Faculty Profiles - SONE, Hirohito

Using a customized DNA microarray for expression profiling of the estrogen-responsive genes to evaluate estrogen activity among natural estrogens and industrial chemicals

内臓脂肪に関する最新情報「地域の中高齢者における．生活機能増進法の具体策～体力年齢の若返り法とその地位システム～」

田中喜代次, 中田由夫, 大藏倫博, 曽根博仁

文部科学省科学技術振興調整費報告書 18-19 2004.1

Shunichi Terasaka, Yukie Aita, Akio Inoue, Shinichi Hayashi, Michiko Nishigaki, Kazuhiko Aoyagi, Hiroki Sasaki, Yuko Wada-Kiyama, Yasuo Sakuma, Shuichi Akaba, Junko Tanaka, Hideko Sone, Junzo Yonemoto, Masao Tanji, Ryoiti Kiyama

Environmental Health Perspectives 112 ( 7 ) 773 - 781 2004

Language：English Publishing type：Research paper (scientific journal) Publisher：Public Health Services, US Dept of Health and Human Services

We developed a DNA microarray to evaluate the estrogen activity of natural estrogens and industrial chemicals. Using MCF-7 cells, we conducted a comprehensive analysis of estrogen-responsive genes among approximately 20,000 human genes. On the basis of reproducible and reliable responses of the genes to estrogen, we selected 172 genes to be used for developing a customized DNA microarray. Using this DNA microarray, we examined estrogen activity among natural estrogens (17β-estradiol, estriol, estrone, genistein), industrial chemicals (diethylstilbestrol, bisphenol A, nonylphenol, methoxychlor), and dioxin. We obtained results identical to those for other bioassays that are used for detecting estrogen activity. On the basis of statistical correlations analysis, these bioassays have shown more sensitivity for dioxin and methoxychlor.

DOI： 10.1289/ehp.6753

Gene interaction network suggests dioxin induces a significant linkage between aryl hydrocarbon receptor and retinoic acid receptor beta

Hirohito Sone

Environmental Health Perspectives 2004

Polymorphism, Heteroplasmy, Mitochondrial Fusion and Diabetes

Aya Sato, Hitoshi Endo, Kazuo Umetsu, Hideyuki Sone, Yoshiko Yanagisawa, Azusa Saigusa, Sayuri Aita, Yasuo Kagawa

Bioscience Reports 23 ( 5-6 ) 313 - 337 2003.10

Language：English Publishing type：Research paper (scientific journal)

Mitochondrial DNA (mtDNA) is highly susceptible to mutations that result in polymorphisms and diseases including diabetes. We analyzed heteroplasmy, polymorphisms related to diabetes, and complementation by fusogenic proteins. Cytoplast fusion and microinjection allow, defects in mutated mtDNA inside a heteroplasmic cell to be complemented by fusing two mitochondria via human fusogenic proteins. We characterized three hfzos as well as two OPA1s that prevent apoptosis. Two coiled coil domains and GTPase domains in these fusogenic proteins regulate membrane fusion. The hfzo genes were expressed mainly in the brain and in muscle that are postmitotic, but not in the pancreas. Under the influence of polymorphisms of mtDNA and nDNA, the vicious circle of reactive oxygen species and mutations in cell can be alleviated by mitochondrial fusion.

DOI： 10.1023/B:BIRE.0000019189.35983.b9

Cross-talk between peroxisome proliferator-activated receptor (PPAR) alpha and liver X receptor (LXR) in nutritional regulation of fatty acid metabolism. I. PPARs suppress sterol regulatory element binding protein-1c promoter through inhibition of LXR signaling Reviewed

T Yoshikawa, T Ide, H Shimano, N Yahagi, M Amemiya-Kudo, T Matsuzaka, S Yatoh, T Kitamine, H Okazaki, Y Tamura, M Sekiya, A Takahashi, AH Hasty, R Sato, H Sone, JI Osuga, S Ishibashi, N Yamada

MOLECULAR ENDOCRINOLOGY 17 ( 7 ) 1240 - 1254 2003.7

Language：English Publishing type：Research paper (scientific journal) Publisher：ENDOCRINE SOC

Liver X receptors (LXRs) and peroxisome proliferator-activated receptors (PPARs) are members of nuclear receptors that form obligate heterodimers with retinoid X receptors (RXRs). These nuclear receptors play crucial roles in the regulation of fatty acid metabolism: LXRs activate expression of sterol regulatory element-binding protein 1c (SREBP-1c), a dominant lipogenic gene regulator, whereas PPARalpha promotes fatty acid beta-oxidation genes. In the current study, effects of PPARs on the LXR-SREBP-1c pathway were investigated. Luciferase assays in human embryonic kidney 293 cells showed that overexpression of PPARalpha and gamma dose-dependently inhibited SREBP-1c promoter activity induced by LXR. Deletion and mutation studies demonstrated that the two LXR response elements (LXREs) in the SREBP-1c promoter region are responsible for this inhibitory effect of PPARs. Gel shift assays indicated that PPARs reduce binding of LXR/RXR to LXRE. PPARalpha-selective agonist enhanced these inhibitory effects. Supplementation with RXR attenuated these inhibitions by PPARs in luciferase and gel shift assays, implicating receptor interaction among LXR, PPAR, and RXR as a plausible mechanism. Competition of PPARalpha ligand with LXR ligand was observed in LXR/RXR binding to LXRE in gel shift assay, in LXR/RXR formation in nuclear extracts by coimmunoprecipitation, and in gene expression of SREBP-1c by Northern blot analysis of rat primary hepatocytes and mouse liver RNA. These data suggest that PPARalpha activation can suppress LXR-SREBP-1c pathway through reduction of LXR/RXR formation, proposing a novel transcription factor cross-talk between LXR and PPARalpha in hepatic lipid homeostasis.

DOI： 10.1210/me.2002-0190

Cross-talk between peroxisome proliferator-activated receptor (PPAR) alpha and liver X receptor (LXR) in nutritional regulation of fatty acid metabolism. II. LXRs suppress lipid degradation gene promoters through inhibition of PPAR signaling Reviewed

T Ide, H Shimano, T Yoshikawa, N Yahagi, M Amemiya-Kudo, T Matsuzaka, M Nakakuki, S Yatoh, Y Iizuka, S Tomita, K Ohashi, A Takahashi, H Sone, T Gotoda, JI Osuga, S Ishibashi, N Yamada

MOLECULAR ENDOCRINOLOGY 17 ( 7 ) 1255 - 1267 2003.7

Language：English Publishing type：Research paper (scientific journal) Publisher：ENDOCRINE SOC

Fatty acid metabolism is transcriptionally regulated by two reciprocal systems: peroxisome proliferator-activated receptor (PPAR)alpha controls fatty acid degradation, whereas sterol regulatory element-binding protein-1c activated by liver X receptor (LXR) regulates fatty acid synthesis. To explore potential interactions between LXR and PPAR, the effect of LXR activation on PPARalpha signaling was investigated. In luciferase reporter gene assays, overexpression of LXRalpha or beta suppressed PPARalpha-induced peroxisome proliferator response element-luciferase activity in a dose-dependent manner. LXR agonists, T0901317 and 22(R)hydroxycholesterol, dose dependently enhanced the suppressive effects of LXRs. Gel shift assays demonstrated that LXR reduced binding of PPARalpha/retinoid X receptor (RXR) alpha to peroxisome proliferator response element. Addition of increasing amounts of RXRalpha restored these inhibitory effects in both luciferase and gel shift assays, suggesting the presence of RXRalpha competition. In vitro protein binding assays demonstrated that activation of LXR by an LXR agonist promoted formation of LXR/RXRalpha and, more importantly, LXR/PPARalpha heterodimers, leading to a reduction of PPARalpha/RXRalpha formation. Supportively, in vivo administration of the LXR ligand to mice and rat primary hepatocytes substantially decreased hepatic mRNA levels of PPARalpha-targeted genes in both basal and PPARalpha agonist-induced conditions. The amount of nuclear PPARalpha/RXR heterodimers in the mouse livers was induced by treatment with PPARalpha ligand, and was suppressed by superimposed LXR ligand. Taken together with data from the accompanying paper (Yoshikawa, T., T. Ide, H. Shimano, N. Yahagi, M. Amemiya-Kudo, T. Matsuzaka, S. Yatoh, T. Kitamine, H. Okazaki, Y. Tamura, M. Sekiya, A. Takahashi, A. H. Hasty, R. Sato, H. Sone, J. Osuga, S. Ishibashi, and N. Yamada, Endocrinology 144: 1240-1254) describing PPARalpha suppression of the LXR-sterol regulatory element-binding protein-1c pathway, we propose the presence of an intricate network of nutritional transcription factors with mutual interactions, resulting in efficient reciprocal regulation of lipid degradation and lipogenesis.

DOI： 10.1210/me.2002-0191

Low-density lipoprotein receptor-related protein 5 (LRP5) is essential for normal cholesterol metabolism and glucose-induced insulin secretion

Takahiro Fujino, Hiroshi Asaba, Man-Jong Kang, Yukio Ikeda, Hideyuki Sone, Shinji Takada, Dong-Ho Kim, Ryoichi X. Ioka, Masao Ono, Hiroko Tomoyori, Minoru Okubo, Toshio Murase, Akihisa Kamataki, Joji Yamamoto, Kenta Magoori, Sadao Takahashi, Yoshiharu Miyamoto, Hisashi Oishi, Masato Nose, Mitsuyo Okazaki, Shinichi Usui, Katsumi Imaizumi, Masashi Yanagisawa, Juro Sakai, Tokuo T. Yamamoto

Proceedings of the National Academy of Sciences of the United States of America 100 ( 1 ) 229 - 234 2003.1

Language：English Publishing type：Research paper (scientific journal)

A Wnt coreceptor low-density lipoprotein receptor-related protein 5 (LRP5) plays an essential role in bone accrual and eye development. Here, we show that LRP5 is also required for normal cholesterol and glucose metabolism. The production of mice lacking LRP5 revealed that LRP5 deficiency led to increased plasma cholesterol levels in mice fed a high-fat diet, because of the decreased hepatic clearance of chylomicron remnants. In addition, when fed a normal diet, LRP5-deficient mice showed a markedly impaired glucose tolerance. The LRPS-deficient islets had a marked reduction in the levels of intracellular ATP and Ca2+ in response to glucose, and thereby glucose-induced insulin secretion was decreased. The intracellular inositol 1,4,5-trisphosphate (IP3) production in response to glucose was also reduced in LRP5-/- islets. Real-time PCR analysis revealed a marked reduction of various transcripts for genes involved in glucose sensing in LRP5-/- islets. Furthermore, exposure of LRP5+/+ islets to Wnt-3a and Wnt-5a stimulates glucose-induced insulin secretion and this stimulation was blocked by the addition of a soluble form of Wnt receptor, secreted Frizzled-related protein-1. In contrast, LRP5-deficient islets lacked the Wnt-3a-stimulated insulin secretion. These data suggest that Wnt/LRP5 signaling contributes to the glucose-induced insulin secretion in the islets.

DOI： 10.1073/pnas.0133792100

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DNA-adduct formation in lungs, nasal mucosa, and livers of rats exposed to urban roadside air in Kawasaki City, Japan

Hiromi Sato, Kazuo T. Suzuki, Hideko Sone, Yuko Yamano, Jun Kagawa, Yasunobu Aoki

Environmental Research 93 ( 1 ) 36 - 44 2003

Language：English Publishing type：Research paper (scientific journal) Publisher：Academic Press Inc.

The potency of ambient air for DNA-adduct formation was estimated using Wistar rats. The animals were maintained in a small-animal facility located beside a main highway intersection in Kawasaki City, Japan, for up to 60 weeks and were exposed to roadside air contaminated mainly with automobile emission (exposure group, EG) or to clean air (control group, CG). Compared to CG, the relative adduct levels (RAL) were increased significantly in EG lungs (17.1-fold (P&lt
0.05)), nasal mucosa, and livers after exposure for 4 weeks. However, there were no significant differences in RAL between EG and CG after exposure for 12 weeks, but they were elevated again in EG after exposure for 48 or 60 weeks. These results suggest that roadside air in this region can cause the generation of DNA adducts. This activity of ambient roadside air can be estimated using experimental animals, indicating that biological monitoring of DNA-adduct formation may be a powerful tool to assess the effect of ambient air on human health. © 2003 Elsevier Science (USA). All rights reserved.

DOI： 10.1016/S0013-9351(03)00063-X

The need to integrate diabetes education and treatment - Reply

Hirohito Sone

Hormone and Metabolic Research 2003

[Large-scale randomized intervention trial on diabetes in Japan]. Reviewed

Sone H, Yamada N

Nihon rinsho. Japanese journal of clinical medicine 60 Suppl 10 44 - 50 2002.10

Genetic and physiological analysis of branched-chain alcohols and isoamyl acetate production in Saccharomyces cerevisiae.

Yoshimoto H, Fukushige T, Yonezawa T, Sone H

2002.8

[Recent studies on hyperlipidemia]. Reviewed

Sone H, Yamada N

Nihon Naika Gakkai zasshi. The Journal of the Japanese Society of Internal Medicine 91 ( 4 ) 1202 - 1207 2002.4

Acetyl-coenzyme A Synthetase is a New Lipogenic Enzyme Controlled by Sterol Regulatory Element-binding Protein-1. Reviewed

Sone, H, Shimano, H, Sakakura, Y, Inoue, N, Amemiya-Kudo, M, Takahashi, A, Yokoo, T, Osawa, M, Iwama, A, Yamada, N

Am J Physiol Endocrinol Metab 282 E222-230 2002.1

Dual regulation of mouse Delta(5)- and Delta(6)-desaturase gene expression by SREBP-1 and PPAR alpha Reviewed

T Matsuzaka, H Shimano, N Yahagi, M Amemiya-Kudo, T Yoshikawa, AH Hasty, Y Tamura, J Osuga, H Okazaki, Y Iizuka, A Takahashi, H Sone, T Gotoda, S Ishibashi, N Yamada

JOURNAL OF LIPID RESEARCH 43 ( 1 ) 107 - 114 2002.1

Language：English Publishing type：Research paper (scientific journal) Publisher：LIPID RESEARCH INC

In the process of seeking sterol regulatory element-binding protein 1a (SREBP-1a) target genes, we identified and cloned a cDNA clone encoding mouse Delta(5)-desaturase (D5D). The hepatic expression of D5D as well as Delta(6)-desaturase (D6D) was highly activated in transgenic mice overexpressing nuclear SREBP-1a, -1c, and -2. Disruption of the SREBP-1 gene significantly reduced the expression of both desaturases in the livers of SREBP-1-deficient mice refed after fasting. The hepatic expression of both desaturases was downregulated by dietary PUFA, which were reported to suppress SREBP-1c gene expression. Sustained expression of hepatic nuclear SREBP-1c protein in the transgenic mice abolished the PUFA suppression of both desaturases. Although these data suggested that SREBP-1c regulates D5D and D6D expression, there was no difference in either the D5D or D6D mRNA level between fasted and refed normal mouse livers, indicating a mechanism for fasting induction of both desaturases. Administration of fibrate, a pharmacological ligand for peroxisome proliferator activating receptor alpha (PPARalpha), caused a significant increase in expression of both desaturases. The data suggested that D5D and D6D expression is dually regulated by SREBP-1c and PPARalpha, two reciprocal transcription factors for fatty acid metabolism, and could be involved in lipogenic gene regulation by producing PUFA.

Genetic and physiological analysis of branched-chain alcohols and isoamyl acetate production in Saccharomyces cerevisiae

Hirohito Sone

Applied Microbiology and Biotechnology 2002

Modal Birefringence dependent supercontinuum due to cross-phase modulation in a dispersion-flattened/decreasing fiber

Hirohito Sone

Optical Review 2002

Influences of polyunsaturated fatty acids and insulin on NO production and ET-1 production in human vascular endothelial cells

Hirohito Sone

Diabetes 2001

Kinematic approach to gait analysis in patients with rheumatoid arthritis involving the knee joint Reviewed

Michihiro Sakauchi, Katsuhiko Narushima, Hirohito Sone, Yutaka Kamimaki, Yuichiro Yamazaki, Shinjiro Kato, Takashi Takita, Norihiro Suzuki, Kimio Moro

Arthritis Care and Research 45 ( 1 ) 35 - 41 2001

Language：English Publishing type：Research paper (scientific journal)

Objective. To analyze abnormal gait patterns in patients with rheumatoid arthritis involving the knee joint. Methods. In 2 patient groups with rheumatoid arthritis, changes in relevant angular parameters in the sagittal plane were analyzed by an electromagnetic tracking instrument. One group consisted of patients with knee joint involvement and severe inflammation without progressive destruction
the other group had knee joint involvement with progressive destruction and low disease activity. Knee angle was measured as the projected angle in the sagittal plane formed by 3 sensors (hip-knee-ankle)
the changing mean angle, angular velocity, and angular acceleration were displayed. Furthermore, the angle formed by the vector element's endpoints for each sensor's displacement (designated α angle) was measured continuously. Results. Compared with age-matched controls, patients with severe inflammatory knee joint involvement showed limitation of a angle change in the stance phase, and patients with knee joint destruction had shortened swing phase duration and decreased α angle change in the swing phase. A sharpened α angular velocity change curve was observed in the latter. Characteristic differences between groups with inflammation and destruction were more clearly evident from the a angle than from the knee angle itself. Conclusion. We observed gait differences between rheumatoid arthritis patients with active inflammatory arthritic knee joint involvement without progressive destruction and those with joint destruction and minimal inflammation. Features of gait disturbance in rheumatoid arthritis were not simple, even with a single major site. Therefore, techniques such as biokinetic gait analysis can provide practical information about functional joint integrity in this patient population that could aid in therapeutic decision making. © 2001 by the American College of Rheumatology.

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