Serum Metabolomics Reveals Cholic Acid, Chenodeoxycholic Acid, and Taurochenodeoxycholic Acid as Potential Biomarkers for Hypothyroid Rats
American Journal of Life Sciences
Volume 3, Issue 4, August 2015, Pages: 295-305
Received: Jun. 7, 2015; Accepted: Jun. 21, 2015; Published: Jul. 8, 2015
Views 3753      Downloads 79
Authors
Hidenori Nagao, Pharmacokinetics Research Department of ASKA Pharmaceutical Co., Ltd., Kawasaki, Japan
Masanori Suzuki, Department of Analytical Research, ASKA Pharma Medical Co., Ltd., Kawasaki, Japan
Hironori Aoki, Pharmacokinetics Research Department of ASKA Pharmaceutical Co., Ltd., Kawasaki, Japan
Kouichi Minato, Pharmacokinetics Research Department of ASKA Pharmaceutical Co., Ltd., Kawasaki, Japan
Article Tools
Follow on us
Abstract
Hypothyroidism decreases energy metabolism including carbohydrate and lipid metabolism and protein synthesis, due to reduced serum levels of the thyroid hormones thyroxine (T4) and triiodothyronine (T3). Although many endogenous serum metabolites are influenced by hypothyroidism, serum metabolomic profiling has rarely been applied to the study of hypothyroidism. In the present study, we investigated potential biomarkers for hypothyroidism using serum metabolomics, and then measured serum levels of these endogenous metabolites using an analytical method: ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry. There was a significant difference in the metabolic profiles of thyroidectomized (Tx) and normal rats. We found that many bile acid (BA) levels were significantly changed in serum of Tx rats. Simultaneous measurement of 12 different BAs in serum revealed that cholic acid (CA), chenodeoxycholic acid (CDCA), and taurochenodeoxycholic acid (TCDCA) levels significantly increased in Tx rats by approximately 25-fold, 11-fold, and 3-fold, respectively, compared with those of control rats. In Tx rats with active hormone T3 replacement, serum T3 levels were returned to physiological levels. However, these changes in BA levels were maintained at a high level. These results indicate that T3 replacement does not normalize the thyroid hormonal milieu. Thus, increased CA, CDCA, and TCDCA levels in serum after Tx may be a homeostatic response to not only T3 but also pro-thyroid hormone T4 deficiency. This study is the first to report that CA, CDCA, and TCDCA may be potential biomarkers for hypothyroidism and the efficacy of thyroid hormone replacement therapy in hypothyroidism.
Keywords
Metabolomics, Biomarker, Bile Acid, Hypothyroidism, Thyroid Hormone Replacement Therapy
To cite this article
Hidenori Nagao, Masanori Suzuki, Hironori Aoki, Kouichi Minato, Serum Metabolomics Reveals Cholic Acid, Chenodeoxycholic Acid, and Taurochenodeoxycholic Acid as Potential Biomarkers for Hypothyroid Rats, American Journal of Life Sciences. Vol. 3, No. 4, 2015, pp. 295-305. doi: 10.11648/j.ajls.20150304.17
References
[1]
T.J. Visser, “Pathways of thyroid hormone metabolism,” Acta Med. Austriaca, vol. 23, pp. 10-16, 1996.
[2]
S.Y. Cheng, “Multiple mechanisms for regulation of the transcriptional activity of thyroid hormone receptors,” Rev. Endocr. Metab. Disord., vol. 1, pp. 9-18, 2000.
[3]
G.R. Williams, “Cloning and characterization of two novel thyroid hormone receptor β isoforms,” Mol. Cell. Biol., vol. 20, pp. 8329-8342, 2000.
[4]
H. Ying, H. Suzuki, L. Zhao, M.C. Willingham, P. Meltzer and S.Y. Cheng, “Mutant thyroid hormone receptor β represses the expression and transcriptional activity of peroxisome proliferator-activated receptor γ during thyroid carcinogenesis,” Cancer Res., vol. 63, pp. 5274-5280, 2003.
[5]
I. Jones, L. Ng, H. Liu and D. Forrest, “An intron control region differentially regulates expression of thyroid hormone receptor β2 in the cochlea, pituitary, and cone photoreceptors,” Mol. Endocrinol., vol. 21, pp. 1108-1119, 2007.
[6]
A.R. Cappola and P.W. Ladenson, “Hypothyroidism and atherosclerosis,” J. Clin. Endocrinol. Metab., vol. 88, pp. 2438-2444, 2003.
[7]
P. Cettour-Rose, C. Theander-Carrillo, C. Asensio, M. Klein, T.J. Visser, A.G. Burger, C.A. Meier and F. Rohner-Jeanrenaud, “Hypothyroidism in rats decreases peripheral glucose utilisation, a defect partially corrected by central leptin infusion,” Diabetologia, vol. 48, pp. 624-633, 2005.
[8]
A. Zhang , H. Sun, G. Yan, Y. Han, Y. Ye and X. Wang, “Urinary metabolic profiling identifies a key role for glycocholic acid in human liver cancer by ultra-performance liquid-chromatography coupled with high-definition mass spectrometry,” Clin. Chim. Acta, vol. 418, pp. 86-90, 2013.
[9]
N. Aranibar, M. Borys, N.A. Mackin, V. Ly, N. Abu-Absi, S. Abu-Absi, M. Niemitz, B. Schilling, Z.J. Li, B. Brock, R.J. Russell 2nd, A. Tymiak and M.D. Reily, “NMR-based metabolomics of mammalian cell and tissue cultures,” J. Biomol. NMR, vol. 49, pp. 195-206, 2011.
[10]
A. Lodi and S.M. Ronen, “Magnetic resonance spectroscopy detectable metabolomics fingerprint of response to antineoplastic treatment,” PLoS ONE, 6:e26155, 2011.
[11]
L.M. Raamsdonk, B. Teusink, D. Broadhurst, N.S. Zhang, A. Hayes, M.C. Walsh, J.A. Berden, K.M. Brindle, D.B. Kell, J.J. Rowland, H.V. Westerhoff, K. van Dam and S.G. Oliver, “A functional genomics strategy that uses metabolome data to reveal the phenotype of silent mutations,” Nat. Biotechnol., vol. 19, pp. 45-50, 2001.
[12]
O. Fiehn, J. Kopka, P. Dormann, T. Altmann, R.N. Trethewey and L. Willmitzer, “Metabolite profiling for plant functional genomics,” Nat. Biotechnol., vol. 18, pp. 1157-1161, 2000.
[13]
L.D. Roberts, A. Koulman and J.L. Griffin, “Towards metabolic biomarkers of insulin resistance and type 2 diabetes: progress from the metabolome,” Lancet Diabetes Endocrinol., vol. 2, pp. 65-75, 2014.
[14]
T. Soga, M. Sugimoto, M. Honma, M. Mori, K. Igarashi, K. Kashikura, S. Ikeda, A. Hirayama, T. Yamamoto, H. Yoshida, M. Otsuka, S. Tsuji, Y. Yatomi, T. Sakuragawa, H. Watanabe, K. Nihei, T. Saito, S. Kawata, H. Suzuki, M. Tomita and M. Suematsu, “Serum metabolomics reveals γ-glutamyl dipeptides as biomarkers for discrimination among different forms of liver disease,” J. Hepatol., vol. 55, pp. 896-905, 2011.
[15]
T.H. Kim, M.Y. Ahn, H.J. Lim, Y.J. Lee, Y.J. Shin, U. De, J. Lee, B.M. Lee, S. Kim and H.S. Kim, “Evaluation of metabolomic profiling against renal toxicity in Sprague-Dawley rats treated with melamine and cyanuric acid,” Arch. Toxicol., vol. 86, pp. 1885-1897, 2012.
[16]
E.J. Want, M. Coen, P. Masson, H.C. Keun, J.T. Pearce, M.D. Reily, D.G. Robertson, C.M. Rohde, E. Holmes, J.C. Lindon, R.S. Plumb and J.K. Nicholson, “Ultra performance liquid chromatography-mass spectrometry profiling of bile acid metabolites in biofluids: application to experimental toxicology studies,” Anal. Chem., vol. 82, pp. 5282-8289, 2010.
[17]
H. Nagao, T. Imazu, H. Hayashi, K. Takahashi and K. Minato, “Influence of thyroidectomy on thyroxine metabolism and turnoverrate in rats,” J. Endocrinol., vol. 210, pp. 117-123, 2011.
[18]
J.T. Herlihy, C. Stacy and H.A. Bertrand, “Long-term food restriction depresses serum thyroid hormone concentrations in the rat,” Mech. Ageing Dev., vol. 53, pp. 9-16, 1990.
[19]
T.T. Nguyen, J.J. Di Stefano, H. Yamada and Y.M. Yen, “Steady state organ distribution and metabolism of thyroxine and 3,5,3'-triiodothyronine in intestine, liver, kidneys, blood and residual carcass of the rat in vivo,” Endocrinology, vol. 133, pp. 2973-2983, 1993.
[20]
S. Fiorucci, S. Cipriani, F. Baldelli and A. Mencarelli, “Bile acid-activated receptors in the treatment of dyslipidemia and related disorders,” Prog. Lipid Res., vol. 49, pp. 171-185, 2010.
[21]
Y. Kawamata, R. Fujii, M. Hosoya, M. Harada, H. Yoshida, M. Miwa, S. Fukusumi, Y. Habata, T. Itoh, Y. Shintani, S. Hinuma, Y. Fujisawa and M. Fujino, “A G protein-coupled receptor responsive to bile acids,” J. Biol. Chem., vol. 278, pp. 9435-9440, 2003.
[22]
T. Maruyama, Y. Miyamoto, T. Nakamura, Y. Tamai, H. Okada, E. Sugiyama, T. Nakamura, H. Itadani and K. Tanaka, “Identification of membrane-type receptor for bile acids (M-BAR),” Biochem. Biophys. Res. Commun., vol. 298, pp. 714-719, 2002.
[23]
M. Watanabe, S.M. Houten, C. Mataki, M.A. Christoffolete, B.W. Kim, H. Sato, N. Messaddeq, J.W. Harney, O. Ezaki, T. Kodama, K. Schoonjans, A.C. Bianco and J. Auwerx, “Bile acids induce energy expenditure by promoting intracellular thyroid hormone activation,” Nature, vol. 439, pp. 484-489, 2006.
[24]
H.F. Escobar-Morreale, M.J. Obregon, F. Escobar Del Rey and G. Morreale De Escobar, “Replacement therapy for hypothyroidism with thyroxine alone does not ensure euthyroidism in all tissues, as studied in thyroidectomized rats,” J. Clin. Invest., vol. 96, pp. 2828-2838, 1995.
[25]
H. Nagao, M. Sasaki, T. Imazu, K. Takahashi, H. Aoki and K. Minato, “Effects of triiodothyronine on turnover rate and metabolizing enzymes for thyroxine in thyroidectomizedrats,” Life Sci., vol. 116, pp. 74-82, 2014.
[26]
A.D. Toft, “Thyroxine therapy,” N. Engl. J. Med., vol. 331, pp. 174-180, 1994.
[27]
H.F. Escobar-Morreale, M.J. Obregón, F. Escobar del Rey and G. Morreale de Escobar, “Tissue-specific patterns of changes in 3,5,3'-triiodo-L-thyronine concentrations in thyroidectomized rats infused with increasing doses of the hormone. Which are the regulatory mechanisms?,” Biochimie, vol. 81, pp. 453-462, 1999.
[28]
G.R. Williams and J.H. Bassett, “Deiodinases: the balance of thyroid hormone: local control of thyroid hormone action: role of type 2 deiodinase,” J. Endocrinol., vol. 209, pp. 261-272, 2011.
[29]
A.C. Bianco, D. Salvatore, B. Gereben, M.J. Berry and P.R. Larsen, “Biochemistry, cellular and molecular biology, and physiological roles of the iodothyronine selenodeiodinases,” Endocr. Rev., vol. 23, pp. 38-89, 2002.
[30]
A.C. Bianco and J.E. Silva, “Nuclear 3,5,3'-triiodothyronine (T3) in brown adipose tissue: receptor occupancy and sources of T3 as determined by in vivo techniques,” Endocrinology, vol. 120, pp. 55-62, 1987.
[31]
J. van Doorn, F. Roelfsema and D. van der Heide, “Conversion of thyroxine to 3,5,3'-triiodothyronine in several rat tissues in vivo: the effect of hypothyroidism,” Acta Endocrinol., vol. 113, pp. 59-64, 1986.
[32]
B. Hagenbuch, “Cellular entry of thyroid hormones by organic anion transporting polypeptides,” Best Pract. Res. Clin. Endocrinol. Metab., vol. 21, pp. 209-221, 2007.
[33]
W.E. Visser, E.C. Friesema, J. Jansen and T.J. Visser, “Thyroid hormone transport by monocarboxylate transporters,” Best Pract. Res. Clin. Endocrinol. Metab., vol. 21, pp. 223-236, 2007.
[34]
E.C. Friesema, A. Grueters, H. Biebermann, H. Krude, A. von Moers, M. Reeser, T.G. Barrett, E.E. Mancilla, J. Svensson, M.H. Kester, G.G. Kuiper, S. Balkassmi, A.G. Uitterlinden, J. Koehrle, P. Rodien, A.P. Halestrap and T.J. Visser, “Association between mutations in a thyroid hormone transporter and severe X-linked psychomotor retardation,” Lancet, vol. 364, pp. 1435-1437, 2004.
[35]
L.M. Roberts, K. Woodford, M. Zhou, D.S. Black, J.E. Haggerty, E.H. Tate, K.K. Grindstaff, W. Mengesha, C. Raman and N. Zerangue, “Expression of the thyroid hormone transporters monocarboxylate transporter-8 (SLC16A2) and organic ion transporter-14 (SLCO1C1) at the blood-brain barrier,” Endocrinology, vol. 149, pp. 6251-6261, 2008.
[36]
S. Mayerl, T.J. Visser, V.M. Darras, S. Horn and H. Heuer, “Impact of Oatp1c1 deficiency on thyroid hormone metabolism and action in the mouse brain,” Endocrinology, vol. 153, pp. 1528-1537, 2012.
ADDRESS
Science Publishing Group
1 Rockefeller Plaza,
10th and 11th Floors,
New York, NY 10020
U.S.A.
Tel: (001)347-983-5186