Exp Clin Endocrinol Diabetes 2017; 125(03): 183-190
DOI: 10.1055/s-0042-112367
Article
© Georg Thieme Verlag KG Stuttgart · New York

Hypothyroidism Induces a Moderate Steatohepatitis Accompanied by Liver Regeneration, Mast Cells Infiltration, and Changes in the Expression of the Farnesoid X Receptor

J. Rodríguez-Castelán
1   Doctorado en Ciencias Biológicas, Universidad Autónoma de Tlaxcala, Tlaxcala, México
,
A. Corona-Pérez
1   Doctorado en Ciencias Biológicas, Universidad Autónoma de Tlaxcala, Tlaxcala, México
,
L. Nicolás-Toledo
2   Centro Tlaxcala de Biología de la Conducta, Universidad Autónoma de Tlaxcala, Tlaxcala, México
,
M. Martínez-Gómez
2   Centro Tlaxcala de Biología de la Conducta, Universidad Autónoma de Tlaxcala, Tlaxcala, México
3   Depto. de Biología Celular y Fisiología, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, México
,
F. Castelán
2   Centro Tlaxcala de Biología de la Conducta, Universidad Autónoma de Tlaxcala, Tlaxcala, México
3   Depto. de Biología Celular y Fisiología, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, México
,
E. Cuevas-Romero
2   Centro Tlaxcala de Biología de la Conducta, Universidad Autónoma de Tlaxcala, Tlaxcala, México
› Author Affiliations
Further Information

Publication History

received 07 April 2016
revised 28 June 2016

accepted 14 July 2016

Publication Date:
04 October 2016 (online)

Abstract

Hypothyroidism is associated with the development of non-alcoholic steatohepatitis, but cellular mechanisms have been scarcely analyzed. Thyroid hormones regulate the synthesis and secretion of bile acids that are endogenous ligands of the farnesoid receptor (FXRα), which have been involved in the development of non-alcoholic steatohepatitis. However, the relationship between thyroid hormones and FXRα expression in the liver is yet unknown. Control (n=6) and methimazole-induced hypothyroid (n=6) female rabbits were used to evaluate the amount of lipids and glycogen, vascularization, hepatocytes proliferation, immune cells infiltration, and expression of FXRα. Student-t or Mann-Whitney U tests were carried out to determine significant differences. Hypothyroidism induced steatosis, glycogen loss, fibrosis, and a minor vascularization in the liver. In contrast, hypothyroidism increased the proliferation of hepatocytes and the infiltration of mast cells, but did not modify the number of immune cells into sinusoids. These changes were associated with a minor anti-FXRα immunoreactivity of periportal hepatocytes and pericentral immune cells. Our results suggest that hypothyroidism induces a moderate non-alcoholic steatohepatitis, alllowing the hepatic regeneration. The FXRα may be involved in the development of non-alcoholic steatohepatitis in hypothyroid subjects.

 
  • References

  • 1 Takahashi Y, Fukusato T. Histopathology of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis. World J Gastroenterol 2014; 20: 15539-15548
  • 2 Nalbantoglu IL, Brunt EM. Role of liver biopsy in nonalcoholic fatty liver disease. World J Gastroenterol 2014; 20: 9026-9037
  • 3 Pagadala MR, Zein CO, Dasarathy S et al. Prevalence of hypothyroidism in nonalcoholic fatty liver disease. Dig Dis Sci 2012; 57: 528-534
  • 4 Ludwig U, Holzner D, Denzer C et al., EMIL-Study . Subclinical and clinical hypothyroidism and non-alcoholic fatty liver disease: a cross-sectional study of a random population sample aged 18 to 65 years. BMC Endocr Disord 2015; 15: 41
  • 5 Taş A, Köklü S, Beyazit Y et al. Thyroid hormone levels predict mortality in intensive care patients with cirrhosis. Am J Med Sci 2012; 344: 175-179
  • 6 Lopez D, Abisambra-Socarrás JF, Bedi M et al. Activation of the hepatic LDL receptor promoter by thyroid hormone. Biochim Biophys Acta 2007; 1771: 1216-1225
  • 7 Kucharz E, Olczyk K, Drózdz M et al. Influence of thyroid hormones and of methylthiouracil upon collagen content in the liver of rats with hepatic fibrosis. Endocrinologie 1986; 24: 21-25
  • 8 Olczyk K, Kucharz E, Dròzdz M. Influence of thyroid hormones and methylthiouracil upon elastin content in the liver of rats with carbon tetrachloride-induced hepatic fibrosis. Endocrinologie 1987; 25: 3-7
  • 9 Baquer NZ, Cascales M, McLean P et al. Effects of thyroid hormone deficiency on the distribution of hepatic metabolites and control of pathways of carbohydrate metabolism in liver and adipose tissue of the rat. Eur J Biochem 1976; 68: 403-413
  • 10 Zhou X, Han Y, Liu J et al. Decreased protein and gene expression of hepatic cholesterol 7a-hydroxylase associated with dilated endoplasmic reticulum in chronic hypothyroid rats. Pathol Int 2009; 59: 729-734
  • 11 Moon JH, Kim HJ, Kim HM et al. Decreased expression of hepatic low-density lipoprotein receptor-related protein 1 in hypothyroidism: a novel mechanism of atherogenic dyslipidemia in hypothyroidism. Thyroid 2013; 23: 1057-1065
  • 12 Adorini L, Pruzanski M, Shapiro D. Farnesoid X receptor targeting to treat nonalcoholic steatohepatitis. Drug Discov Today 2012; 17: 988-997
  • 13 Ma Y, Huang Y, Yan L et al. Synthetic FXR agonist GW4064 prevents diet-induced hepatic steatosis and insulin resistance. Pharm Res 2013; 30: 1447-1457
  • 14 McMahan RH, Wang XX, Cheng LL et al. Bile acid receptor activation modulates hepatic monocyte activity and improves nonalcoholic fatty liver disease. J Biol Chem 2013; 288: 11761-11770
  • 15 Laukkarinen J, Sand J, Saaristo R et al. Is bile flow reduced in patients with hypothyroidism?. Surgery 2003; 133: 288-293
  • 16 Ellis EC. Suppression of bile acid synthesis by thyroid hormone in primary human hepatocytes. World J Gastroenterol 2006; 12: 4640-4645
  • 17 Mukaisho K, Araki Y, Sugihara H et al. High serum bile acids cause hyperthyroidism and goiter. Dig Dis Sci 2008; 53: 1411-1416
  • 18 Mousa-Balabel TM, Mohamed RA. Effect of different photoperiods and melatonin treatment on rabbit reproductive performance. Vet Q 2011; 31: 165-171
  • 19 Rodríguez-Castelán J, Martínez-Gómez M, Castelán F et al. Hypothyroidism affects vascularization and promotes immune cells infiltration into pancreatic islets of female rabbits. Int J Endocrinol 2015; 2015: 917806
  • 20 Rodríguez-Castelán J, Nicolás L, Morimoto S et al. The Langerhans islet cells of female rabbits are differentially affected by hypothyroidism depending on the islet size. Endocrine 2015; 48: 811-817
  • 21 Yao X, Hou S, Zhang D et al. Regulation of fatty acid composition and lipid storage by thyroid hormone in mouse liver. Cell Biosci 2014; 4: 38
  • 22 Georgakopoulou EA, Tsimaratou K, Evangelou K et al. Specific lipofuscin staining as a novel biomarker to detect replicative and stress-induced senescence. A method applicable in cryo-preserved and archival tissues. Aging 2013; 5: 37-50
  • 23 Corona-Pérez A, Díaz-Muñoz M, Rodríguez IS et al. High sucrose intake ameliorates the accumulation of hepatic triacylglycerol promoted by restraint stress in young rats. Lipids 2015; 50: 1103-1113
  • 24 Zhong CJ, Wang K, Zhang L et al. Mast cell activation is involved in stress-induced epithelial barrier dysfunction in the esophagus. J. Dig Dis 2015; 16: 186-196
  • 25 Demir Ş, Ünübol M, Aypak SÜ et al. Histopathologic evaluation of nonalcoholic fatty liver disease in hypothyroidism-induced rats. Int J Endocrinol 2016; 2016: 5083746
  • 26 Kusunoki M, Tsutsumi K, Hara T et al. Correlation between lipid and glycogen contents in liver and insulin resistance in high-fat-fed rats treated with the lipoprotein lipase activator NO-1886. Metabolism 2002; 51: 792-795
  • 27 Kemp HF, Hundal HS, Taylor PM. Glucose transport correlates with GLUT2 abundance in rat liver during altered thyroid status. Mol Cell Endocrinol 1997; 128: 97-102
  • 28 Müller MJ, Seitz HJ. Interrelation between thyroid state and the effect of glucagon on gluconeogenesis in perfused rat livers. Biochem Pharmacol 1987; 36: 1623-1627
  • 29 Cable EE, Finn PD, Stebbins JW et al. Reduction of hepatic steatosis in rats and mice after treatment with a liver-targeted thyroid hormone receptor agonist. Hepatology 2009; 49: 407-417
  • 30 McCuskey RS, Ito Y, Robertson GR et al. Hepatic microvascular dysfunction during evolution of dietary steatohepatitis in mice. Hepatology 2004; 40: 386-393
  • 31 Farrell GC, Teoh NC, McCuskey RS. Hepatic microcirculation in fatty liver disease. Anat Rec 2008; 291: 684-692
  • 32 Ijaz S, Yang W, Winslet MC et al. Impairment of hepatic microcirculation in fatty liver. Microcirculation 2003; 10: 447-456
  • 33 Spadaro L, Bolognesi M, Pierobon A et al. Alterations in thyroid Doppler arterial resistance indices, volume and hormones in cirrhosis: relationships with splanchnic haemodynamics. Ultrasound Med Biol 2004; 30: 19-25
  • 34 Rosenstengel S, Stoeppeler S, Bahde R et al. Type of steatosis influences microcirculation and fibrogenesis in different rat strains. J Invest Surg 2011; 24: 273-282
  • 35 Hamano M, Ezaki H, Kiso S et al. Lipid overloading during liver regeneration causes delayed hepatocyte DNA replication by increasing ER stress in mice with simple hepatic steatosis. J Gastroenterol 2014; 49: 305-316
  • 36 Veteläinen R, van Vliet AK, van Gulik TM. Severe steatosis increases hepatocellular injury and impairs liver regeneration in a rat model of partial hepatectomy. Ann Surg 2007; 245: 44-50
  • 37 López-Fontal R, Zeini M, Través PG et al. Mice lacking thyroid hormone receptor Beta show enhanced apoptosis and delayed liver commitment for proliferation after partial hepatectomy. PLoS One 2010; 5:
  • 38 Khandoga A, Mende K, Iskandarov E et al. Augmenter of liver regeneration attenuates inflammatory response in the postischemic mouse liver in vivo. J Surg Res 2014; 192: 187-194
  • 39 Vonghia L, Francque S. Cross talk of the immune system in the adipose tissue and the liver in non-alcoholic steatohepatitis: Pathology and beyond. World J Hepatol 2015; 7: 1905-1912
  • 40 Koruk ST, Ozardali I, Dincoglu D et al. Increased liver mast cells in patients with chronic hepatitis C. Indian J Pathol Microbiol 2011; 54: 736-740
  • 41 Yamashiro M, Kouda W, Kono N et al. Distribution of intrahepatic mast cells in various hepatobiliary disorders. An immunohistochemical study. Virchows Arch 1998; 433: 471-479
  • 42 Yang MQ, Ma YY, Ding J et al. The role of mast cells in ischemia and reperfusion injury. Inflamm Res 2014; 63: 899-905
  • 43 Gebhardt R, Matz-Soja M. Liver zonation: Novel aspects of its regulation and its impact on homeostasis. World J Gastroenterol 2014; 20: 8491-8504
  • 44 Borude P, Edwards G, Walesky C et al. Hepatocyte-specific deletion of farnesoid X receptor delays but does not inhibit liver regeneration after partial hepatectomy in mice. Hepatology 2012; 56: 2344-2352
  • 45 Fickert P, Fuchsbichler A, Moustafa T et al. Farnesoid X receptor critically determines the fibrotic response in mice but is expressed to a low extent in human hepatic stellate cells and periductal myofibroblasts. Am J Pathol 2009; 175: 2392-2405
  • 46 Anaya-Hernández A, Méndez-Tepepa M, Hernández-Aragón LG et al. Farnesoid X receptor immunolocalization in reproductive tissues of adult female rabbits. Acta Histochem 2014; 116: 1068-1074
  • 47 Zandieh-Doulabi B, Dop E, Schneiders M et al. Zonal expression of the thyroid hormone receptor alpha isoforms in rodent liver. J Endocrinol 2003; 179: 379-385
  • 48 Perrotta C, Buldorini M, Assi E et al. The thyroid hormone triiodothyronine controls macrophage maturation and functions: protective role during inflammation. Am J Pathol 2014; 184: 230-247
  • 49 Cano-Europa E, Blas-Valdivia V, Franco-Colin M et al. Methimazole-induced hypothyroidism causes cellular damage in the spleen, heart, liver, lung and kidney. Acta Histochem 2011; 113: 1-5