論文 - 渡辺　光博

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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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