectrometry (CE-MS). In order to obtain a fatigued animal group, rats were placed in a cage filled with water to a height of 2.2 cm for 5 days. A food-restricted group, in which rats were limited to 10 g/d of food (around 50% of the control group), was also assessed. The food-restricted group exhibited weight reduction similar to that of the fatigued group. CE-MS measurements were performed to evaluate the profile of food intake-dependent metabolic changes, as well as the profile in fatigue loading, resulting in the identification of 48 metabolites in plasma. Multivariate analyses using hierarchical clustering and principal component analysis revealed that the plasma metabolome in the fatigued group showed clear differences from those in the control and food-restricted groups. In the fatigued group, we found distinctive changes in metabolites related to branched-chain amino acid metabolism, urea cycle, and proline metabolism. Specifically, the fatigued group exhibited significant increases in valine, leucine, isoleucine, and 2-oxoisopentanoate, and significant decreases in citrulline and hydroxyproline compared with the control and food-restricted groups. Plasma levels of total nitric oxide were increased in the fatigued group, indicating systemic oxidative stress. Further, plasma metabolites involved in the citrate cycle, such as cis-aconitate and isocitrate, were reduced in the fatigued group. The levels of ATP were significantly decreased in the liver and skeletal muscle, indicative of a deterioration in energy metabolism in these organs. Thus, this comprehensive metabolic analysis furthered our understanding of the pathophysiology of fatigue, and identified potential diagnostic biomarkers based on fatigue pathophysiology.

HIF-1α in myeloid cells promotes adipose tissue remodeling toward insulin resistance

Takikawa, Akiko; Mahmood, Arshad; Nawaz, Allah; Kado, Tomonobu; Okabe, Keisuke; Yamamoto, Seiji; Aminuddin, Aminuddin; Senda, Satoko; Tsuneyama, Koichi; Tsuneyama, Koichi; Ikutani, Masashi; Watanabe, Yasuharu; Igarashi, Yoshiko; Nagai, Yoshinori; Nagai, Yoshinori; Takatsu, Kiyoshi; Takatsu, Kiyoshi; Koizumi, Keiichi; Imura, Johji; Goda, Nobuhito; Sasahara, Masakiyo; Matsumoto, Michihiro; Saeki, Kumiko; Nakagawa, Takashi; Fujisaka, Shiho; Usui, Isao; Tobe, Kazuyuki

Diabetes 65(12) p.3649 - 36592016/12-2016/12

DOIScopus

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ISSN:00121797

Outline:©2016 by the American Diabetes Association.Adipose tissue hypoxia is an important feature of pathological adipose tissue expansion. Hypoxia-inducible factor- 1a (HIF-1α) in adipocytes reportedly induces oxidative stress and fibrosis, rather than neoangiogenesis via vascular endothelial growth factor (VEGF)-A. We previously reported thatmacrophages in crown-like structures (CLSs) are both hypoxic and inflammatory. In the current study, we examined how macrophage HIF-1α is involved in high-fat diet (HFD)-induced inflammation, neovascularization, hypoxia, and insulin resistance using mice with myeloid cell-specific HIF-1α deletion that were fed an HFD. Myeloid cell-specific HIF-1a gene deletion protected against HFD-induced inflammation, CLS formation, poor vasculature development in the adipose tissue, and systemic insulin resistance. Despite a reduced expression of Vegfa in epididymal white adipose tissue (eWAT), the preadipocytes and endothelial cells of HIF-1α-deficient mice expressed higher levels of angiogenic factors, including Vegfa, Angpt1, Fgf1, and Fgf10 in accordance with preferable eWAT remodeling. Our in vitro study revealed that lipopolysaccharide-Treated bone marrow-derived macrophages directly inhibited the expression of angiogenic factors in 3T3-L1 preadipocytes. Thus, macrophage HIF- 1α is involved not only in the formation of CLSs, further enhancing the inflammatory responses, but also in the inhibition of neoangiogenesis in preadipocytes. We concluded that these two pathways contribute to the obesity-related physiology of pathological adipose tissue expansion, thus causing systemic insulin resistance.

Type i neuregulin1α is a novel local mediator to suppress hepatic gluconeogenesis in mice

Arai, Takatomo; Ono, Yumika; Arimura, Yujiro; Sayama, Keimon; Suzuki, Tomohiro; Shinjo, Satoko; Kanai, Mai; Abe, Shin Ichi; Semba, Kentaro; Goda, Nobuhito

Scientific Reports 72017/02-2017/02

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Outline:© 2017 The Author(s). Neuregulin1 is an epidermal growth factor (EGF)-like domain-containing protein that has multiple isoforms and functions as a local mediator in the control of various cellular functions. Here we show that type I isoform of neuregulin1 with an α-type EGF-like domain (Nrg1α) is the major isoform in mouse liver and regulates hepatic glucose production. Forced expression of Nrg1α in mouse liver enhanced systemic glucose disposal and decreased hepatic glucose production with reduced fasting blood glucose levels. Nuclear forkhead box protein O1 (FoxO1) and its downstream targets, PEPCK and G6Pase, were suppressed in liver and isolated hepatocytes by Nrg1α overexpression. In contrast, silencing of Nrg1α enhanced glucose production with increased PEPCK and G6Pase expressions in cAMP/dexamethasone-stimulated hepatocytes. Mechanistically, the recombinant α-type EGF-like domain of NRG1α (rNRG1α) stimulated the ERBB3 signalling pathway in hepatocytes, resulting in decreased nuclear FoxO1 accumulation via activation of both the AKT and ERK pathways. In addition, acute treatment with rNRG1α also suppressed elevation of blood glucose levels after both glucose and pyruvate challenge. Although a liver-specific deletion of Nrg1 gene in mice showed little effect on systemic glucose metabolism, these results suggest that NRG1α have a novel regulatory function in hepatic gluconeogenesis by regulating the ERBB3-AKT/ERK-FoxO1 cascade.

Disruption of the mitochondria-associated ER membrane (MAM) plays a central role in palmitic acid–induced insulin resistance

Shinjo, Satoko; Shinjo, Satoko; Jiang, Shuying; Nameta, Masaaki; Suzuki, Tomohiro; Kanai, Mai; Kanai, Mai; Nomura, Yuta; Goda, Nobuhito

Experimental Cell Research 359(1) p.86 - 932017/10-2017/10

PubMedDOIScopus

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ISSN:00144827

Outline:© 2017 Elsevier Inc. The mitochondria-associated ER membrane (MAM) is a specialized subdomain of ER that physically connects with mitochondria. Although disruption of inter-organellar crosstalk via the MAM impairs cellular homeostasis, its pathological significance in insulin resistance in type 2 diabetes mellitus remains unclear. Here, we reveal the importance of reduced MAM formation in the induction of fatty acid–evoked insulin resistance in hepatocytes. Palmitic acid (PA) repressed insulin-stimulated Akt phosphorylation in HepG2 cells within 12 h. Treatment with an inhibitor of the ER stress response failed to restore PA-mediated suppression of Akt activation. Mitochondrial reactive oxygen species (ROS) production did not increase in PA-treated cells. Even short-term exposure (3 h) to PA reduced the calcium flux from ER to mitochondria, followed by a significant decrease in MAM contact area, suggesting that PA suppressed the functional interaction between ER and mitochondria. Forced expression of mitofusin-2, a critical component of the MAM, partially restored MAM contact area and ameliorated the PA-elicited suppression of insulin sensitivity with Ser473 phosphorylation of Akt selectively improved. These results suggest that loss of proximity between ER and mitochondria, but not perturbation of homeostasis in the two organelles individually, plays crucial roles in PA-evoked Akt inactivation in hepatic insulin resistance.

Application of nanosheets as an anti-adhesion barrier in partial hepatectomy

Niwa, Daisuke;Koide, Masatsugu;Fujie, Toshinori;Goda, Nobuhito;Takeoka, Shinji

JOURNAL OF BIOMEDICAL MATERIALS RESEARCH PART B-APPLIED BIOMATERIALS 101(7) p.1251 - 12582013-2013

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ISSN:1552-4973

Index markers of chronic fatigue syndrome with dysfunction of TCA and urea cycles

Yamano, Emi;Sugimoto, Masahiro;Hirayama, Akiyoshi;Kume, Satoshi;Yamato, Masanori;Jin, Guanghua;Tajima, Seiki;Goda, Nobuhito;Iwai, Kazuhiro;Fukuda, Sanae;Yamaguti, Kouzi;Kuratsune, Hirohiko;Soga, Tomoyoshi;Watanabe, Yasuyoshi;Kataoka, Yosky

SCIENTIFIC REPORTS 62016-2016

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ISSN:2045-2322

HIF-1 alpha in Myeloid Cells Promotes Adipose Tissue Remodeling Toward Insulin Resistance

Takikawa, Akiko;Mahmood, Arshad;Nawaz, Allah;Kado, Tomonobu;Okabe, Keisuke;Yamamoto, Seiji;Aminuddin, Aminuddin;Senda, Satoko;Tsuneyama, Koichi;Ikutani, Masashi;Watanabe, Yasuharu;Igarashi, Yoshiko;Nagai, Yoshinori;Takatsu, Kiyoshi;Koizumi, Keiichi;Imura, Johji;Goda, Nobuhito;Sasahara, Masakiyo;Matsumoto, Michihiro;Saeki, Kumiko;Nakagawa, Takashi;Fujisaka, Shiho;Usui, Isao;Tobe, Kazuyuki

DIABETES 65(12) p.3649 - 36592016-2016

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ISSN:0012-1797

Regulation of Glycolysis by Pdk Functions as a Metabolic Checkpoint for Cell Cycle Quiescence in Hematopoietic Stem Cells

Takubo, Keiyo;Nagamatsu, Go;Kobayashi, Chiharu I.;Nakamura-Ishizu, Ayako;Kobayashi, Hiroshi;Ikeda, Eiji;Goda, Nobuhito;Rahimi, Yasmeen;Johnson, Randall S.;Soga, Tomoyoshi;Hirao, Atsushi;Suematsu, Makoto;Suda, Toshio

CELL STEM CELL 12(1) p.49 - 612013-2013

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ISSN:1934-5909

Hypoxia and fatty liver.

Suzuki Tomohiro;Shinjo Satoko;Arai Takatomo;Kanai Mai;Goda Nobuhito

Hypoxia and fatty liver. 20(41) 2014-2014

DOI

Detail

ISSN:2219-2840

Outline::The liver is a central organ that metabolizes excessive nutrients for storage in the form of glycogen and lipids and supplies energy-producing substrates to the peripheral tissues to maintain their function, even under starved conditions. These processes require a considerable amount of oxygen, which causes a steep oxygen gradient throughout the hepatic lobules. Alcohol consumption and/or excessive food intake can alter the hepatic metabolic balance drastically, which can precipitate fatty liver disease, a major cause of chronic liver diseases worldwide, ranging from simple steatosis, through steatohepatitis and hepatic fibrosis, to liver cirrhosis. Altered hepatic metabolism and tissue remodeling in fatty liver disease further disrupt hepatic oxygen homeostasis, resulting in severe liver hypoxia. As master regulators of adaptive responses to hypoxic stress, hypoxia-inducible factors (HIFs) modulate various cellular and organ functions, including erythropoiesis, angiogenesis, metabolic demand, and cell survival, by activating their target genes during fetal development and also in many disease conditions such as cancer, heart failure, and diabetes. In the past decade, it has become clear that HIFs serve as key factors in the regulation of lipid metabolism and fatty liver formation. This review discusses the molecular mechanisms by which hypoxia and HIFs regulate lipid metabolism in the development and progression of fatty liver disease.

Books And Publication

細胞:低酸素ストレス応答が拓く新しい疾患生物学

合田 亘人

2013-

医学のあゆみ:HIFを介した防御機構:低酸素ストレス下のエネルギー代謝制御

合田 亘人、加藤 早由華

2012-

生化学:HIFによる肝臓内糖・脂質代謝制御機構

合田 亘人

2012-

血管医学Vascular Biology & Medicine:肝疾患とHIFを介した低酸素応答

合田 亘人、長内 康太

2012-

呼吸器NEWS&VIEWS:低酸素転写制御因子とSDB

合田 亘人、鈴木 智大

2012-

イラストで徹底理解するシグナル伝達キーワード事典:低酸素シグナリング -HIFシグナリング-

合田 亘人、金井 麻衣

2012-

実験医学:概論-多彩な生命現象に働く低酸素応答システム

中山 恒、合田 亘人

2012-

実験医学:HIFが制御するエネルギー代謝

合田 亘人、鈴木 智大、金井 麻衣

2012-

アルコールと医学生物学:アルコール性脂肪肝における低酸素応答性転写制御因子HIF-1の機能解析

合田 亘人

2011-

実験医学:肝細胞の不均一性と肝代謝制御

合田 亘人、金井 麻衣

2011-

Patent

Reference Number:1889

ニューレグリン1α様活性を有するポリペプチド及び糖尿病治療用医薬組成物(日本)

合田 亘人, 新井 理智, 大野 友美絵

2017- 26742、2018-131413

Research Grants & Projects

Grant-in-aids for Scientific Research Adoption Situation

Research Classification:

Analysis of pathological roles of hypoxic responses in the regulation of organ metabolism in fatty liver diseases

2011/-0-2014/-0

Allocation Class:¥5330000

Research Classification:

Molecular mechanisms of ductus arteriosus closure

2011/-0-2014/-0

Allocation Class:¥19110000

Research Classification:

Role of HIF-1 in the regulation of inflammatory responses through sensing alterations in microenvironments of immune cells

Allocation Class:¥3200000

Research Classification:

Role of hypoxia inducible factor-1α in the regulation of hypoxic responses in liver.

Allocation Class:¥5800000

Research Classification:

Analysis of molecular mechanisms by which heme oxygenase-carbon monoxide pathway regulates cellular functions under physiological and pathophysiological conditions using newly developed gene targeting mice.

Allocation Class:¥11200000

Research Classification:

Investigation of immuno-regulatory competency of dietary substances and its application for our own beneficial ends

Allocation Class:¥395330000

Research Classification:

The regulation of in vitro megakaryocyte differentiation and platelet production by hypoxia

2013/-0-2015/-0

Allocation Class:¥4290000

On-campus Research System

Special Research Project

低酸素応答性転写因子HIFを介した肝脂肪蓄積制御機構の解明

2010

Research Results Outline:肝臓は生体内で脂肪組織に次いで生理的条件下で脂肪を蓄積する能力を有する臓器である。一方、脂質の過剰摂取、ウイルス性肝炎、糖尿病やアルコール摂取は病的な肝臓は生体内で脂肪組織に次いで生理的条件下で脂肪を蓄積する能力を有する臓器である。一方、脂質の過剰摂取、ウイルス性肝炎、糖尿病やアルコール摂取は病的な過剰の脂質沈着を肝臓に引き起こし、所謂‘脂肪肝’と呼ばれる病態になる。これまで脂肪肝は可逆性の良性...肝臓は生体内で脂肪組織に次いで生理的条件下で脂肪を蓄積する能力を有する臓器である。一方、脂質の過剰摂取、ウイルス性肝炎、糖尿病やアルコール摂取は病的な過剰の脂質沈着を肝臓に引き起こし、所謂‘脂肪肝’と呼ばれる病態になる。これまで脂肪肝は可逆性の良性疾患として捉えられてきたが、近年脂肪肝の遷延は脂肪性肝炎、肝線維症や肝硬変などのさらに進行した病態へと高率に進展することが明らかになってきた。肝移植以外に進行性肝疾患に対する効果的な治療法がない現状では、脂肪肝発症・進展を如何に食い止めるかが緊急の課題となっている。低酸素は循環障害などに起因する絶対的な酸素供給の低下のみならず、酸素供給を上回る酸素消費の増加によっても生じる病態である。脂肪肝では、脂肪蓄積による物理的な肝微小循環傷害と代償性脂質代謝亢進に伴うミトコンドリア酸素消費の増加により肝臓が低酸素状態に陥ることから、低酸素への適応が肝脂肪肝蓄積に係わっていると考えられる。そこで、本研究では肝脂肪蓄積に低酸素により誘導される転写制御因子Hypoxia inducible factor-1(HIF-1)が重要な制御因子として機能しているのではないかと仮説を立て、脂肪肝におけるHIF-1の時空間的局在と病態生理学的意義について、エタノール性脂肪肝モデルを用いて解析を行った。その結果、マウスに5%エタノール混餌食4週間投与を行うと、肝小葉内中心静脈領域がpimonidazoleで強く染色され低酸素に陥っていることが明らかになった。また、この低酸素領域に一致して、核内にHIF-1発現の亢進が認められる肝細胞が局在することが分かった。さらに、HIF-1発現亢進に一致し、HIF-1標的遺伝子のVEGFやPGKの遺伝子発現も増加しており、このことはエタノール投与による脂肪肝発症過程で肝臓が低酸素に陥り、その結果HIF-1の転写活性化が生じることを示唆している。一方、肝臓特異的HIF-1alpha遺伝子マウスは、野生型と比較してエタノール応答性脂肪蓄積が増悪することが、oil red O染色、肝臓および血清脂質量の生化学的解析より明らかになった。このことは、低酸素で活性化される転写制御因子HIF-1がエタノール誘導性肝脂肪蓄積に対する抑制因子として機能していることを示唆している。今後、さらにHIF-1による脂肪肝制御機構について詳細に解析を進める予定である。

低酸素応答システムによる肝脂肪蓄積制御の分子基盤の解明

2011

Research Results Outline: 肝実質細胞に脂質が蓄積した状態は脂肪肝と総称され、肥満、糖尿病、アルコール過剰摂取などの生活習慣に起因する肝疾患の最もありふれた初期病態である。これ 肝実質細胞に脂質が蓄積した状態は脂肪肝と総称され、肥満、糖尿病、アルコール過剰摂取などの生活習慣に起因する肝疾患の最もありふれた初期病態である。これまで脂肪肝は可逆性の良性肝疾患と捉えられてきたが、しかし近年、慢性化した脂肪肝の一部が脂肪性肝炎、... 肝実質細胞に脂質が蓄積した状態は脂肪肝と総称され、肥満、糖尿病、アルコール過剰摂取などの生活習慣に起因する肝疾患の最もありふれた初期病態である。これまで脂肪肝は可逆性の良性肝疾患と捉えられてきたが、しかし近年、慢性化した脂肪肝の一部が脂肪性肝炎、肝硬変、さらには肝細胞がんへと進展することが明らかになり、これらの疾患に対する効果的な治療法や予防法の開発のために脂肪肝発症に係わる分子メカニズムの解明が急務となっている。 これまで我々は、脂肪肝の発症過程で生じる低酸素環境が病態の形成および進展に係わっていると仮説を立て、病態モデルマウスを作成してその検証に取り組んできた。その成果として、生体内における低酸素応答の中心分子であるhypoxia inducible factor-1 (HIF-1)が、アルコール性脂肪肝の進展に対して抑制的に働く防御因子であることを明らかにしてきた。本研究では、HIF-1による肝脂肪蓄積抑制機構に係わる分子メカニズムの解明に取り組んだ。まず、HIF-1欠損マウス(HIFKO)で認められた脂肪蓄積増強機構に、脂肪酸合成系の活性化が関与している可能性を考え、定量的RT-PCR法を用いて遺伝子発現解析を行った。その結果、解析した脂肪酸合成に係わる全ての遺伝子が、エタノール混餌食4週間投与によりコントロールマウスと比較して増加していることが明らかになった。また、エタノール混餌食を2週間投与したHIFKOマウスからの肝臓を同様に解析したところ、脂質代謝の中心的な転写制御因子であるsterol regulatory element binding protein (SREBP)1cおよび下流の標的遺伝子のacetyl CoA carboxylase (ACC)以外の遺伝子は、エタノール混餌食2週間投与時より減少していることが明らかになった。一方、SREBP1cとACCの遺伝子発現は、エタノール混餌食投与により時間依存性に増加し、4週間の投与によりHIFKOマウスとコントロールマウスの間でさらに発現量の差が著明になることが明らかになった。次に、SREBP1cの制御にアディポネクチンが関与している可能性を考え、血清中アディポネクチン濃度の測定を行った。その結果、コントロールマウスでは食餌投与後2週間に一過性の上昇が認められ、4週間でも投与前より増加していることが明らかになった。一方、HIFKOマウスもコントロールマウスと同様な反応を示し、両者間で差が認められなかった。以上の結果より、エタノール性脂肪肝形成において、肝臓内HIF-1がSREBP1cとACCの遺伝子発現抑制による脂肪酸合成低下を介して病態防御的に機能することが示された。

死細胞から放出されるシグナル分子の同定とその病態生理学的役割の解明

2011Collaborator:松田 七美

Research Results Outline:細胞競合とは、増殖が速い生存細胞群(勝ち組)が、増殖が遅く細胞死によって排除される死細胞群(負け組)に競合し、細胞死、細胞の増殖と周期、分化などが統合細胞競合とは、増殖が速い生存細胞群(勝ち組)が、増殖が遅く細胞死によって排除される死細胞群(負け組)に競合し、細胞死、細胞の増殖と周期、分化などが統合的に制御されることにより、一定の大きさと機能をもつ器官が形成される現象である。これまでに細胞競合制...細胞競合とは、増殖が速い生存細胞群(勝ち組)が、増殖が遅く細胞死によって排除される死細胞群(負け組)に競合し、細胞死、細胞の増殖と周期、分化などが統合的に制御されることにより、一定の大きさと機能をもつ器官が形成される現象である。これまでに細胞競合制御因子として、癌遺伝子c-MycのショウジョウバエホモログdMycが報告されているが、その分子機構は不明である。研究分担者である松田は、ショウジョウバエの翅原基、及び培養細胞株を用いて、dMycにより制御される細胞競合モデルを確立し、予備的解析より死細胞-生存細胞間の細胞運命決定に、それぞれの細胞群における1)エネルギー代謝変化、2)分泌因子が関わることを見いだした。本研究では、分子生物学的・生化学的解析、及びメタボローム解析により、競合する死細胞と生存細胞それぞれの細胞特性変化とエネルギー代謝ステータスとの関係の網羅的分析、及び新規細胞競合制御因子の同定と機能解析を行うことより、細胞競合の分子機構の解明を目指した。 ショウジョウバエ培養細胞株S2を用いたin vitro細胞競合モデル系において、勝ち組細胞と負け組細胞におけるエネルギー代謝ステータス解析系の構築を行った。勝ち組となる高dMyc細胞(メタロチオネインプロモーターの下流にdMycを連結させたベクターの導入により、CuSO4処理によりdMycを発現誘導できる安定発現細胞株; pMT-dMyc/S2細胞)と、負け組となる低dMyc細胞(アクチンプロモーターベクターの導入により核移行シグナル付きGFPを恒常的に発現する野生型細胞株; pAc5.1-GFP/S2細胞)を共培養する技術を応用し、3通りの方法((i)直接共培養系、(ii)間接共培養系、及び(iii) 単培養系における直接共培養上清アッセイ系)により、dMycにより制御される細胞競合のモデルを作製した。それぞれのモデルにおいて、細胞死の初期マーカーである活性型カスパーゼ-3抗体による免疫染色、及び細胞増殖解析による細胞特性評価系をセットアップした。(iii) の単培養系における直接共培養上清アッセイ系を用いて、定量的PCR解析により、競合する勝ち組細胞(生細胞)と負け組細胞(死細胞)における糖代謝関連因子について、解析を行った。その結果、勝ち組となる細胞群(生細胞群)において、グルコーストランスポーターGLUT-1、及びGLUT-3の顕著な発現上昇(10〜15倍)がみられ、一方、負け組となる細胞群(死細胞群)においても、GLUT-1、及びGLUT-3の上昇(2〜3倍)がみられることが明らかとなった。さらに、勝ち組、及び負け組の両細胞群において、RNA干渉法によるGLUT-1、及びGLUT-3の機能抑制を行ったところ、勝ち組(生細胞)、あるいは負け組(死細胞)としてのそれぞれの特性が失われ、細胞競合が認められなくなることが明らかとなった。これらの結果は、両細胞群の代謝ステータスの変化が、細胞競合が生じるために必要であることを示唆している。 現在、(iii) の単培養系における直接共培養上清アッセイ系を用いて、勝ち組となる細胞群(生細胞群)、及び負け組となる細胞群(死細胞群)における代謝ステータスの詳細について明らかにするため、メタボローム解析を行うための準備を進めている。

脂肪蓄積を制御する新しい低酸素ストレス応答の解明

2014

Research Results Outline:本研究では、脂肪組織において異常な脂肪蓄積が認められる肥満病態に対する低酸素を標的とした新規治療法の開発を目指して、細胞内の脂肪蓄積に対する低酸素スト本研究では、脂肪組織において異常な脂肪蓄積が認められる肥満病態に対する低酸素を標的とした新規治療法の開発を目指して、細胞内の脂肪蓄積に対する低酸素ストレス応答を介した新しい制御機構の解明に取り組んだ。その結果、低酸素ストレス応答の中心分子のHIFの...本研究では、脂肪組織において異常な脂肪蓄積が認められる肥満病態に対する低酸素を標的とした新規治療法の開発を目指して、細胞内の脂肪蓄積に対する低酸素ストレス応答を介した新しい制御機構の解明に取り組んだ。その結果、低酸素ストレス応答の中心分子のHIFの恒常的な活性化が脂肪細胞における脂質蓄積を抑制することを見出した。また、この応答が細胞自律的であること、転写共役因子として機能する分子との相互作用が関与している可能性が明らかになった。さらに、リピドーム解析結果からHIFが量的制御のみならず、脂質の質的制御にも関与している可能性が示された。

低酸素応答システムを介した新しい脂質代謝制御機構の探索とその機能の解明

2013

Research Results Outline:好気的生物は酸素利用が限られた環境に曝されると、劇的な代謝リモデリングを誘起しエネルギー産生を維持することで生体機能の恒常性を保つ。この代謝リモデリン好気的生物は酸素利用が限られた環境に曝されると、劇的な代謝リモデリングを誘起しエネルギー産生を維持することで生体機能の恒常性を保つ。この代謝リモデリングの制御にかかわる中心的な分子が低酸素誘導性転写制御因子HIFである。本研究では、糖質にならび生体...好気的生物は酸素利用が限られた環境に曝されると、劇的な代謝リモデリングを誘起しエネルギー産生を維持することで生体機能の恒常性を保つ。この代謝リモデリングの制御にかかわる中心的な分子が低酸素誘導性転写制御因子HIFである。本研究では、糖質にならび生体内の重要なエネルギー源である脂質の代謝制御における、HIFによる新しい調節機構の探索とその機能解明を目指した。この目的遂行のために、新たな遺伝学的なin vivoスクリーニング系を確立し、その結果としてHIFが脂肪組織における脂肪細胞および細胞内脂肪滴のサイズの制御にかかわることを見出した。

脂肪蓄積を制御する新しい低酸素ストレス応答の解明

2015Collaborator:横野 航太, 山田 祥子, 横関 京介, 田中 裕子, 橋本 昂士郎

Research Results Outline:肥満は糖尿病や動脈硬化など健康寿命の延伸を妨げる重篤な疾患の共通した基盤病態である。本研究では、肥満の形成・進展における低酸素の病態生理学的意義を明ら肥満は糖尿病や動脈硬化など健康寿命の延伸を妨げる重篤な疾患の共通した基盤病態である。本研究では、肥満の形成・進展における低酸素の病態生理学的意義を明らかにすることを目指し、ショウジョウバエを用いた遺伝的スクリーニングによる新しい低酸素ストレス関連因...肥満は糖尿病や動脈硬化など健康寿命の延伸を妨げる重篤な疾患の共通した基盤病態である。本研究では、肥満の形成・進展における低酸素の病態生理学的意義を明らかにすることを目指し、ショウジョウバエを用いた遺伝的スクリーニングによる新しい低酸素ストレス関連因子の同定とその機能解析に取り組んだ。その結果、脂肪組織において、低酸素ストレス応答の中心分子HIFの恒常的な活性化により惹起された脂肪蓄積抑制にかかわる遺伝子の同定に成功した。また、3T3-L1細胞を用いた解析から、この遺伝子のマウスオロソログの発現抑制が脂肪蓄積を抑制することも見出した。

新規ヘパトカインのニューレグリン1による糖代謝制御機構の解明

2016Collaborator:合田 亘人, 新井 理智, 有村 祐次郎, 大野 友美絵

Research Results Outline:本課題では、肝臓で発現する膜貫通型成長因子ニューレグリン1(Nrg1)のバリアントフォームの同定と糖代謝制御における機能について解析を行った。その結果本課題では、肝臓で発現する膜貫通型成長因子ニューレグリン1(Nrg1)のバリアントフォームの同定と糖代謝制御における機能について解析を行った。その結果、肝臓ではType1型Nrg1が主に発現していることが分かった。正常マウスにこの遺伝子を強制発現さ...本課題では、肝臓で発現する膜貫通型成長因子ニューレグリン1(Nrg1)のバリアントフォームの同定と糖代謝制御における機能について解析を行った。その結果、肝臓ではType1型Nrg1が主に発現していることが分かった。正常マウスにこの遺伝子を強制発現させると糖負荷時の血糖上昇抑制が認められた。この血糖降下はNrg1の糖新生抑制作用によること、切断・分泌されたNrg1の細胞外ドメインが肝細胞自身に働きかけることで発現していることを明らかにした。以上の結果より、肝臓で発現するType1型Nrg1は肝臓局所で作用し肝糖産生能を抑制するヘパトカインであると結論づけた(Arai et al, Sci Rep., 2017)。

低酸素ストレス応答による新しいNAFLD病態制御機構の解明

2014

Research Results Outline:本研究では、非アルコール性脂肪性肝疾患NAFLDの発症や進展過程における低酸素に対する肝細胞のストレス応答の新しい生物作用を明らかにすることを目指した本研究では、非アルコール性脂肪性肝疾患NAFLDの発症や進展過程における低酸素に対する肝細胞のストレス応答の新しい生物作用を明らかにすることを目指した。その結果、低酸素応答の中心分子HIF-1が、コリン欠乏食誘導性NAFLDの肝脂肪蓄積に対する内因...本研究では、非アルコール性脂肪性肝疾患NAFLDの発症や進展過程における低酸素に対する肝細胞のストレス応答の新しい生物作用を明らかにすることを目指した。その結果、低酸素応答の中心分子HIF-1が、コリン欠乏食誘導性NAFLDの肝脂肪蓄積に対する内因性防御因子として機能することを見出した。また、HIF-1による脂肪蓄積防御機構に、転写共役因子として機能するlipin1の発現亢進を介したペルオキシゾーム内脂肪酸のb酸化制御が関与していることを明らかにした。さらに、リピドーム解析結果から、HIF-1の機能欠損により、肝臓内に超長鎖脂肪酸を含む中性脂肪が異常に蓄積することを見出した。

HIF-1 による肝内糖代謝リモデリング制御機構の解明

2007

Research Results Outline: 本研究課題では、糖尿病下における肝臓内の糖関連酵素発現リモデリングにおける生体内低酸素感受性転写制御因子であるhypoxia inducible f 本研究課題では、糖尿病下における肝臓内の糖関連酵素発現リモデリングにおける生体内低酸素感受性転写制御因子であるhypoxia inducible factor-1(HIF-1)の生物作用について、肝臓特異的にHIF-1活性を欠失させた遺伝子改変マ... 本研究課題では、糖尿病下における肝臓内の糖関連酵素発現リモデリングにおける生体内低酸素感受性転写制御因子であるhypoxia inducible factor-1(HIF-1)の生物作用について、肝臓特異的にHIF-1活性を欠失させた遺伝子改変マウス(HIFKO)を用いて検討を行った。その結果、通常食摂取したHIFKOマウスは、空腹時血糖(FBS)、経口糖負荷試験(OGTT)およびインスリン負荷試験(ITT)で、コントロールマウスと同等の血糖変化を示し、また主要な肝臓内糖関連酵素の発現量とその発現分布には大きな変化が認められなかった。一方、高糖質・脂質食(HFSD)を5週間摂取させた場合、コントロールマウスと比較してFBSおよびITTでは有意な変化は認められなかったが、OGTTでは投与後1時間まで有意な血糖上昇が認められた。OGTT時の初期インスリン分泌能は両群間において全く変化なかったが、後期インスリン分泌はHIFKOマウスにおいて上昇傾向が認められた。一方、単位面積当たりの膵臓のラ氏島数および細胞陽性率には、両群間において大きな変化は認められなかった。これらの結果は、HIFKOマウスにおいて認められた血糖クリアランス能の低下は、膵臓のインスリン分泌能の低下および骨格筋・脂肪組織などの末梢臓器におけるインスリン感受性の低下がプライマリーな原因ではなく、肝臓自身の糖処理能力の減少によるものであると考えられた。そこで、HFSD食5週間投与後の肝臓における主要な糖関連酵素発現を、遺伝子およびタンパク質レベルで詳細に解析を行った。その結果、低酸素に応答してHIF-1依存性に発現変化する代表的な解糖系酵素phosphoglycerate kinaseやpyruvate kinaseの発現は、HFSD投与によりHIFKOおよびコントロールマウスにおいてほんの僅かであるが上昇するものの、両群間において差は認められなかった。しかし、肝細胞へのグルコース取り込みを制御するglucokinase発現については、コントロールマウスでは5倍程度誘導が認められたものの、HIFKOマウスではこのような誘導が完全に抑制されていたことが明らかになった。以上の結果より、HIF-1は糖尿病発症初期に誘導され、肝臓におけるグルコース取り込みを制御することで、血糖降下作用を有していることが明らかになった。

細胞内酸素代謝に基づいた新たな低酸素感知・応答機構の解明

2008

Research Results Outline:本研究課題では、次の2つの研究プロジェクトを同時に進めてきた。1)低酸素感知・応答機構の生物学的機能の解析昨年度に引き続き、糖尿病下における肝臓内の糖本研究課題では、次の2つの研究プロジェクトを同時に進めてきた。1)低酸素感知・応答機構の生物学的機能の解析昨年度に引き続き、糖尿病下における肝臓内の糖関連酵素発現リモデリングにおける低酸素感受性転写制御因子であるhypoxia inducible ...本研究課題では、次の2つの研究プロジェクトを同時に進めてきた。1)低酸素感知・応答機構の生物学的機能の解析昨年度に引き続き、糖尿病下における肝臓内の糖関連酵素発現リモデリングにおける低酸素感受性転写制御因子であるhypoxia inducible factor-1(HIF-1)の生物作用について検討を行った。これまで高糖質・脂質食の短期投与では、HIF-1依存性のグルコキナーゼ発現制御を介して肝臓における糖の取り込みを促進することでHIF-1が血糖降下作用を有することを明らかにしてきたが、今年度は25週間の長期投与を行うことで全身性および肝臓におけるインスリン抵抗性の発症に対するHIF-1の生物作用について検討を進めた。糖負荷試験およびインスリン負荷試験の結果、HIF-1欠損マウスでは肝臓のみならず骨格筋や脂肪組織におけるインスリン抵抗性が増強することが明らかになり、HIF-1が糖尿病抑制因子として機能することが明らかになった。現在、その分子メカニズムについて解析を進めている。2)新規低酸素感知蛋白質の検索HIF-1alphaの特定のプロリン残基が酸素濃度依存的に水酸化されることが低酸素応答の制御に重要であることが明らかにされて以来、この反応機構を触媒するalpha-KG/Fe(II)依存性酸素添加酵素群の中に新規低酸素感知蛋白質が存在する可能性が高まってきている。本研究課題では、プロリン水酸化をターゲットとした酸素センサータンパク質の検索を目的として、プロリン水酸化を特異的に認識する単クローン抗体の作成に取り組んだ。ペプチド抗原を用いたELISAの結果、これまでに少なくとも2種類の候補抗体を得ることができた。現在これらの抗体がHIF-1alphaに代表されるnativeなプロリン水酸化タンパク質を認識できるか否かについて検討を重ねている。この確認が得られた後には、この抗体で免疫沈降されるタンパク質の同定を質量分析により明らかにしていく予定である。

Lecture Course

Course TitleSchoolYearTerm
Science and Engineering Laboratory 1A IVSchool of Fundamental Science and Engineering2019spring semester
Science and Engineering Laboratory 1A IVSchool of Creative Science and Engineering2019spring semester
Science and Engineering Laboratory 1A IVSchool of Advanced Science and Engineering2019spring semester
Science and Engineering LaboratorySchool of Fundamental Science and Engineering2019fall semester
Science and Engineering Laboratory 1BSchool of Fundamental Science and Engineering2019fall semester
Science and Engineering Laboratory 1B VSchool of Fundamental Science and Engineering2019fall semester
Science and Engineering LaboratorySchool of Creative Science and Engineering2019fall semester
Science and Engineering Laboratory 1BSchool of Creative Science and Engineering2019fall semester
Science and Engineering Laboratory 1B VSchool of Creative Science and Engineering2019fall semester
Science and Engineering LaboratorySchool of Advanced Science and Engineering2019fall semester
Science and Engineering Laboratory 1BSchool of Advanced Science and Engineering2019fall semester
Science and Engineering Laboratory 1B VSchool of Advanced Science and Engineering2019fall semester
Life Science and Medical Bio-science Seminar ISchool of Advanced Science and Engineering2019spring semester
Life Science and Medical Bio-science Seminar I [S Grade]School of Advanced Science and Engineering2019spring semester
Anatomy and Histology:LaboratorySchool of Advanced Science and Engineering2019fall semester
Anatomy and Histology:Laboratory [S Grade]School of Advanced Science and Engineering2019fall semester
Molecular Cell Biology ASchool of Advanced Science and Engineering2019fall semester
Molecular Cell Biology A [S Grade]School of Advanced Science and Engineering2019fall semester
BiochemistrySchool of Advanced Science and Engineering2019spring semester
Biochemistry [S Grade]School of Advanced Science and Engineering2019spring semester
Life Science and Medical Bio-science Seminar IISchool of Advanced Science and Engineering2019fall semester
Life Science and Medical Bio-science Seminar II [S Grade]School of Advanced Science and Engineering2019fall semester
Introduction to Clinical MedicineSchool of Advanced Science and Engineering2019fall semester
Introduction to Clinical Medicine [S Grade]School of Advanced Science and Engineering2019fall semester
Advanced Life Science and Medical Bioscience LaboratorySchool of Advanced Science and Engineering2019spring semester
Life Science and Medical Bio-science Laboratory IISchool of Advanced Science and Engineering2019spring semester
Life Science and Medical Bio-science Laboratory II [S Grade]School of Advanced Science and Engineering2019spring semester
Pharmacology BSchool of Advanced Science and Engineering2019summer quarter
Pharmacology B [S Grade]School of Advanced Science and Engineering2019summer quarter
Graduation ResearchSchool of Advanced Science and Engineering2019full year
Graduation Research [S Grade]School of Advanced Science and Engineering2019full year
Medical BiochemistrySchool of Advanced Science and Engineering2019spring semester
Life Science and Medical Bio-science Laboratory IVSchool of Advanced Science and Engineering2019spring semester
Life Science and Medical Bio-science Laboratory VSchool of Advanced Science and Engineering2019fall semester
Life Science and Medical Bioscience Seminar IISchool of Advanced Science and Engineering2019spring semester
Bioscience Practicals ASchool of Advanced Science and Engineering2019fall semester
Bioscience Practicals BSchool of Advanced Science and Engineering2019spring semester
Graduation Thesis ASchool of Advanced Science and Engineering2019fall semester
Graduation Thesis BSchool of Advanced Science and Engineering2019spring semester
Master's Thesis (Department of Life Science and Medical Bioscience)Graduate School of Advanced Science and Engineering2019full year
Research on Molecular Medicine and BiochemistryGraduate School of Advanced Science and Engineering2019full year
Research on Molecular Medicine and BiochemistryGraduate School of Advanced Science and Engineering2019full year
Advanced Medical BiochemistryGraduate School of Advanced Science and Engineering2019spring semester
Seminar on Molecular Medicine and Biochemistry AGraduate School of Advanced Science and Engineering2019spring semester
Seminar on Molecular Medicine and Biochemistry AGraduate School of Advanced Science and Engineering2019spring semester
Seminar on Molecular Medicine and Biochemistry BGraduate School of Advanced Science and Engineering2019fall semester
Seminar on Molecular Medicine and Biochemistry BGraduate School of Advanced Science and Engineering2019fall semester
Master's Thesis (Department of Life Science and Medical Bioscience)Graduate School of Advanced Science and Engineering2019full year
Advanced Medical BiochemistryGraduate School of Advanced Science and Engineering2019an intensive course(spring)
Research on Molecular Medicine and BiochemistryGraduate School of Advanced Science and Engineering2019full year
Practical Training for Career BuildingGraduate School of Advanced Science and Engineering2019full year