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Horm Metab Res 2019; 51(02): 127-133
DOI: 10.1055/a-0822-3066
Endocrine Care
© Georg Thieme Verlag KG Stuttgart · New York

Reduced Gene Expression of Peroxisome Proliferator-Activated Receptor Gamma Coactivator-1α in Whole Blood in Euthyroid Patients One Year After Hemithyroidectomy for Benign Euthyroid Goiter

Tina Toft Kristensen
1   Department of Ear, Nose, Throat and Maxillofacial Surgery, Zealand University Hospital in Køge and Roskilde, Køge, Denmark
,
Palle Lyngsie Pedersen
2   Department of Clinical Biochemistry, Næstved Hospital, Region Zealand, Næstved, Denmark
,
Jacob Larsen
3   Department of Pathology, Zealand University Hospital in Køge and Roskilde, Køge, Denmark
,
Anne-Dorthe Feldthusen
4   Department of Gynecology and Obstetrics, Næstved Hospital, Region Zealand, Næstved, Denmark
,
Søren Jelstrup
1   Department of Ear, Nose, Throat and Maxillofacial Surgery, Zealand University Hospital in Køge and Roskilde, Køge, Denmark
,
Christina Ellervik
5   Department of Production, Research, and Innovation, Region Zealand, Sorø, Denmark
6   Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
› Author Affiliations
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Publication History

received 20 April 2018

accepted 11 December 2018

Publication Date:
13 February 2019 (online)

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Abstract

We have previously reported decreased thyroid function within the laboratory reference range and changes in mitochondrial function after hemithyroidectomy. Peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) and coactivator-1β (PGC-1β) are key regulators of mitochondrial biogenesis and function. The aim was to examine the influence of hemithyroidectomy on the longitudinal change in mRNA expression of these genes. In addition, we measured longitudinal changes in mRNA expressions of the mitochoncrial-related genes nuclear factor erythroid-derived 2-like 2 (NFE2L2), mitochondrial transcription factor A (TFAM), and sodium dismutase 2 (SOD2). Twenty-eight patients were examined before and 1, 3, 6, and 12 months after hemithyroidectomy for benign euthyroid goiter. Thyroid stimulating hormone (TSH) and thyroid hormones were measured, and whole blood gene expression of PGC-1α, PGC-1β, NFE2L2, TFAM, and SOD2 was examined by reverse transcription quantitative Polymerase Chain Reaction. We used mixed effect regression models to investigate changes in gene expression with time. Averaged over all follow-up visits, TSH increased (p=0.001), tT3 declined (p=0.01), and fT4/tT3 ratio increased (p=0.03) over one-year follow-up, but fT4 remained unchanged. Averaged over all follow-up visits, whole blood PGC-1α levels (p<0.001) and SOD2 (p=0.009) levels declined, but PGC-1β, TFAM, and NFE2L2 did not change over one-year follow-up. The study demonstrates significant downregulation of whole blood PGC-1α and SOD2 gene expressions in hemithyroidectomized patients with a concomitant increase in TSH concentration within the reference range. Thus, hemithyroidectomized patients may likely have impaired mitochondrial function.

Key words

thyroidectomy - thyroid hormone - hypothyroidism - peroxisome proliferator-activated receptor gamma coactivator-1α - sodium dismutase 2

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  • References

  • 1 Said M, Chiu V, Haigh PI. Hypothyroidism after hemithyroidectomy. World J Surg 2013; 37: 2839-2844
    CrossrefPubMedGoogle Scholar
  • 2 Ahn D, Sohn JH, Jeon JH. hypothyroidism following hemithyroidectomy: incidence, risk factors, and clinical characteristics. J Clin Endocrinol Metab 2016; 101: 1429-1436
    CrossrefPubMedGoogle Scholar
  • 3 Park S, Jeon MJ, Song E, Oh HS, Kim M, Kwon H, Kim TY, Hong SJ, Shong YK, Kim WB, Sung TY, Kim WG. Clinical features of early and late postoperative hypothyroidism after lobectomy. J Clin Endocrinol Metab 2017; 102: 1317-1324
    CrossrefPubMedGoogle Scholar
  • 4 Verloop H, Louwerens M, Schoones JW, Kievit J, Smit JW, Dekkers OM. Risk of hypothyroidism following hemithyroidectomy: Systematic review and meta-analysis of prognostic studies. J Clin Endocrinol Metab 2012; 97: 2243-2255
    CrossrefPubMedGoogle Scholar
  • 5 Toft Kristensen T, Larsen J, Pedersen PL, Feldthusen AD, Ellervik C, Jelstrup S, Kvetny J. Weight gain and serum tsh increase within the reference range after hemithyroidectomy indicate lowered thyroid function. J Thyroid Res 2014; 892573
    PubMedGoogle Scholar
  • 6 Toft Kristensen T, Larsen J, Pedersen PL, Feldthusen AD, Anthonsen S, Jelstrup S, Kvetny J. Persistent metabolic changes after hemithyroidectomy for benign euthyroid goiter. Eur Thyroid J 2014; 10-16
    PubMedGoogle Scholar
  • 7 Kim B. Thyroid hormone as a determinant of energy expenditure and the basal metabolic rate. Thyroid 2008; 18: 141-144
    CrossrefPubMedGoogle Scholar
  • 8 Weitzel JM, Iwen AK. Coordination of mitochondrial biogenesis by thyroid hormone. Mol Cell Endocrinol 2011; 342: 1-7
    CrossrefPubMedGoogle Scholar
  • 9 Kuiper GG, Kester MH, Peeters RP, Visser TJ. Biochemical mechanisms of thyroid hormone deiodination. Thyroid 2005; 15: 787-798
    CrossrefPubMedGoogle Scholar
  • 10 Cheng SY, Leonard JL, Davis PJ. Molecular aspects of thyroid hormone actions. Endocr Rev 2010; 31: 139-170
    CrossrefPubMedGoogle Scholar
  • 11 Puigserver P, Spiegelman BM. Peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1 alpha): Transcriptional coactivator and metabolic regulator. Endocr Rev 2003; 24: 78-90
    CrossrefPubMedGoogle Scholar
  • 12 Lin J, Puigserver P, Donovan J, Tarr P, Spiegelman BM. Peroxisome proliferator-activated receptor gamma coactivator 1beta (PGC-1beta), a novel PGC-1-related transcription coactivator associated with host cell factor. J Biol Chem 2002; 277: 1645-1648
    CrossrefPubMedGoogle Scholar
  • 13 Irrcher I, Adhihetty PJ, Sheehan T, Joseph AM, Hood DA. PPARgamma coactivator-1alpha expression during thyroid hormone- and contractile activity-induced mitochondrial adaptations. Am J Physiol Cell Physiol 2003; 284: C1669-C1677
    CrossrefPubMedGoogle Scholar
  • 14 Scarpulla RC, Vega RB, Kelly DP. Transcriptional integration of mitochondrial biogenesis. Trends EndocrinolMetab 2012; 23: 459-466
    PubMedGoogle Scholar
  • 15 Baldelli S, Aquilano K, Ciriolo MR. Punctum on two different transcription factors regulated by PGC-1alpha: Nuclear factor erythroid-derived 2-like 2 and nuclear respiratory factor 2. Biochim Biophys Acta 2013; 1830: 4137-4146
    CrossrefPubMedGoogle Scholar
  • 16 Larsson NG, Wang J, Wilhelmsson H, Oldfors A, Rustin P, Lewandoski M, Barsh GS, Clayton DA. Mitochondrial transcription factor A is necessary for mtDNA maintenance and embryogenesis in mice. Nat Genet 1998; 18: 231-236
    CrossrefPubMedGoogle Scholar
  • 17 Karnati S, Luers G, Pfreimer S, Baumgart-Vogt E. Mammalian SOD2 is exclusively located in mitochondria and not present in peroxisomes. Histochem Cell Biol 2013; 140: 105-117
    CrossrefPubMedGoogle Scholar
  • 18 Fabricius MH, Wilms LK, Larsen J, Pedersen PL, Anthonsen S, Kvetny J. Measure of expression of mitochondrial related genes in human mononuclear blood cells, adipose white tissue and smooth muscle cells. Clin Chim Acta 2010; 411: 749-573
    CrossrefPubMedGoogle Scholar
  • 19 Andersen S, Pedersen KM, Bruun NH, Laurberg P. Narrow individual variations in serum T(4) and T(3) in normal subjects: A clue to the understanding of subclinical thyroid disease. J Clin Endocrinol Metab 2002; 87: 1068-1072
    CrossrefPubMedGoogle Scholar
  • 20 Kvetny J, Wilms L, Pedersen PL, Larsen J. Subclinical hypothyroidism affects mitochondrial function. Horm Metab Res 2010; 42: 324-327
    Article in Thieme ConnectPubMedGoogle Scholar
  • 21 Sivitz WI, Yorek MA. Mitochondrial dysfunction in diabetes: From molecular mechanisms to functional significance and therapeutic opportunities. Antioxid Redox Signal 2010; 12: 537-577
    CrossrefPubMedGoogle Scholar
  • 22 Konukoglu D, Ercan M, Hatemi H. Plasma viscosity in female patients with hypothyroidism: Effects of oxidative stress and cholesterol. Clin Hemorheol Microcirc 2002; 27: 107-113
    PubMedGoogle Scholar
  • 23 Torun AN, Kulaksizoglu S, Kulaksizoglu M, Pamuk BO, Isbilen E, Tutuncu NB. Serum total antioxidant status and lipid peroxidation marker malondialdehyde levels in overt and subclinical hypothyroidism. Clin Endocrinol (Oxf) 2009; 70: 469-474
    CrossrefPubMedGoogle Scholar
  • 24 Reddy VS, Gouroju S, Suchitra MM, Suresh V, Sachan A, Srinivasa Rao PV, Bitla AR. Antioxidant defense in overt and subclinical hypothyroidism. Horm Metab Res 2013; 45: 754-758
    Article in Thieme ConnectPubMedGoogle Scholar
  • 25 Crunkhorn S, Patti ME. Links between thyroid hormone action, oxidative metabolism, and diabetes risk?. Thyroid 2008; 18: 227-237
    CrossrefPubMedGoogle Scholar
  • 26 Wulf A, Harneit A, Kroger M, Kebenko M, Wetzel MG, Weitzel JM. T3-mediated expression of PGC-1alpha via a far upstream located thyroid hormone response element. Mol Cell Endocrinol 2008; 287: 90-95
    CrossrefPubMedGoogle Scholar
  • 27 Venditti P, Bari A, Di SL, Cardone A, Della RF, D'Esposito M, Di MS. Involvement of PGC-1, NRF-1, and NRF-2 in metabolic response by rat liver to hormonal and environmental signals. Mol Cell Endocrinol 2009; 305: 22-29
    CrossrefPubMedGoogle Scholar
  • 28 Bahi L, Garnier A, Fortin D, Serrurier B, Veksler V, Bigard AX, Ventura-Clapier R. Differential effects of thyroid hormones on energy metabolism of rat slow- and fast-twitch muscles. J Cell Physiol 2005; 203: 589-598
    CrossrefPubMedGoogle Scholar
  • 29 Lesmana R, Sinha RA, Singh BK, Zhou J, Ohba K, Wu Y, Yau WW, Bay BH, Yen PM. thyroid hormone stimulation of autophagy is essential for mitochondrial biogenesis and activity in skeletal muscle. Endocrinology 2016; 157: 23-38
    CrossrefPubMedGoogle Scholar
  • 30 Gharib H, Papini E, Garber JR, Duick DS, Harrell RM, Hegedus L, Paschke R, Valcavi R, Vitti P. Nodules AAATFoT. American Association of Clinical Endocrinologists, American College of Endocrinology, and Associazione Medici Endocrinologi Medical Guidelines for Clinical Practice for the Diagnosis and Management of Thyroid Nodules - 2016 Update. Endocr Pract 2016; 22: 622-639
    PubMedGoogle Scholar
  • 31 Haugen BR, Alexander EK, Bible KC, Doherty GM, Mandel SJ, Nikiforov YE, Pacini F, Randolph GW, Sawka AM, Schlumberger M, Schuff KG, Sherman SI, Sosa JA, Steward DL, Tuttle RM, Wartofsky L. 2015 American Thyroid Association Management Guidelines for Adult Patients with Thyroid Nodules and Differentiated Thyroid Cancer: The American Thyroid Association Guidelines Task Force on Thyroid Nodules and Differentiated Thyroid Cancer. Thyroid 2016; 26: 1-133
    CrossrefPubMedGoogle Scholar
  • 32 Mootha VK, Lindgren CM, Eriksson KF, Subramanian A, Sihag S, Lehar J, Puigserver P, Carlsson E, Ridderstrale M, Laurila E, Houstis N, Daly MJ, Patterson N, Mesirov JP, Golub TR, Tamayo P, Spiegelman B, Lander ES, Hirschhorn JN, Altshuler D, Groop LC. PGC-1alpha-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes. Nat Genet 2003; 34: 267-273
    CrossrefPubMedGoogle Scholar
  • 33 Mehran L, Amouzegar A, Bakhtiyari M, Mansournia MA, Kheirkhah Rahimabad P, Tohidi M, Azizi F. Variations in serum free thyroxin concentration within normal ranges predict the incidence of metabolic syndrome in non-obese adults: A Cohort Study. Thyroid 2017; 27: 886-893
    CrossrefPubMedGoogle Scholar
  • 34 Jun JE, Jee JH, Bae JC, Jin SM, Hur KY, Lee MK, Kim TH, Kim SW, Kim JH. Association between changes in thyroid hormones and incident type 2 diabetes: A seven-year longitudinal study. Thyroid 2017; 27: 29-38
    CrossrefPubMedGoogle Scholar
  • 35 Ito M, Miyauchi A, Kang S, Hisakado M, Yoshioka W, Ide A, Kudo T, Nishihara E, Kihara M, Ito Y, Kobayashi K, Miya A, Fukata S, Nakamura H, Amino N. Effect of the presence of remnant thyroid tissue on the serum thyroid hormone balance in thyroidectomized patients. Eur J Endocrinol 2015; 173: 333-340
    CrossrefPubMedGoogle Scholar