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Animal Models

Hormone signaling and fatty liver in females: analysis of estrogen receptor α mutant mice

International Journal of Obesity volume 41, pages 945–954 (2017)Cite this article

Subjects

Abstract

Background:

Treatment with estrogen in early menopausal women protects against development of hepatic steatosis and nonalcoholic fatty liver disease but estrogen has undesirable side effects, which negate its beneficial effects in premenopausal and postmenopausal women. Targeted therapies require better understanding of the target sites and mechanisms by which estrogen signaling exerts its protective effects in women. Estrogen receptor α (ERα) is thought to be the primary mediator for estrogen signaling to protect against hepatic steatosis. ERα has several mechanisms for signal transduction: (1) inducing gene transcription by direct binding to specific DNA sequences, (2) inducing tethered transcription with other DNA-binding factors, and (3) stimulating nongenomic action through membrane-associated ERα. However, it is still unclear which mechanisms mediate ERα-dependent protection against hepatic steatosis.

Methods:

To understand the mechanisms of estrogen signaling for protection against hepatic steatosis in females, we analyzed the global ERα knockout mouse (αERKO), ERα DNA-binding domain mutant mouse (KIKO) and liver-specific ERα knockout mouse (LERKO) fed high-fat diets (HFD). The KIKO mouse disrupts the direct DNA-binding transcription activity but retains tethered transcription regulation and nongenomic action. Hepatic steatosis was evaluated by scoring the macrovesicular and microvesicular steatosis as well as serum alanine aminotransferase (ALT) levels. We analyzed serum testosterone to assess its correlation with hepatic steatosis.

Results:

Liver fat accumulation was far greater in HFD-fed αERKO and KIKO females than in HFD-fed wild-type (WT) controls. Conversely, HFD-fed LERKO females did not accumulate excess liver fat. HFD-fed αERKO and KIKO females showed higher microvesicular steatosis and ALT levels than WT controls that correlated with increased serum testosterone levels.

Conclusions:

ERα-mediated direct transcription in non-hepatic tissues is essential for estrogen-mediated protection against hepatic steatosis in HFD-fed females. The balance between non-hepatic estrogen signaling and hepatic or non-hepatic testosterone action may control hepatic steatosis.

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References

  1. Tiniakos DG, Vos MB, Brunt EM . Nonalcoholic fatty liver disease: pathology and pathogenesis. Annu Rev Pathol 2010; 5: 145–171.

    Article  CAS  Google Scholar 

  2. Ford ES, Kohl HW, Mokdad AH, Ajani UA . Sedentary behavior, physical activity, and the metabolic syndrome among U.S. adults. Obes Res 2005; 13: 608–614.

    Article  Google Scholar 

  3. Ambrosini GL, Huang RC, Mori TA, Hands BP, O'Sullivan TA, de Klerk NH et al. Dietary patterns and markers for the metabolic syndrome in Australian adolescents. Nutr Metab Cardiovasc Dis 2010; 20: 274–283.

    Article  CAS  Google Scholar 

  4. Koulouri O, Ostberg J, Conway GS . Liver dysfunction in Turner's syndrome: prevalence, natural history and effect of exogenous oestrogen. Clin Endocrinol (Oxf) 2008; 69: 306–310.

    Article  CAS  Google Scholar 

  5. Saphner T, Triest Robertson S, Li H, Holzman P . The association of nonalcoholic steatohepatitis and tamoxifen in patients with breast cancer. Cancer 2009; 115: 3189–3195.

    Article  CAS  Google Scholar 

  6. Flegal KM, Carroll MD, Ogden CL, Johnson CL . Prevalence and trends in obesity among US adults, 1999-2000. JAMA 2002; 288: 1723–1727.

    Article  Google Scholar 

  7. Munoz J, Derstine A, Gower BA . Fat distribution and insulin sensitivity in postmenopausal women: influence of hormone replacement. Obes Res 2002; 10: 424–431.

    Article  CAS  Google Scholar 

  8. Beral V, Bull D, Reeves G Million Women Study Collaborators. Endometrial cancer and hormone-replacement therapy in the Million Women Study. Lancet 2005; 365: 1543–1551.

    Article  Google Scholar 

  9. D'Eon TM, Souza SC, Aronovitz M, Obin MS, Fried SK, Greenberg AS . Estrogen regulation of adiposity and fuel partitioning. Evidence of genomic and non-genomic regulation of lipogenic and oxidative pathways. J Biol Chem 2005; 280: 35983–35991.

    Article  CAS  Google Scholar 

  10. Hewitt KN, Pratis K, Jones MEE, Simpson ER . Estrogen replacement reverses the hepatic steatosis phenotype in the male aromatase knockout mouse. Endocrinology 2004; 145: 1842–1848.

    Article  CAS  Google Scholar 

  11. Chow JDY, Jones MEE, Prelle K, Simpson ER, Boon WC . A selective estrogen receptor α agonist ameliorates hepatic steatosis in the male aromatase knockout mouse. J Endocrinol 2011; 210: 323–334.

    Article  CAS  Google Scholar 

  12. Maffei L, Murata Y, Rochira V, Tubert G, Aranda C, Vazquez M et al. Dysmetabolic syndrome in a man with a novel mutation of the aromatase gene: effects of testosterone, alendronate, and estradiol treatment. J Clin Endocrinol Metab 2004; 89: 61–70.

    Article  CAS  Google Scholar 

  13. Smith EP, Boyd J, Frank GR, Takahashi H, Cohen RM, Specker B et al. Estrogen resistance caused by a mutation in the estrogen-receptor gene in a man. N Engl J Med 1994; 331: 1056–1061.

    Article  CAS  Google Scholar 

  14. Heine PA, Taylor JA, Iwamoto GA, Lubahn DB, Cooke PS . Increased adipose tissue in male and female estrogen receptor-alpha knockout mice. Proc Natl Acad Sci USA 2000; 97: 12729–12734.

    Article  CAS  Google Scholar 

  15. Bryzgalova G, Gao H, Ahren B, Zierath JR, Galuska D, Steiler TL et al. Evidence that oestrogen receptor-alpha plays an important role in the regulation of glucose homeostasis in mice: insulin sensitivity in the liver. Diabetologia 2006; 49: 588–597.

    Article  CAS  Google Scholar 

  16. Arao Y, Coons LA, Zuercher WJ, Korach KS . Transactivation function-2 of estrogen receptor α contains transactivation function-1-regulating element. J Biol Chem 2015; 290: 17611–17627.

    Article  CAS  Google Scholar 

  17. Jakacka M, Ito M, Weiss J, Chien PY, Gehm BD, Jameson JL . Estrogen receptor binding to DNA is not required for its activity through the nonclassical AP1 pathway. J Biol Chem 2001; 276: 13615–13621.

    Article  CAS  Google Scholar 

  18. Acconcia F, Ascenzi P, Bocedi A, Spisni E, Tomasi V, Trentalance A et al. Palmitoylation-dependent estrogen receptor alpha membrane localization: regulation by 17beta-estradiol. Mol Biol Cell 2005; 16: 231–237.

    Article  CAS  Google Scholar 

  19. Jakacka M, Ito M, Martinson F, Ishikawa T, Lee E-J, Jameson JL . An estrogen receptor (ER) alpha deoxyribonucleic acid-binding domain knock-in mutation provides evidence for nonclassical ER pathway signaling in vivo. Mol Endocrinol 2002; 16: 2188–2201.

    Article  CAS  Google Scholar 

  20. Zhu L, Brown WC, Cai Q, Krust A, Chambon P, McGuinness OP et al. Estrogen treatment after ovariectomy protects against fatty liver and may improve pathway-selective insulin resistance. Diabetes 2013; 62: 424–434.

    Article  CAS  Google Scholar 

  21. Matic M, Bryzgalova G, Gao H, Antonson P, Humire P, Omoto Y et al. Estrogen signalling and the metabolic syndrome: targeting the hepatic estrogen receptor alpha action. PLoS One 2013; 8: e57458.

    Article  CAS  Google Scholar 

  22. Hewitt SC, Kissling GE, Fieselman KE, Jayes FL, Gerrish KE, Korach KS . Biological and biochemical consequences of global deletion of exon 3 from the ER gene. FASEB J 2010; 24: 4660–4667.

    Article  CAS  Google Scholar 

  23. Yeh MM, Brunt EM . Pathology of fatty liver: differential diagnosis of non-alcoholic fatty liver disease. Diagn Histopathol 2008; 14: 586–597.

    Article  Google Scholar 

  24. Farese RV, Zechner R, Newgard CB, Walther TC . The problem of establishing relationships between hepatic steatosis and hepatic insulin resistance. Cell Metab 2012; 15: 570–573.

    Article  CAS  Google Scholar 

  25. Tsochatzis E, Papatheodoridis GV, Archimandritis AJ . The evolving role of leptin and adiponectin in chronic liver diseases. Am J Gastroenterol 2006; 101: 2629–2640.

    Article  CAS  Google Scholar 

  26. Page ST, Herbst KL, Amory JK, Coviello AD, Anawalt BD, Matsumoto AM et al. Testosterone administration suppresses adiponectin levels in men. J Androl 2005; 26: 85–92.

    CAS  PubMed  Google Scholar 

  27. Park CJ, Zhao Z, Glidewell-Kenney C, Lazic M, Chambon P, Krust A et al. Genetic rescue of nonclassical ERα signaling normalizes energy balance in obese Erα-null mutant mice. J Clin Invest 2011; 121: 604–612.

    Article  CAS  Google Scholar 

  28. Liu S, Le May C, Wong WPS, Ward RD, Clegg DJ, Marcelli M et al. Importance of extranuclear estrogen receptor-alpha and membrane G protein-coupled estrogen receptor in pancreatic islet survival. Diabetes 2009; 58: 2292–2302.

    Article  CAS  Google Scholar 

  29. Hewitt SC, Li L, Grimm SA, Winuthayanon W, Hamilton KJ, Pockette B et al. Novel DNA motif binding activity observed in vivo with an estrogen receptor α mutant mouse. Mol Endocrinol 2014; 28: 899–911.

    Article  Google Scholar 

  30. Ahlbory-Dieker DL, Stride BD, Leder G, Schkoldow J, Trölenberg S, Seidel H et al. DNA binding by estrogen receptor-α is essential for the transcriptional response to estrogen in the liver and the uterus. Mol Endocrinol 2011; 23: 1544–1555.

    Article  Google Scholar 

  31. Behari J, Li H, Liu S, Stefanovic-Racic M, Alonso L, O'Donnell CP et al. β-catenin links hepatic metabolic zonation with lipid metabolism and diet-induced obesity in mice. Am J Pathol 2014; 184: 3284–3298.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank David Monroy and NIEHS Comparative Medicine Branch staff for animal care; Huaxia Cui and Michael Meuhlbauer (Duke Molecular Physiology Institute) for hormone assays; the staff of the NIEHS Histology Core for histology; and the staff of NIEHS Molecular Genomics Core Laboratory for microarray analysis. This study was funded by grants from the Division of Intramural Research of the NIEHS/NIH (to KSK, 1ZIAES70065), the NIDDK/NIH (to SHU, F32DK93200) and the American Diabetes Association (to MF, 7-13-BS-050).

Author contributions

SHU, DEM, KJH and SLL conceived and carried out the experiments. YA, SCH, MF and KSK conceived the experiments and analyzed data. All authors were involved in writing the paper and had final approval of the submitted version.

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Author notes

  1. S Hart-Unger and Y Arao: These authors contributed equally to this work.

Authors and Affiliations

  1. Reproductive and Development Biology Laboratory, National Institute of Environmental Health Sciences/NIH, Research Triangle Park, NC, USA

    S Hart-Unger, Y Arao, K J Hamilton, S L Lierz, S C Hewitt & K S Korach

  2. Division of Pediatric Endocrinology and Diabetes, Duke University Medical Center, Durham, NC, USA

    S Hart-Unger & M Freemark

  3. National Toxicology Program Pathology Group, National Institute of Environmental Health Sciences/NIH, Research Triangle Park, NC, USA

    D E Malarkey

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  1. S Hart-Unger
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Correspondence to K S Korach.

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Hart-Unger, S., Arao, Y., Hamilton, K. et al. Hormone signaling and fatty liver in females: analysis of estrogen receptor α mutant mice. Int J Obes 41, 945–954 (2017). https://doi.org/10.1038/ijo.2017.50

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