論文 - 渡辺　光博

Bile acids induce energy expenditure by promoting intracellular thyroid hormone activation.

Watanabe M, Houten SM, Mataki C, Christoffolete MA, Kim BW, Sato H, Messaddeq N, Harney JW, Ezaki O, Kodama T, Schoonjans K, Bianco AC, Auwerx J.

Nature 439   484 - 489 2006年

研究論文（学術雑誌）, 共著, 査読有り

　概要を見る

While bile acids (BAs) have long been known to be essential in dietary lipid absorption and cholesterol catabolism, in recent years an important role for BAs as signalling molecules has emerged. BAs activate mitogen-activated protein kinase pathways1,2, are ligands for the G-protein-coupled receptor (GPCR) TGR53,4 and activate nuclear hormone receptors such as farnesoid X receptor α (FXR-α; NR1H4)5,6,7. FXR-α regulates the enterohepatic recycling and biosynthesis of BAs by controlling the expression of genes such as the short heterodimer partner (SHP; NR0B2)8,9 that inhibits the activity of other nuclear receptors. The FXR-α-mediated SHP induction also underlies the downregulation of the hepatic fatty acid and triglyceride biosynthesis and very-low-density lipoprotein production mediated by sterol-regulatory-element-binding protein 1c10. This indicates that BAs might be able to function beyond the control of BA homeostasis as general metabolic integrators. Here we show that the administration of BAs to mice increases energy expenditure in brown adipose tissue, preventing obesity and resistance to insulin. This novel metabolic effect of BAs is critically dependent on induction of the cyclic-AMP-dependent thyroid hormone activating enzyme type 2 iodothyronine deiodinase (D2) because it is lost in D2-/- mice. Treatment of brown adipocytes and human skeletal myocytes with BA increases D2 activity and oxygen consumption. These effects are independent of FXR-α, and instead are mediated by increased cAMP production that stems from the binding of BAs with the G-protein-coupled receptor TGR5. In both rodents and humans, the most thermogenically important tissues are specifically targeted by this mechanism because they coexpress D2 and TGR5. The BA–TGR5–cAMP–D2 signalling pathway is therefore a crucial mechanism for fine-tuning energy homeostasis that can be targeted to improve metabolic control.

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Vitamin D and energy homeostasis: of mice and men.

Bouillon R, Carmeliet G, Lieben L, Watanabe M, Perino A, Auwerx J, Schoonjans K, Verstuyf A.

Nature Rev Endocrinol 10 （ (2) ） 79 - 87 2013年11月

研究論文（学術雑誌）, 共著, 査読有り

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Absence of S6K1 protects against age- and diet-induced obesity while enhancing insulin sensitivity.

Um SH, Frigerio F. Watanabe M, Picard F, Joaquin M, Sticker M, Fumagalli S, Allegrini PR, Kozma SC, Auwerx J, Thomas G.

Nature 431   200 - 205 2004年

研究論文（学術雑誌）, 共著, 査読有り

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Bile acids lower triglyceride levels via a pathway involving FXR, SHP, and SREBP-1c.

Watanabe M, Houten SM, Wang L, Moschetta A, Mangelsdorf DJ, Heyman RA, Moore DD, Auwerx J.

J Clin Invest 113   1408 - 1418 2004年

研究論文（学術雑誌）, 共著, 査読有り

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Lowering Bile Acid Pool Size with a Synthetic Farnesoid X Receptor (FXR) Agonist Induces Obesity and Diabetes through Reduced Energy Expenditure.

Watanabe M, Horai Y, Houten S M., Morimoto K, Sugizaki T, Arita E, Mataki C, Sato H, Tanigawara Y, Schoonjans K, Itoh H, Auwerx J

Journal of Biological Chemistry 286 （ 30 ） 26913-26920 2011年07月

研究論文（学術雑誌）, 共著, 査読有り

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Bile Acid Binding Resin Improves Metabolic Control through the Induction of Energy Expenditure

Watanabe M, Morimoto M, Houten S, Kaneko-Iwasaki N, Sugizaki T, Horai Y, Mataki C, Sato H, Murahashi K, Arita E, Schoonjans K, Suzuki T, Itoh H and Auwerx J.

PLOS ONE 7 （ 8 ）  2012年08月

研究論文（学術雑誌）, 共著, 査読有り

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Combined deletion of Fxr and Shp in mice induces Cyp17a1 and results in juvenile onset cholestasis.

Anakk S. Watanabe M. Ochsner SA, McKenna NJ, Finegold MJ, Moore DD.

Journal of Clinical Investigation 121 （ 1 ） 86-95 2011年01月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  0021-9738

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Cysteine sulfinic acid decarboxylase regulation: A role for farnesoid X receptor and small heterodimer partner in murine hepatic taurine metabolism

Kerr TA, Matsumoto Y, Matsumoto H, Xie Y, Hirschberger LL, Stipanuk MH, Anakk S, Moore DD, Watanabe M, Kennedy S, Davidson NO.

Hepatology Research 44 （ 10 ） E218 - 28 2014年10月

研究論文（学術雑誌）, 共著, 査読有り

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Sodium ferrous citrate and 5-aminolevulinic acid improve type 2 diabetes by maintaining muscle and mitochondrial health

Naho Kitamura, Shiyang Zhang, Jean-David Morel, Utana Nagano, Tanon Taworntawat, Shotaro Hosoda, Anna Nakamura, Yoko Ogawa, Giorgia Benegiamo, Johan Auwerx, Kazuo Tsubota, Yoko Yokoyama, Mitsuhiro Watanabe

Obesity (Silver Spring) vol.31 （ 4 ） 1038 - 1049 2023年04月

学位論文（博士）, 最終著者, 査読有り

　概要を見る

Objective
Improving mitochondrial function is a promising strategy for intervention in type 2 diabetes mellitus. This study investigated the preventive effects of sodium ferrous citrate (SFC) and 5-aminolevulinic acid phosphate (ALA) on several metabolic dysfunctions associated with obesity because they have been shown to alleviate abnormal glucose metabolism in humans.

Methods
Six-week-old male C57BL/6J mice were fed with a normal diet, a high-fat diet, or a high-fat diet supplemented with SFC and ALA for 15 weeks.

Results
The simultaneous supplementation of SFC + ALA to high-fat diet-fed mice prevented loss of muscle mass, improved muscle strength, and reduced obesity and insulin resistance. SFC + ALA prevented abnormalities in mitochondrial morphology and reverted the diet effect on the skeletal muscle transcriptome, including the expression of glucose uptake and mitochondrial oxidative phosphorylation-related genes. In addition, SFC + ALA prevented the decline in mitochondrial DNA copy number by enhancing mitochondrial DNA maintenance and antioxidant transcription activity, both of which are impaired in high-fat diet-fed mice during long-term fasting.

Conclusions
These findings suggest that SFC + ALA supplementation exerts its preventive effects in type 2 diabetes mellitus via improved skeletal muscle and mitochondrial health, further validating its application as a promising strategy for the prevention of obesity-induced metabolic disorders.

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Iron supplementation regulates the progression of high fat diet induced obesity and hepatic steatosis via mitochondrial signaling pathways

Kitamura N., Yokoyama Y., Taoka H., Nagano U., Hosoda S., Taworntawat T., Nakamura A., Ogawa Y., Tsubota K., Watanabe M.

Scientific Reports （Scientific Reports）  11 （ 1 ） 10753 2021年05月

研究論文（学術雑誌）, 共著

　概要を見る

Disruption of iron metabolism is closely related to metabolic diseases. Iron deficiency is frequently associated with obesity and hepatic steatosis. However, the effects of iron supplementation on obesity and energy metabolism remain unclear. Here we show that a high-fat diet supplemented with iron reduces body weight gain and hepatic lipid accumulation in mice. Iron supplementation was found to reduce mitochondrial morphological abnormalities and upregulate gene transcription involved in mitochondrial function and beta oxidation in the liver and skeletal muscle. In both these tissues, iron supplementation increased the expression of genes involved in heme or iron–sulfur (Fe–S) cluster synthesis. Heme and Fe–S cluster, which are iron prosthetic groups contained in electron transport chain complex subunits, are essential for mitochondrial respiration. The findings of this study demonstrated that iron regulates mitochondrial signaling pathways—gene transcription of mitochondrial component molecules synthesis and their energy metabolism. Overall, the study elucidates the molecular basis underlying the relationship between iron supplementation and obesity and hepatic steatosis progression, and the role of iron as a signaling molecule.

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Asperuloside Improves Obesity and Type 2 Diabetes through Modulation of Gut Microbiota and Metabolic Signaling

Nakamura A., Yokoyama Y., Tanaka K., Benegiamo G., Hirayama A., Zhu Q., Kitamura N., Sugizaki T., Morimoto K., Itoh H., Fukuda S., Auwerx J., Tsubota K., Watanabe M.

iScience （iScience）  23 （ 9 ）  2020年09月

研究論文（学術雑誌）, 共著

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Human Metabolism; Microbiome

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Agaricus brasiliensis KA21 May Prevent Diet-Induced Nash through Its Antioxidant, Anti-Inflammatory, and Anti-Fibrotic Activities in the Liver

Nakamura A., Zhu Q., Yokoyama Y., Kitamura N., Uchida S., Kumadaki K., Tsubota K., Watanabe M.

Foods （Foods）  8 （ 11 ）  2019年11月

研究論文（学術雑誌）, 共著

　概要を見る

Non-alcoholic steatohepatitis (NASH) is a progressive disease that occurs in the liver. As the number of people with NASH has increased, effective prevention and treatment strategies are needed. Agaricus brasiliensis KA21 (AGA) is a mushroom native to Brazil and is considered a healthy food because of its purported health benefits, including its antioxidant properties. In this study, we focused on the oxidative stress that accompanies the onset of NASH and examined whether AGA can prevent NASH development through its antioxidant activity. We used a mouse model of NASH in which pathogenesis was promoted by dietary induction. Supplementation with AGA attenuated the development of hepatic fibrosis, which is a characteristic feature of late-stage NASH. This effect appeared to be mechanistically linked to an AGA-promoted reduction in hepatic oxidative stress. These results demonstrate a novel role for AGA in NASH prevention.

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Melon GliSODin® prevents diet-induced NASH onset by reducing fat synthesis and improving liver function

Nakamura A., Kitamura N., Yokoyama Y., Uchida S., Kumadaki K., Tsubota K., Watanabe M.

Nutrients （Nutrients）  11 （ 8 ） E1779 2019年08月

　概要を見る

A high-calorie diet causes fat accumulation and oxidative stress in the liver, leading to fatty liver and eventually non-alcoholic steatohepatitis (NASH). Melon GliSODin® is used as a nutritional supplement because of its antioxidant activity. This study aimed to assess the antioxidant activity of Melon GliSODin® and its effectiveness in preventing NASH, which primarily results from oxidative stress. Furthermore, we verified the protective effect of Melon GliSODin® by administering it to a mouse model of diet-induced NASH. Melon GliSODin® suppressed liver fibrosis and fat accumulation, which is characteristic of the NASH phenotype. Gene expression analysis confirmed the suppression of fat synthesis and activation of antioxidative mechanisms. These results show that Melon GliSODin® mitigates NASH onset at the molecular level, suggesting its potential application as a NASH preventive agent.

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Vegetarian diets and glycemic control in diabetes: a systematic review and meta-analysis.

Yokoyama Y, Barnard ND, Levin SM, Watanabe M.

Cardiovascular Diagonosis Therapy 4 （ (5) ） 373 - 382 2014年10月

共著, 査読有り

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Metabolic Effects of Bee Larva-Derived Protein in Mice: Assessment of an Alternative Protein Source

Yoko Yokoyama, Kawori Shinohara, Naho Kitamura, Anna Nakamura, Ai Onoue, Kazuki Tanaka, Akiyoshi Hirayama, Wanping Aw, Shigeru Nakamura, Yoko Ogawa, Shinji Fukuda, Kazuo Tsubota, Mitsuhiro Watanabe

Foods.  10 （ 11 ） 2642 2021年11月

研究論文（学術雑誌）, 共著, 最終著者, 査読有り

　概要を見る

Food crises caused by growing global population or environmental changes are predicted in the near future; therefore, sustainable solutions are needed. Edible insects, which are rich in protein and can save feed and environmental resources, have the potential to be a sustainable alternative protein source. However, there is limited evidence on the impact on health. In this study, we investigated the biological effects of ingesting bee larva by examining their effects on amino acid, lipid, and glucose metabolism in animal models. In our animal experiments, the replacement of casein as a protein source, with edible insects, did not seem to cause any deficiency in murine amino acid levels in the plasma and liver. Metabolomic analysis of plasma metabolites showed decreased 3-methylhistidine and increased nicotinamide in the bee larva-derived protein-fed mice. Decreased levels of plasma 3-metylhistidine, an indicator of muscle degradation, implies that replacement to bee-larva protein from casein did not cause muscle degradation in vivo. We further investigated effects of increased plasma nicotinamide on peripheral tissue and found an increase in expression levels of genes involved in glucose uptake in muscle and thermogenesis in adipose tissue. These data imply that bee larva is a potential sustainable, safe and healthy alternative protein source.

Keywords: bee larva; edible insects; metabolite; nutrition balance; protein.

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A high-salt/high fat diet alters circadian locomotor activity and glucocorticoid synthesis in mice

Yokoyama Y., Nakamura T.J., Yoshimoto K., Ijyuin H., Tachikawa N., Oda H., Shiraishi R., Shinohara K., Kumadaki K., Honda S., Nakamura A., Kitamura N., Tsubota K., Watanabe M.

PLoS ONE （PLoS ONE）  15 （ 5 ） e0233386 2020年05月

共著

　概要を見る

Salt is an essential nutrient; however, excessive salt intake is a prominent public health concern worldwide. Various physiological functions are associated with circadian rhythms, and disruption of circadian rhythms is a prominent risk factor for cardiovascular diseases, cancer, and immune disease. Certain nutrients are vital regulators of peripheral circadian clocks. However, the role of a high-fat and high-salt (HFS) diet in the regulation of circadian gene expression is unclear. This study aimed to investigate the effect of an HFS diet on rhythms of locomotor activity, caecum glucocorticoid secretion, and clock gene expression in mice. Mice administered an HFS diet displayed reduced locomotor activity under normal light/dark and constant dark conditions in comparison with those administered a normal diet. The diurnal rhythm of caecum glucocorticoid secretion and the expression levels of glucocorticoid-related genes and clock genes in the adrenal gland were disrupted with an HFS diet. These results suggest that an HFS diet alters locomotor activity, disrupts circadian rhythms of glucocorticoid secretion, and downregulates peripheral adrenal gland circadian clock genes.

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Impaired pancreatic growth, beta cell mass, and beta cell function in E2F1 (-/- )mice.

Fajas L, Annicotte JS, Miard S, Sarruf D, Watanabe M, Auwerx J.

J Clin Invest. 113 （ 9 ） 1288 - 1295 2004年05月

研究論文（学術雑誌）, 共著, 査読有り

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Activation of peroxisome proliferator-activated receptor delta induces fatty acid beta-oxidation in skeletal muscle and attenuates metabolic syndrome.

Tanaka T, Yamamoto J, Iwasaki S, Asaba H, Hamura H, Ikeda Y, Watanabe M, Magoori K, Ioka RX, Tachibana K, Watanabe Y, Uchiyama Y, Sumi K, Iguchi H, Ito S, Doi T, Hamakubo T, Naito M, Auwerx J, Yanagisawa M, Kodama T, Sakai J.

Proc Natl Acad Sci U S A. 100 （ 26 ） 15924 - 15929 2003年12月

研究論文（学術雑誌）, 共著, 査読有り

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Compensation by the muscle limits the metabolic consequences of lipodystrophy in PPAR gamma hypomorphic mice.

Koutnikova H, Cock TA, Watanabe M, Houten SM, Champy MF, Dierich A, Auwerx J.

Proc Natl Acad Sci U S A. 100 （ 24 ） 14457 - 14462 2003年11月

研究論文（学術雑誌）, 共著, 査読有り

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Progesterone receptor knockout mice have an improved glucose homeostasis secondary to beta -cell proliferation.

Picard F, Watanabe M, Schoonjans K, Lydon J, O'Malley BW, Auwerx J.

Proc Natl Acad Sci U S A. 99 （ 24 ） 15644 - 15648 2002年11月

研究論文（学術雑誌）, 共著, 査読有り

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TGR5 potentiates GLP-1 secretion in response to anionic exchange resins.

Harach T, Pols TW, Nomura M, Maida A, Watanabe M, Auwerx J, Schoonjans K.

Nature. Sci Rep. 2   430 2012年

研究論文（学術雑誌）, 共著, 査読有り

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Bile Acids Increase Levels of MicroRNAs 221 and 222, Leading to Degradation of CDX2 During Esophageal Carcinogenesis

Matsuzaki J, Suzuki H, Tsugawa H, Watanabe M, Hossain S, Arai E, Saito Y, Sekine S, Akaike T, Kanai Y, Mukaisho KI, Auwerx J, Hibi T.

Gastroenterology 145 （ 6 ） 1300 - 1311 2013年12月

共著, 査読有り

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Bile acid binding resin improves hepatic insulin sensitivity by reducing cholesterol but not triglyceride levels in the liver.

Tagawa H, Irie J, Itoh A, Kusumoto Y, Kato M, Kobayashi N, Tanaka K, Morinaga R, Fujita M, Nakajima Y, Morimoto K, Sugizaki T, Kawano Y, Yamada S, Kawai T, Watanabe M, Itoh H.

Diabetes Res Clin Pract 109 （ (1) ） 85 - 94 2015年

研究論文（学術雑誌）, 共著, 査読有り

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The Niemann-Pick C1 like 1 (NPC1L1) inhibitor ezetimibe improves metabolic disease via decreased liver X receptor (LXR) activity in liver of obese male mice.

Sugizaki T, Watanabe M(Corresponding Author), Horai Y, Kaneko-Iwasaki N, Arita E, Miyazaki T, Morimoto K, Honda A, Irie J, Itoh H.

Endocrinology 155 （ (8) ） 2810 - 2810 2014年04月

研究論文（学術雑誌）, 単著, 査読有り

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Intestinal Bile Acid Composition Modulates Prohormone Convertase 1/3 (PC1/3) Expression and Consequent GLP-1 Production in Male Mice.

Morimoto K, Watanabe M, Sugizaki T, Irie J, Itoh H.

Endocrinology 157 （ 3 ） 1071 - 1081 2016年03月

研究論文（学術雑誌）, 共著

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Bile acid binding resin prevents fat accumulation through intestinal microbiota in high-fat diet-induced obesity in mice. Metabolism.

Kusumoto Y, Irie J, Iwabu K, Tagawa H, Itoh A, Kato M, Kobayashi N, Tanaka K, Kikuchi R, Fujita M, Nakajima Y, Morimoto K, Sugizaki T, Yamada S, Kawai T, Watanabe M, Oike Y, Itoh H.

Metabolism 71   1 - 6 2017年06月

研究論文（学術雑誌）, 共著

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Sutureless microvascular anastomosis assisted by an expandable shape-memory alloy stent.

Saegusa N, Sarukawa S, Ohta K, Takamatsu K, Watanabe M, Sugino T, Nakagawa M, Akiyama Y, Kusuhara M, Kishi K, Inoue K.

PLoS One 12 （ 7 ） e0181520 2017年07月

研究論文（学術雑誌）, 共著

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Claudin 2 deficiency reduces bile flow and increases susceptibility to cholesterol gallstone disease in mice.

Matsumoto K, Imasato M, Yamazaki Y, Tanaka H, Watanabe M, Eguchi H, Nagano H, Hikita H, Tatsumi T, Takehara T, Tamura A, Tsukita S.

Gastroenterology 147 （ (5) ） 1134 - 1145 2014年07月

共著, 査読有り

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Bile acids induce monocyte differentiation toward interleukin-12 hypo-producing dendritic cells via a TGR5-dependent pathway.

Ichikawa R, Takayama T, Yoneno K, Kamada N, Kitazume MT, Higuchi H, Matsuoka K, Watanabe M, Itoh H, Kanai T, Hisamatsu T, Hibi T.

Immunology 136 （ 2 ） 153 - 162 2012年06月

共著, 査読有り

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Loss of claudin-15, but not claudin-2, causes Na+ deficiency and glucose malabsorption in mouse small intestine.

Tamura A, Hayashi H, Imasato M, Yamazaki Y, Hagiwara A, Wada M, Noda T, Watanabe M, Suzuki Y, and Tsukita S.

Gastroenterology 140   913 - 923 2011年03月

共著, 査読有り

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Serum bile acid along with plasma incretins and serum high-molecular weight adiponectin levels are increased after bariatric surgery.

Nakatani H, Kasama K, Oshiro t, Watanabe M, Hirose H, Itoh H.

Metabolism 58   1400 - 1407 2009年

共著, 査読有り

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Loss of Orphan Receptore Small Heterodimer Partner Sensitizes Mice to liver injury from obstructive cholestasis.

Park YJ, Qatanani M, Chua SS, LaRey JL, Johnson SA, Watanabe M, Moore DD, Lee YK

Hepatology 47 （ 5 ） 1578 - 1586 2008年05月

研究論文（学術雑誌）, 共著, 査読有り

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Ligand-dependent contribution of RXRbeta to cholesterol homeostasis in Sertoli cells.

Mascrez B, Ghyselinck NB, Watanabe M, Annicotte JS, Chambon P, Auwerx J, Mark M.

EMBO Rep. 5   285 - 290 2004年

査読有り

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The regulation of glucose and lipid homeostasis via PLTP as a mediator of BAT–liver communication

Sponton C.H., Hosono T., Taura J., Jedrychowski M.P., Yoneshiro T., Wang Q., Takahashi M., Matsui Y., Ikeda K., Oguri Y., Tajima K., Shinoda K., Pradhan R.N., Chen Y., Brown Z., Roberts L.S., Ward C.C., Taoka H., Yokoyama Y., Watanabe M., Karasawa H., Nomura D.K., Kajimura S.

EMBO Reports （EMBO Reports）  21 （ 9 ） e49848 2020年07月

ISSN  1469221X

　概要を見る

While brown adipose tissue (BAT) is well-recognized for its ability to dissipate energy in the form of heat, recent studies suggest multifaced roles of BAT in the regulation of glucose and lipid homeostasis beyond stimulating thermogenesis. One of the functions involves interorgan communication with metabolic organs, such as the liver, through BAT-derived secretory factors, a.k.a., batokine. However, the identity and the roles of such mediators remain insufficiently understood. Here, we employed proteomics and transcriptomics in human thermogenic adipocytes and identified previously unappreciated batokines, including phospholipid transfer protein (PLTP). We found that increased circulating levels of PLTP, via systemic or BAT-specific overexpression, significantly improve glucose tolerance and insulin sensitivity, increased energy expenditure, and decrease the circulating levels of cholesterol, phospholipids, and sphingolipids. Such changes were accompanied by increased bile acids in the circulation, which in turn enhances glucose uptake and thermogenesis in BAT. Our data suggest that PLTP is a batokine that contributes to the regulation of systemic glucose and lipid homeostasis as a mediator of BAT-liver interorgan communication.

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Claudin-3 regulates bile canalicular paracellular barrier and cholesterol gallstone core formation in mice

Tanaka H., Imasato M., Yamazaki Y., Matsumoto K., Kunimoto K., Delpierre J., Meyer K., Zerial M., Kitamura N., Watanabe M., Tamura A., Tsukita S.

Journal of Hepatology （Journal of Hepatology）  69 （ 6 ） 1308 - 1316 2018年12月

研究論文（学術雑誌）, 共著,  ISSN  01688278

　概要を見る

Background & Aims: Most cholesterol gallstones have a core consisting of inorganic and/or organic calcium salts, although the mechanisms of core formation are poorly understood. We examined whether the paracellular permeability of ions at hepatic tight junctions is involved in the core formation of cholesterol gallstones, with particular interest in the role of phosphate ion, a common food additive and preservative. Methods: We focused on claudin-3 (Cldn3), a paracellular barrier-forming tight junction protein whose expression in mouse liver decreases with age. Since Cldn3-knockout mice exhibited gallstone diseases, we used them to assess the causal relationship between paracellular phosphate ion permeability and the core formation of cholesterol gallstones. Results: In the liver of Cldn3-knockout mice, the paracellular phosphate ion permeability through hepatic tight junctions was significantly increased, resulting in calcium phosphate core formation. Cholesterol overdose caused cholesterol gallstone disease in these mice. Conclusion: We revealed that in the hepatobiliary system, Cldn3 functions as a paracellular barrier for phosphate ions, to help maintain biliary ion homeostasis. We provide in vivo evidence that elevated phosphate ion concentrations play a major role in the lifestyle- and age-related risks of developing cholesterol gallstone disease under cholesterol overdose. Lay summary: Herein, we reveal a new mechanism for cholesterol gallstone formation, in which increased paracellular phosphate ion permeability across hepatobiliary epithelia causes calcium phosphate core formation and cholesterol gallstones. Thus, altered phosphate ion metabolism under cholesterol overdose plays a major role in the lifestyle- and age-related risks of developing cholesterol gallstone disease.

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Lithocholic acid, a bacterial metabolite reduces breast cancer cell proliferation and aggressiveness

Mikó E., Vida A., Kovács T., Ujlaki G., Trencsényi G., Márton J., Sári Z., Kovács P., Boratkó A., Hujber Z., Csonka T., Antal-Szalmás P., Watanabe M., Gombos I., Csoka B., Kiss B., Vígh L., Szabó J., Méhes G., Sebestyén A., Goedert J.J., Bai P.

Biochimica et Biophysica Acta - Bioenergetics （Biochimica et Biophysica Acta - Bioenergetics）  1859 （ 9 ） 958 - 974 2018年09月

研究論文（学術雑誌）,  ISSN  00052728

　概要を見る

Our study aimed at finding a mechanistic relationship between the gut microbiome and breast cancer. Breast cancer cells are not in direct contact with these microbes, but disease could be influenced by bacterial metabolites including secondary bile acids that are exclusively synthesized by the microbiome and known to enter the human circulation. In murine and bench experiments, a secondary bile acid, lithocholic acid (LCA) in concentrations corresponding to its tissue reference concentrations (< 1 μM), reduced cancer cell proliferation (by 10–20%) and VEGF production (by 37%), aggressiveness and metastatic potential of primary tumors through inducing mesenchymal-to-epithelial transition, increased antitumor immune response, OXPHOS and the TCA cycle. Part of these effects was due to activation of TGR5 by LCA. Early stage breast cancer patients, versus control women, had reduced serum LCA levels, reduced chenodeoxycholic acid to LCA ratio, and reduced abundance of the baiH (7α/β-hydroxysteroid dehydroxylase, the key enzyme in LCA generation) gene in fecal DNA, all suggesting reduced microbial generation of LCA in early breast cancer.

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Bile acid metabolism regulated by the gut microbiota promotes non-alcoholic steatohepatitis-associated hepatocellular carcinoma in mice

Yamada S., Takashina Y., Watanabe M., Nagamine R., Saito Y., Kamada N., Saito H.

Oncotarget （Oncotarget）  9 （ 11 ） 9925 - 9939 2018年01月

研究論文（学術雑誌）

　概要を見る

Gut microbiota plays a significant role in the development of hepatocellular carcinoma (HCC) in non-alcoholic steatohepatitis (NASH). However, understanding of the precise mechanism of this process remains incomplete. A new class steatohepatitis-inducing high-fat diet (HFD), namely STHD-01, can promote the development of HCC without the administration of chemical carcinogens. Using this diet, we comprehensively analyzed changes in the gut microbiota and its metabolic functions during the development of HCC in NASH. Mice fed the STHD-01 developed NASH within 9 weeks. NASH further progressed into HCC by 41 weeks. Treatment with antibiotics significantly attenuated liver pathology and suppressed tumor development, indicating the critical role of the gut microbiota in tumor development in this model. Accumulation of cholesterol and bile acids in the liver and feces increased after feeding the mice with STHD-01. Treatment with antibiotics did not reverse these phenotypes. In contrast, accumulation of secondary bile acids was dramatically reduced after the treatment with antibiotics, suggesting the critical role of the gut microbiota in the conversion of primary bile acids to secondary bile acids. Secondary bile acids such as deoxycholic acid activated the mTOR, pathway in hepatocytes. Activation of mTOR was observed in the liver of mice fed STHD-01, and the activation was reduced when mice were treated with antibiotics. Collectively, bile acid metabolism by the gut microbiota promotes HCC development in STHD-01- induced NASH.

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Dietary Cholesterol Reduces Plasma Triacylglycerol in Apolipoprotein E-Null Mice: Suppression of Lipin-1 and -2 in the Glycerol-3-Phosphate Pathway.

30. Obama T, Nagaoka S, Akagi K, Kato R, Horiuchi N, Horai Y, Aiuchi T, Arata S, Yamaguchi T, Watanabe M, Itabe H.

PLoS ONE 6 （ 8 ） e22917 2011年08月

研究論文（学術雑誌）, 共著, 査読有り

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PARP-2 controls adipocyte differentiation and adipose tissue function through the regulation of the activity of the RXR/PPARgamma heterodimer.

Bai P, Houten SM, Huber A, Schreiber V, Watanabe M, Kiss B, de Murcia G, Auwerx J, Ménissier-de Murcia J.

J Biol Chem 282 （ 52 ） 37738 - 37746 2007年12月

共著, 査読有り

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Tysnd1 Deficiency in Mice Interferes with the Peroxisomal Localization of PTS2 Enzymes, Causing Lipid Metabolic Abnormalities and Male Infertility

Mizuno Y, Ninomiya Y, Nakachi Y, Iseki M, Iwasa H, Akita M, Tsukui T, Shimozawa N, Ito C, Toshimori K, Nishimukai M, Hara H, Maeba R, Okazaki T, Alodaib AN, Al Amoudi M, Jacob M, Alkuraya FS, Horai Y, Watanabe M, Motegi H, Wakana S, Noda T, Kurochkin IV, Mizuno Y, Schönbach C, Okazaki Y.

PLoS Genet 9 （ 2 ） e1003286 2013年02月

研究論文（学術雑誌）, 共著, 査読有り

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Randomized, crossover clinical efficacy trial in humans and mice on tear secretion promotion and lacrimal gland protection by molecular hydrogen

Kubota M., Kawashima M., Inoue S., Imada T., Nakamura S., Kubota S., Watanabe M., Takemura R., Tsubota K.

Scientific Reports 11 （ 1 ）  2021年12月

共著

　概要を見る

The incidence of dry eye disease is increasing worldwide because of the aging population and increasing use of information technology. Dry eye disease manifests as tear-layer instability and inflammation caused by osmotic hypersensitization in tear fluids; however, to our knowledge, no agent that treats both pathologies simultaneously is available. Molecular hydrogen (H2) is known to be effective against various diseases; therefore, we aimed to elucidate the effects of H2 on tear dynamics and the treatment of dry eye disease. We revealed that administering a persistent H2-generating supplement increased the human exhaled H2 concentration (p < 0.01) and improved tear stability (p < 0.01) and dry eye symptoms (p < 0.05) significantly. Furthermore, H2 significantly increased tear secretion in healthy mice (p < 0.05) and significantly suppressed tear reduction in a murine dry eye model (p = 0.007). H2 significantly and safely improved tear stability and dry eye symptoms in a small exploratory group of 10 human subjects, a subset of whom reported dry eye symptoms prior to treatment. Furthermore, it increased tear secretion rapidly in normal mice. Therefore, H2 may be a safe and effective new treatment for dry eye disease and thus larger trials are warranted.

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Neuroprotective role of retinal SIRT3 against acute photo-stress.

Ban N, Ozawa Y, Osada H, Lin JB, Toda E, Watanabe M, Yuki K, Kubota S, Apte RS, Tsubota K.

NPJ Aging Mech Dis .  ３   19 2017年12月

研究論文（学術雑誌）, 共著

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Aerobic exercise increases tear secretion in type 2 diabetic mice.

Sano K, Kawashima M, Ito A, Inaba T, Morimoto K, Watanabe M, Tsubota K.

Invest Ophthalmol Vis Sci. 55 （ (7) ） 4287 - 4294 2014年05月

研究論文（学術雑誌）, 共著, 査読有り

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Calorie restriction (CR) and CR mimetics for the prevention and treatment of age-related eye disorders

Kawashima M, Ozawa Y, Shinmura K, Inaba T, Nakamura S, Kawakita T, Tsubota K.

Experimental Gerontology 48 （ 10 ） 1096 - 1100 2013年10月

共著, 査読有り

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Light-dark condition regulates sirtuin mRNA levels in the retina

Ban N, Ozawa Y, Inaba T, Miyake S, Shinmura K, Tsubota K.

Experimental Gerontology 48 （ 11 ） 1212 - 1217 2013年04月

研究論文（学術雑誌）, 共著, 査読有り

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Dietary Lactoferrin Alleviates Age-Related Lacrimal Gland Dysfunction in Mice.

Kawashima M, Kawakita T, Inaba T, Okada N, Ito M, Shimmura S, Watanabe M, Shinmura K, Tsubota K.

PLoS ONE 7 （ 3 ） 1 - 8 2012年03月

研究論文（学術雑誌）, 共著, 査読有り

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In vitro algaecide effect of disinfectants on Prototheca zopfii genotypes 1 and 2.

Sobukawa H, Watanabe M, Kano R, Ito T, Onozaki M, Hasegawa A, Kamata H.

J Vet Med Sci .  73 （ 11 ） 1527 - 1529 2011年11月

研究論文（学術雑誌）, 共著

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Induction of the acyl-coenzyme A synthetase gene by fibrates and fatty acids is mediated by a peroxisome proliferator response element in the C promoter.

Schoonjans K, Watanabe M, Suzuki H, Mahfoudi M, Krey G, Wahli W, Grimaldi P, Staels B, Yamamoto T, Auwerx J.

J Biol Chem. 270 （ 33 ） 19269 - 19276 1995年08月

研究論文（学術雑誌）, 共著, 査読有り

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Multiple promoters in rat acyl-CoA synthetase gene mediate differential expression of multiple transcripts with 5'-end heterogeneity.

Suzuki H, Watanabe M, Fujino T, Yamamoto T.

J Biol Chem. 270 （ 16 ） 9676 - 9682 1995年04月

研究論文（学術雑誌）, 共著, 査読有り

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肝トリグリセリド合成の制御機構の解析 コレステロール摂取によるlipin発現の抑制.

小浜孝士, 赤木和貴, 長岡彩香, 堀内尚美, 加藤里奈, 山口智広, 渡辺光博, 板部洋之.

脂質生化学研究 52   115 - 118 2010年05月

研究論文（学術雑誌）, 共著,  ISSN  02851520

胆汁酸代謝網羅的解析による老化機構解明

渡辺光博

上原記念生命科学財団研究報告集 23   1 - 7 2009年12月

研究論文（大学，研究機関等紀要）, 単著

シグナル伝達分子としての胆汁酸の生態制御機能網羅的解析と老化制御研究への応用

渡辺光博, 谷川原祐介, 伊藤裕.

大和証券ヘルス財団研究業績集 32   58 - 63 2009年03月

研究論文（大学，研究機関等紀要）, 共著

Porphyran from discolored nori prevents metabolic syndrome through microbiota-bile acid-ceramide

Yokoyama Y.,Takashina Y., Morel J-D.,Taworntawat T.,Kitamura N., Nagano U., Tanigaki T., Nakamura A., Miyazaki T., Taoka H., Mottis A., Perino A., Shinjo A., Suzuki N., Takekawa S., Fukuda S., Honda A., Ishihara K., Arita M., Tsubota K., Auwerx J., Watanabe M.

iScience （Science Direct）  28 （ 6 ） 112603 2025年06月

研究論文（学術雑誌）, 共著, 最終著者, 責任著者

　概要を見る

Nori is a component of the traditional Japanese diet. The Japanese have a low prevalence of obesity and cardiovascular disease worldwide, and components of nori may have disease-preventive effects. Here, we focused on porphyran, which is abundant in nori that is discarded due to discoloration, and investigated the effects of nori-derived porphyran on gut microbiota, bile acid composition, and ceramide synthesis. Administration of porphyran to mice prevented obesity, diabetes, metabolic dysfunction-associated steatohepatitis (MASH), and hepatocellular carcinoma (HCC). This improvement correlates with a decrease in secondary bile acids, a decrease in intestinal farnesoid X receptor (FXR) signaling, and a marked decrease in blood ceramide. Porphyran, abundant in discolored nori, should be the subject of future translational research to prevent diseases with significant unmet medical needs and improve global environmental sustainability.

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