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Role of Estrogens in the Regulation of Liver Lipid Metabolism

  • Brian T. Palmisano
  • Lin Zhu
  • John M. Stafford
Chapter
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1043)

Abstract

Before menopause, women are protected from atherosclerotic heart disease associated with obesity relative to men. Sex hormones have been proposed as a mechanism that differentiates this risk. In this review, we discuss the literature around how the endogenous sex hormones and hormone treatment approaches after menopause regulate fatty acid, triglyceride, and cholesterol metabolism to influence cardiovascular risk.

The important regulatory functions of estrogen signaling pathways with regard to lipid metabolism have been in part obscured by clinical trials with hormone treatment of women after menopause, due to different formulations, routes of delivery, and pairings with progestins. Oral hormone treatment with several estrogen preparations increases VLDL triglyceride production. Progestins oppose this effect by stimulating VLDL clearance in both humans and animals. Transdermal estradiol preparations do not increase VLDL production or serum triglycerides.

Many aspects of sex differences in atherosclerotic heart disease risk are influenced by the distributed actions of estrogens in the muscle, adipose, and liver. In humans, 17β-estradiol (E2) is the predominant circulating estrogen and signals through estrogen receptor alpha (ERα), estrogen receptor beta (ERβ), and G-protein-coupled estrogen receptor (GPER). Over 1000 human liver genes display a sex bias in their expression, and the top biological pathways are in lipid metabolism and genes related to cardiovascular disease. Many of these genes display variation depending on estrus cycling in the mouse. Future directions will likely rely on targeting estrogens to specific tissues or specific aspects of the signaling pathways in order to recapitulate the protective physiology of premenopause therapeutically after menopause.

Notes

Funding Sources

The Department of Veterans Affairs (BX002223) and NIH (R01DK109102) provided support to JMS. BP is supported by the Vanderbilt Medical Scientist Training Program (T32GM07347) and (F30DK104514).

References

  1. Aguilar-Salinas, C. A., Garcia-Garcia, E., Gomez Perez, F. J., & Rull, J. A. (2002). The healthy women bias and hormone replacement therapy in women with type 2 diabetes. Diabetes Care, 25(1), 246–247.CrossRefPubMedGoogle Scholar
  2. Arai, T., Wang, N., Bezouevski, M., Welch, C., & Tall, A. R. (1999). Decreased atherosclerosis in heterozygous low density lipoprotein receptor-deficient mice expressing the scavenger receptor BI transgene. The Journal of Biological Chemistry, 274(4), 2366–2371.CrossRefPubMedGoogle Scholar
  3. Arii, K., Suehiro, T., Yamamoto, M., Ito, H., & Hashimoto, K. (1997). Suppression of plasma cholesteryl ester transfer protein activity in acute hyperinsulinemia and effect of plasma nonesterified fatty acid. Metabolism, 46(10), 1166–1170. doi:S0026-0495(97)90211-0 [pii].CrossRefPubMedGoogle Scholar
  4. Badeau, R. M., Metso, J., Wahala, K., Tikkanen, M. J., & Jauhiainen, M. (2009). Human macrophage cholesterol efflux potential is enhanced by HDL-associated 17beta-estradiol fatty acyl esters. The Journal of Steroid Biochemistry and Molecular Biology, 116(1–2), 44–49.  https://doi.org/10.1016/j.jsbmb.2009.04.008.CrossRefPubMedGoogle Scholar
  5. Badeau, R. M., Metso, J., Kovanen, P. T., Lee-Rueckert, M., Tikkanen, M. J., & Jauhiainen, M. (2013). The impact of gender and serum estradiol levels on HDL-mediated reverse cholesterol transport. European Journal of Clinical Investigation, 43(4), 317–323.  https://doi.org/10.1111/eci.12044.CrossRefPubMedGoogle Scholar
  6. Baksu, B., Davas, I., Agar, E., Akyol, A., & Uluocak, A. (2007). Do different delivery systems of estrogen therapy influence serum lipids differently in surgically menopausal women? The Journal of Obstetrics and Gynaecology Research, 33(3), 346–352.  https://doi.org/10.1111/j.1447-0756.2007.00534.x.CrossRefPubMedGoogle Scholar
  7. Barrera, J., Chambliss, K. L., Ahmed, M., Tanigaki, K., Thompson, B., McDonald, J. G., Mineo, C., & Shaul, P. W. (2014). Bazedoxifene and conjugated estrogen prevent diet-induced obesity, hepatic steatosis, and type 2 diabetes in mice without impacting the reproductive tract. American Journal of Physiology Endocrinology and Metabolism, 307(3), E345–E354.  https://doi.org/10.1152/ajpendo.00653.2013.CrossRefPubMedGoogle Scholar
  8. Barrett-Connor, E., Slone, S., Greendale, G., Kritz-Silverstein, D., Espeland, M., Johnson, S. R., Waclawiw, M., & Fineberg, S. E. (1997). The postmenopausal estrogen/progestin interventions study: Primary outcomes in adherent women. Maturitas, 27(3), 261–274.CrossRefPubMedGoogle Scholar
  9. Barrows, B. R., & Parks, E. J. (2006). Contributions of different fatty acid sources to very low-density lipoprotein-triacylglycerol in the fasted and fed states. The Journal of Clinical Endocrinology and Metabolism, 91(4), 1446–1452.  https://doi.org/10.1210/jc.2005-1709.CrossRefPubMedGoogle Scholar
  10. Barrows, B. R., Timlin, M. T., & Parks, E. J. (2005). Spillover of dietary fatty acids and use of serum nonesterified fatty acids for the synthesis of VLDL-triacylglycerol under two different feeding regimens. Diabetes, 54(9), 2668–2673.CrossRefPubMedGoogle Scholar
  11. Bjornstrom, L., & Sjoberg, M. (2005). Mechanisms of estrogen receptor signaling: Convergence of genomic and nongenomic actions on target genes. Molecular Endocrinology, 19(4), 833–842.  https://doi.org/10.1210/me.2004-0486.CrossRefPubMedGoogle Scholar
  12. Bonds, D. E., Lasser, N., Qi, L., Brzyski, R., Caan, B., Heiss, G., Limacher, M. C., Liu, J. H., Mason, E., Oberman, A., O'Sullivan, M. J., Phillips, L. S., Prineas, R. J., & Tinker, L. (2006). The effect of conjugated equine oestrogen on diabetes incidence: The women’s health initiative randomised trial. Diabetologia, 49(3), 459–468.  https://doi.org/10.1007/s00125-005-0096-0.CrossRefPubMedGoogle Scholar
  13. Bourassa, P. A., Milos, P. M., Gaynor, B. J., Breslow, J. L., & Aiello, R. J. (1996). Estrogen reduces atherosclerotic lesion development in apolipoprotein E-deficient mice. Proceedings of the National Academy of Sciences of the United States of America, 93(19), 10022–10027.PubMedCentralCrossRefPubMedGoogle Scholar
  14. Bryzgalova, G., Gao, H., Ahren, B., Zierath, J. R., Galuska, D., Steiler, T. L., Dahlman-Wright, K., Nilsson, S., Gustafsson, J. A., Efendic, S., & Khan, A. (2006). Evidence that oestrogen receptor-alpha plays an important role in the regulation of glucose homeostasis in mice: Insulin sensitivity in the liver. Diabetologia, 49(3), 588–597.  https://doi.org/10.1007/s00125-005-0105-3.CrossRefPubMedGoogle Scholar
  15. Bryzgalova, G., Lundholm, L., Portwood, N., Gustafsson, J. A., Khan, A., Efendic, S., & Dahlman-Wright, K. (2008). Mechanisms of antidiabetogenic and body weight-lowering effects of estrogen in high-fat diet-fed mice. American Journal of Physiology. Endocrinology and Metabolism, 295(4), E904–E912.  https://doi.org/10.1152/ajpendo.90248.2008.PubMedCentralCrossRefPubMedGoogle Scholar
  16. Burch, J. C., Byrd, B. F., Jr., & Vaughn, W. K. (1974). The effects of long-term estrogen on hysterectomized women. American Journal of Obstetrics and Gynecology, 118(6), 778–782.CrossRefPubMedGoogle Scholar
  17. Bush, T. L., Cowan, L. D., Barrett-Connor, E., Criqui, M. H., Karon, J. M., Wallace, R. B., Tyroler, H. A., & Rifkind, B. M. (1983). Estrogen use and all-cause mortality. Preliminary results from the lipid research clinics program follow-up study. JAMA, 249(7), 903–906.CrossRefPubMedGoogle Scholar
  18. Camporez, J. P., Jornayvaz, F. R., Lee, H. Y., Kanda, S., Guigni, B. A., Kahn, M., Samuel, V. T., Carvalho, C. R., Petersen, K. F., Jurczak, M. J., & Shulman, G. I. (2013). Cellular mechanism by which estradiol protects female ovariectomized mice from high-fat diet-induced hepatic and muscle insulin resistance. Endocrinology, 154(3), 1021–1028.  https://doi.org/10.1210/en.2012-1989.PubMedCentralCrossRefPubMedGoogle Scholar
  19. Canoy, D., Boekholdt, S. M., Wareham, N., Luben, R., Welch, A., Bingham, S., Buchan, I., Day, N., & Khaw, K. T. (2007). Body fat distribution and risk of coronary heart disease in men and women in the European prospective investigation into cancer and nutrition in Norfolk cohort: A population-based prospective study. Circulation, 116(25), 2933–2943.  https://doi.org/10.1161/CIRCULATIONAHA.106.673756.CrossRefPubMedGoogle Scholar
  20. Chambliss, K. L., Wu, Q., Oltmann, S., Konaniah, E. S., Umetani, M., Korach, K. S., Thomas, G. D., Mineo, C., Yuhanna, I. S., Kim, S. H., Madak-Erdogan, Z., Maggi, A., Dineen, S. P., Roland, C. L., Hui, D. Y., Brekken, R. A., Katzenellenbogen, J. A., Katzenellenbogen, B. S., & Shaul, P. W. (2010). Non-nuclear estrogen receptor alpha signaling promotes cardiovascular protection but not uterine or breast cancer growth in mice. The Journal of Clinical Investigation, 120(7), 2319–2330.  https://doi.org/10.1172/JCI38291.PubMedCentralCrossRefPubMedGoogle Scholar
  21. Chambliss, K. L., Barrera, J., Umetani, M., Umetani, J., Kim, S. H., Madak-Erdogan, Z., Huang, L., Katzenellenbogen, B. S., Katzenellenbogen, J. A., Mineo, C., & Shaul, P. W. (2016). Nonnuclear estrogen receptor activation improves hepatic steatosis in female mice. Endocrinology, 157(10), 3731–3741.  https://doi.org/10.1210/en.2015-1629.PubMedCentralCrossRefPubMedGoogle Scholar
  22. Chen, F. P., Lee, N., Soong, Y. K., & Huang, K. E. (2001). Comparison of transdermal and oral estrogen-progestin replacement therapy: Effects on cardiovascular risk factors. Menopause, 8(5), 347–352.CrossRefPubMedGoogle Scholar
  23. Chow, J. D., Jones, M. E., Prelle, K., Simpson, E. R., & Boon, W. C. (2011). A selective estrogen receptor alpha agonist ameliorates hepatic steatosis in the male aromatase knockout mouse. The Journal of Endocrinology, 210(3), 323–334.  https://doi.org/10.1530/JOE-10-0462.CrossRefPubMedGoogle Scholar
  24. Ciana, P., Raviscioni, M., Mussi, P., Vegeto, E., Que, I., Parker, M. G., Lowik, C., & Maggi, A. (2003). In vivo imaging of transcriptionally active estrogen receptors. Nature Medicine, 9(1), 82–86.  https://doi.org/10.1038/nm809.CrossRefPubMedGoogle Scholar
  25. Clegg, D., Hevener, A. L., Moreau, K. L., Morselli, E., Criollo, A., Van Pelt, R. E., & Vieira-Potter, V. J. (2017). Sex hormones and cardiometabolic health: Role of estrogen and estrogen receptors. Endocrinology, 158(5), 1095–1105.  https://doi.org/10.1210/en.2016-1677.CrossRefPubMedGoogle Scholar
  26. Colditz, G. A., Willett, W. C., Stampfer, M. J., Rosner, B., Speizer, F. E., & Hennekens, C. H. (1987). Menopause and the risk of coronary heart disease in women. The New England Journal of Medicine, 316(18), 1105–1110.  https://doi.org/10.1056/NEJM198704303161801.CrossRefPubMedGoogle Scholar
  27. Cole, L. K., Jacobs, R. L., & Vance, D. E. (2010). Tamoxifen induces triacylglycerol accumulation in the mouse liver by activation of fatty acid synthesis. Hepatology, 52(4), 1258–1265.  https://doi.org/10.1002/hep.23813.CrossRefPubMedGoogle Scholar
  28. Cooper, A. D., Nutik, R., & Chen, J. (1987). Characterization of the estrogen-induced lipoprotein receptor of rat liver. Journal of Lipid Research, 28(1), 59–68.PubMedGoogle Scholar
  29. Cote, I., Yasari, S., Pighon, A., Barsalani, R., Rabasa-Lhoret, R., Prud'homme, D., & Lavoie, J. M. (2012). Liver fat accumulation may be dissociated from adiposity gain in ovariectomized rats. Climacteric, 15(6), 594–601.  https://doi.org/10.3109/13697137.2011.637650.CrossRefPubMedGoogle Scholar
  30. Criqui, M. H., Suarez, L., Barrett-Connor, E., McPhillips, J., Wingard, D. L., & Garland, C. (1988). Postmenopausal estrogen use and mortality. Results from a prospective study in a defined, homogeneous community. American Journal of Epidemiology, 128(3), 606–614.CrossRefPubMedGoogle Scholar
  31. Croft, P., & Hannaford, P. (1989). Risk factors for acute myocardial infarction in women. BMJ, 298(6674), 674.PubMedCentralCrossRefPubMedGoogle Scholar
  32. Davis, R. A. (1997). Evolution of processes and regulators of lipoprotein synthesis: From birds to mammals. The Journal of Nutrition, 127(5 Suppl), 795S–800S.CrossRefPubMedGoogle Scholar
  33. de Koning, L., Merchant, A. T., Pogue, J., & Anand, S. S. (2007). Waist circumference and waist-to-hip ratio as predictors of cardiovascular events: Meta-regression analysis of prospective studies. European Heart Journal, 28(7), 850–856.  https://doi.org/10.1093/eurheartj/ehm026.CrossRefPubMedGoogle Scholar
  34. De Marinis, E., Martini, C., Trentalance, A., & Pallottini, V. (2008). Sex differences in hepatic regulation of cholesterol homeostasis. The Journal of Endocrinology, 198(3), 635–643.  https://doi.org/10.1677/JOE-08-0242.CrossRefPubMedGoogle Scholar
  35. de Oliveira, M. C., Gilglioni, E. H., de Boer, B. A., Runge, J. H., de Waart, D. R., Salgueiro, C. L., Ishii-Iwamoto, E. L., Oude Elferink, R. P., & Gaemers, I. C. (2016). Bile acid receptor agonists INT747 and INT777 decrease oestrogen deficiency-related postmenopausal obesity and hepatic steatosis in mice. Biochimica et Biophysica Acta, 1862(11), 2054–2062.  https://doi.org/10.1016/j.bbadis.2016.07.012.CrossRefPubMedGoogle Scholar
  36. de Vries, R., Perton, F. G., Dallinga-Thie, G. M., van Roon, A. M., Wolffenbuttel, B. H., van Tol, A., & Dullaart, R. P. (2005). Plasma cholesteryl ester transfer is a determinant of intima-media thickness in type 2 diabetic and nondiabetic subjects: Role of CETP and triglycerides. Diabetes, 54(12), 3554–3559.CrossRefPubMedGoogle Scholar
  37. Della Torre, S., Rando, G., Meda, C., Stell, A., Chambon, P., Krust, A., Ibarra, C., Magni, P., Ciana, P., & Maggi, A. (2011). Amino acid-dependent activation of liver estrogen receptor alpha integrates metabolic and reproductive functions via IGF-1. Cell Metabolism, 13(2), 205–214.  https://doi.org/10.1016/j.cmet.2011.01.002.CrossRefPubMedGoogle Scholar
  38. Della Torre, S., Mitro, N., Fontana, R., Gomaraschi, M., Favari, E., Recordati, C., Lolli, F., Quagliarini, F., Meda, C., Ohlsson, C., Crestani, M., Uhlenhaut, N. H., Calabresi, L., & Maggi, A. (2016). An essential role for liver ER alpha in coupling hepatic metabolism to the reproductive cycle. Cell Reports, 15(2), 360–371.  https://doi.org/10.1016/j.celrep.2016.03.019.PubMedCentralCrossRefPubMedGoogle Scholar
  39. Di Croce, L., Bruscalupi, G., & Trentalance, A. (1996). Independent behavior of rat liver LDL receptor and HMGCoA reductase under estrogen treatment. Biochemical and Biophysical Research Communications, 224(2), 345–350.  https://doi.org/10.1006/bbrc.1996.1031.CrossRefPubMedGoogle Scholar
  40. Di Croce, L., Vicent, G. P., Pecci, A., Bruscalupi, G., Trentalance, A., & Beato, M. (1999). The promoter of the rat 3-hydroxy-3-methylglutaryl coenzyme A reductase gene contains a tissue-specific estrogen-responsive region. Molecular Endocrinology, 13(8), 1225–1236.  https://doi.org/10.1210/mend.13.8.0333.CrossRefPubMedGoogle Scholar
  41. Distefano, E., Marino, M., Gillette, J. A., Hanstein, B., Pallottini, V., Bruning, J., Krone, W., & Trentalance, A. (2002). Role of tyrosine kinase signaling in estrogen-induced LDL receptor gene expression in HepG2 cells. Biochimica et Biophysica Acta, 1580(2–3), 145–149.CrossRefPubMedGoogle Scholar
  42. El Khoudary, S. R., Hutchins, P. M., Matthews, K. A., Brooks, M. M., Orchard, T. J., Ronsein, G. E., & Heinecke, J. W. (2016). Cholesterol efflux capacity and subclasses of HDL particles in healthy women transitioning through menopause. The Journal of Clinical Endocrinology and Metabolism, 101(9), 3419–3428.  https://doi.org/10.1210/jc.2016-2144.PubMedCentralCrossRefPubMedGoogle Scholar
  43. Espeland, M. A., Hogan, P. E., Fineberg, S. E., Howard, G., Schrott, H., Waclawiw, M. A., & Bush, T. L. (1998). Effect of postmenopausal hormone therapy on glucose and insulin concentrations. PEPI Investigators. Postmenopausal Estrogen/Progestin Interventions. Diabetes Care, 21(10), 1589–1595.CrossRefPubMedGoogle Scholar
  44. Fabbrini, E., Magkos, F., Mohammed, B. S., Pietka, T., Abumrad, N. A., Patterson, B. W., Okunade, A., & Klein, S. (2009). Intrahepatic fat, not visceral fat, is linked with metabolic complications of obesity. Proceedings of the National Academy of Sciences of the United States of America, 106(36), 15430–15435.  https://doi.org/10.1073/pnas.0904944106.PubMedCentralCrossRefPubMedGoogle Scholar
  45. Ferrara, A., Karter, A. J., Ackerson, L. M., Liu, J. Y., Selby, J. V., & Northern California Kaiser Permanente Diabetes R. (2001). Hormone replacement therapy is associated with better glycemic control in women with type 2 diabetes: The Northern California Kaiser Permanente Diabetes Registry. Diabetes Care, 24(7), 1144–1150.CrossRefPubMedGoogle Scholar
  46. Finan, B., Yang, B., Ottaway, N., Stemmer, K., Muller, T. D., Yi, C. X., Habegger, K., Schriever, S. C., Garcia-Caceres, C., Kabra, D. G., Hembree, J., Holland, J., Raver, C., Seeley, R. J., Hans, W., Irmler, M., Beckers, J., de Angelis, M. H., Tiano, J. P., Mauvais-Jarvis, F., Perez-Tilve, D., Pfluger, P., Zhang, L., Gelfanov, V., DiMarchi, R. D., & Tschop, M. H. (2012). Targeted estrogen delivery reverses the metabolic syndrome. Nature Medicine, 18(12), 1847–1856.  https://doi.org/10.1038/nm.3009.PubMedCentralCrossRefPubMedGoogle Scholar
  47. Finkelstein, J. S., Lee, H., Burnett-Bowie, S. A., Pallais, J. C., Yu, E. W., Borges, L. F., Jones, B. F., Barry, C. V., Wulczyn, K. E., Thomas, B. J., & Leder, B. Z. (2013). Gonadal steroids and body composition, strength, and sexual function in men. The New England Journal of Medicine, 369(11), 1011–1022.  https://doi.org/10.1056/NEJMoa1206168.PubMedCentralCrossRefPubMedGoogle Scholar
  48. Freedman, D. S., Otvos, J. D., Jeyarajah, E. J., Shalaurova, I., Cupples, L. A., Parise, H., D’Agostino, R. B., Wilson, P. W., & Schaefer, E. J. (2004). Sex and age differences in lipoprotein subclasses measured by nuclear magnetic resonance spectroscopy: The Framingham Study. Clinical Chemistry, 50(7), 1189–1200.  https://doi.org/10.1373/clinchem.2004.032763.CrossRefPubMedGoogle Scholar
  49. Frias, J. P., Macaraeg, G. B., Ofrecio, J., Yu, J. G., Olefsky, J. M., & Kruszynska, Y. T. (2001). Decreased susceptibility to fatty acid-induced peripheral tissue insulin resistance in women. Diabetes, 50(6), 1344–1350.CrossRefPubMedGoogle Scholar
  50. Fukata, Y., Yu, X., Imachi, H., Nishiuchi, T., Lyu, J., Seo, K., Takeuchi, A., Iwama, H., Masugata, H., Hoshikawa, H., Hosomi, N., Iwasaki, Y., & Murao, K. (2014). 17beta-Estradiol regulates scavenger receptor class BI gene expression via protein kinase C in vascular endothelial cells. Endocrine, 46(3), 644–650.  https://doi.org/10.1007/s12020-013-0134-5.CrossRefPubMedGoogle Scholar
  51. Galien, R., & Garcia, T. (1997). Estrogen receptor impairs interleukin-6 expression by preventing protein binding on the NF-κB site. Nucleic Acids Research, 25(12), 2424–2429.  https://doi.org/10.1093/nar/25.12.2424.PubMedCentralCrossRefPubMedGoogle Scholar
  52. Gao, H., Bryzgalova, G., Hedman, E., Khan, A., Efendic, S., Gustafsson, J. A., & Dahlman-Wright, K. (2006). Long-term administration of estradiol decreases expression of hepatic lipogenic genes and improves insulin sensitivity in ob/ob mice: A possible mechanism is through direct regulation of signal transducer and activator of transcription 3. Molecular Endocrinology, 20(6), 1287–1299.  https://doi.org/10.1210/me.2006-0012.CrossRefPubMedGoogle Scholar
  53. Gao, H., Falt, S., Sandelin, A., Gustafsson, J. A., & Dahlman-Wright, K. (2008). Genome-wide identification of estrogen receptor alpha-binding sites in mouse liver. Molecular Endocrinology, 22(1), 10–22.  https://doi.org/10.1210/me.2007-0121.PubMedCentralCrossRefPubMedGoogle Scholar
  54. Glueck, C. J., Fallat, R. W., & Scheel, D. (1975). Effects of estrogenic compounds on triglyceride kinetics. Metabolism, 24(4), 537–545. doi:0026-0495(75)90078-5 [pii].CrossRefPubMedGoogle Scholar
  55. Grady, D., Rubin, S. M., Petitti, D. B., Fox, C. S., Black, D., Ettinger, B., Ernster, V. L., & Cummings, S. R. (1992). Hormone therapy to prevent disease and prolong life in postmenopausal women. Annals of Internal Medicine, 117(12), 1016–1037.CrossRefPubMedGoogle Scholar
  56. Grady, D., Herrington, D., Bittner, V., Blumenthal, R., Davidson, M., Hlatky, M., Hsia, J., Hulley, S., Herd, A., Khan, S., Newby, L. K., Waters, D., Vittinghoff, E., Wenger, N., & Group HR. (2002). Cardiovascular disease outcomes during 6.8 years of hormone therapy: Heart and estrogen/progestin replacement study follow-up (HERS II). JAMA : The Journal of the American Medical Association, 288(1), 49–57.CrossRefPubMedGoogle Scholar
  57. Grodstein, F., & Stampfer, M. (1995). The epidemiology of coronary heart disease and estrogen replacement in postmenopausal women. Progress in Cardiovascular Diseases, 38(3), 199–210.CrossRefPubMedGoogle Scholar
  58. Hammond, C. B., Jelovsek, F. R., Lee, K. L., Creasman, W. T., & Parker, R. T. (1979). Effects of long-term estrogen replacement therapy. I. Metabolic effects. American Journal of Obstetrics and Gynecology, 133(5), 525–536.CrossRefPubMedGoogle Scholar
  59. Henderson, B. E., Paganini-Hill, A., & Ross, R. K. (1991). Decreased mortality in users of estrogen replacement therapy. Archives of Internal Medicine, 151(1), 75–78.CrossRefPubMedGoogle Scholar
  60. Hernandez Avila, M., Walker, A. M., & Jick, H. (1990). Use of replacement estrogens and the risk of myocardial infarction. Epidemiology, 1(2), 128–133.CrossRefPubMedGoogle Scholar
  61. Hevener, A., Reichart, D., Janez, A., & Olefsky, J. (2002). Female rats do not exhibit free fatty acid-induced insulin resistance. Diabetes, 51(6), 1907–1912.CrossRefPubMedGoogle Scholar
  62. Hodis, H. N., Mack, W. J., Lobo, R. A., Shoupe, D., Sevanian, A., Mahrer, P. R., Selzer, R. H., Liu Cr, C. R., Liu Ch, C. H., Azen, S. P., & Estrogen in the Prevention of Atherosclerosis Trial Research G. (2001). Estrogen in the prevention of atherosclerosis. A randomized, double-blind, placebo-controlled trial. Annals of Internal Medicine, 135(11), 939–953.CrossRefPubMedGoogle Scholar
  63. Hodis, H. N., Mack, W. J., Azen, S. P., Lobo, R. A., Shoupe, D., Mahrer, P. R., Faxon, D. P., Cashin-Hemphill, L., Sanmarco, M. E., French, W. J., Shook, T. L., Gaarder, T. D., Mehra, A. O., Rabbani, R., Sevanian, A., Shil, A. B., Torres, M., Vogelbach, K. H., Selzer, R. H., & Women’s Estrogen-Progestin Lipid-Lowering Hormone Atherosclerosis Regression Trial Research G. (2003). Hormone therapy and the progression of coronary-artery atherosclerosis in postmenopausal women. The New England Journal of Medicine, 349(6), 535–545.  https://doi.org/10.1056/NEJMoa030830.CrossRefPubMedGoogle Scholar
  64. Hodis, H. N., Mack, W. J., Henderson, V. W., Shoupe, D., Budoff, M. J., Hwang-Levine, J., Li, Y., Feng, M., Dustin, L., Kono, N., Stanczyk, F. Z., Selzer, R. H., Azen, S. P., & Group ER. (2016). Vascular effects of early versus late postmenopausal treatment with estradiol. The New England Journal of Medicine, 374(13), 1221–1231.  https://doi.org/10.1056/NEJMoa1505241.PubMedCentralCrossRefPubMedGoogle Scholar
  65. Hsia, J., Langer, R. D., Manson, J. E., Kuller, L., Johnson, K. C., Hendrix, S. L., Pettinger, M., Heckbert, S. R., Greep, N., Crawford, S., Eaton, C. B., Kostis, J. B., Caralis, P., Prentice, R., & Investigato, W. H. I. (2006). Conjugated equine estrogens and coronary heart disease – The women’s health initiative. Archives of Internal Medicine, 166(3), 357–365.  https://doi.org/10.1001/Archinte.166.3.357.CrossRefPubMedGoogle Scholar
  66. Hu, F. B., Grodstein, F., Hennekens, C. H., Colditz, G. A., Johnson, M., Manson, J. E., Rosner, B., & Stampfer, M. J. (1999). Age at natural menopause and risk of cardiovascular disease. Archives of Internal Medicine, 159(10), 1061–1066.CrossRefPubMedGoogle Scholar
  67. Hulley, S., Grady, D., Bush, T., Furberg, C., Herrington, D., Riggs, B., & Vittinghoff, E. (1998). Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Heart and estrogen/progestin replacement study (HERS) research group. JAMA, 280(7), 605–613.CrossRefPubMedGoogle Scholar
  68. Jensen, M. D., Martin, M. L., Cryer, P. E., & Roust, L. R. (1994). Effects of estrogen on free fatty acid metabolism in humans. The American Journal of Physiology, 266(6 Pt 1), E914–E920.PubMedGoogle Scholar
  69. Jiang, X. C., Moulin, P., Quinet, E., Goldberg, I. J., Yacoub, L. K., Agellon, L. B., Compton, D., Schnitzer-Polokoff, R., & Tall, A. R. (1991). Mammalian adipose tissue and muscle are major sources of lipid transfer protein mRNA. The Journal of Biological Chemistry, 266(7), 4631–4639.PubMedGoogle Scholar
  70. Johansson, L. E., Danielsson, A. P., Parikh, H., Klintenberg, M., Norstrom, F., Groop, L., & Ridderstrale, M. (2012). Differential gene expression in adipose tissue from obese human subjects during weight loss and weight maintenance. The American Journal of Clinical Nutrition, 96(1), 196–207.  https://doi.org/10.3945/ajcn.111.020578.CrossRefPubMedGoogle Scholar
  71. Jones, M. E., Thorburn, A. W., Britt, K. L., Hewitt, K. N., Wreford, N. G., Proietto, J., Oz, O. K., Leury, B. J., Robertson, K. M., Yao, S., & Simpson, E. R. (2000). Aromatase-deficient (ArKO) mice have a phenotype of increased adiposity. Proceedings of the National Academy of Sciences of the United States of America, 97(23), 12735–12740.  https://doi.org/10.1073/pnas.97.23.12735.PubMedCentralCrossRefPubMedGoogle Scholar
  72. Jones, M. E., Thorburn, A. W., Britt, K. L., Hewitt, K. N., Misso, M. L., Wreford, N. G., Proietto, J., Oz, O. K., Leury, B. J., Robertson, K. M., Yao, S., & Simpson, E. R. (2001). Aromatase-deficient (ArKO) mice accumulate excess adipose tissue. The Journal of Steroid Biochemistry and Molecular Biology, 79(1–5), 3–9.CrossRefPubMedGoogle Scholar
  73. Jornayvaz, F. R., Birkenfeld, A. L., Jurczak, M. J., Kanda, S., Guigni, B. A., Jiang, D. C., Zhang, D., Lee, H. Y., Samuel, V. T., & Shulman, G. I. (2011). Hepatic insulin resistance in mice with hepatic overexpression of diacylglycerol acyltransferase 2. Proceedings of the National Academy of Sciences of the United States of America, 108(14), 5748–5752.  https://doi.org/10.1073/pnas.1103451108.PubMedCentralCrossRefPubMedGoogle Scholar
  74. Kannel, W. B., Hjortland, M. C., McNamara, P. M., & Gordon, T. (1976). Menopause and risk of cardiovascular disease: The Framingham study. Annals of Internal Medicine, 85(4), 447–452.CrossRefPubMedGoogle Scholar
  75. Kim, H. J., & Kalkhoff, R. K. (1975). Sex steroid influence on triglyceride metabolism. The Journal of Clinical Investigation, 56(4), 888–896.  https://doi.org/10.1172/JCI108168.PubMedCentralCrossRefPubMedGoogle Scholar
  76. Kim, J. H., Meyers, M. S., Khuder, S. S., Abdallah, S. L., Muturi, H. T., Russo, L., Tate, C. R., Hevener, A. L., Najjar, S. M., Leloup, C., & Mauvais-Jarvis, F. (2014). Tissue-selective estrogen complexes with bazedoxifene prevent metabolic dysfunction in female mice. Molecular Metabolism, 3(2), 177–190.  https://doi.org/10.1016/j.molmet.2013.12.009.PubMedCentralCrossRefPubMedGoogle Scholar
  77. Kissebah, A. H., Harrigan, P., & Wynn, V. (1973). Mechanism of hypertriglyceridaemia associated with contraceptive steroids. Hormone and Metabolic Research, 5(3), 184–190.  https://doi.org/10.1055/s-0028-1093969.CrossRefPubMedGoogle Scholar
  78. Kushwaha, R. S., Hazzard, W. R., Gagne, C., Chait, A., & Albers, J. J. (1977). Type III hyperlipoproteinemia: Paradoxical hypolipidemic response to estrogen. Annals of Internal Medicine, 87(5), 517–525.CrossRefPubMedGoogle Scholar
  79. Levin, E. R. (2009). Plasma membrane estrogen receptors. Trends in Endocrinology and Metabolism, 20(10), 477–482.  https://doi.org/10.1016/j.tem.2009.06.009.PubMedCentralCrossRefPubMedGoogle Scholar
  80. Li, C., Briggs, M. R., Ahlborn, T. E., Kraemer, F. B., & Liu, J. (2001). Requirement of Sp1 and estrogen receptor alpha interaction in 17beta-estradiol-mediated transcriptional activation of the low density lipoprotein receptor gene expression. Endocrinology, 142(4), 1546–1553.  https://doi.org/10.1210/endo.142.4.8096.CrossRefPubMedGoogle Scholar
  81. Liao, C. C., Chiu, Y. S., Chiu, W. C., Tung, Y. T., Chuang, H. L., Wu, J. H., & Huang, C. C. (2015). Proteomics analysis to identify and characterize the molecular signatures of hepatic steatosis in ovariectomized rats as a model of postmenopausal status. Nutrients, 7(10), 8752–8766.  https://doi.org/10.3390/nu7105434.PubMedCentralCrossRefPubMedGoogle Scholar
  82. Lindberg, M. K., Weihua, Z., Andersson, N., Moverare, S., Gao, H., Vidal, O., Erlandsson, M., Windahl, S., Andersson, G., Lubahn, D. B., Carlsten, H., Dahlman-Wright, K., Gustafsson, J. A., & Ohlsson, C. (2002). Estrogen receptor specificity for the effects of estrogen in ovariectomized mice. The Journal of Endocrinology, 174(2), 167–178.CrossRefPubMedGoogle Scholar
  83. Lloyd-Jones, D., Adams, R., Carnethon, M., De Simone, G., Ferguson, T. B., Flegal, K., Ford, E., Furie, K., Go, A., Greenlund, K., Haase, N., Hailpern, S., Ho, M., Howard, V., Kissela, B., Kittner, S., Lackland, D., Lisabeth, L., Marelli, A., McDermott, M., Meigs, J., Mozaffarian, D., Nichol, G., O'Donnell, C., Roger, V., Rosamond, W., Sacco, R., Sorlie, P., Stafford, R., Steinberger, J., Thom, T., Wasserthiel-Smoller, S., Wong, N., Wylie-Rosett, J., Hong, Y., & American Heart Association Statistics C, Stroke Statistics S. (2009). Heart disease and stroke statistics – 2009 update: A report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation, 119(3), e21–181.  https://doi.org/10.1161/CIRCULATIONAHA.108.191261.CrossRefPubMedGoogle Scholar
  84. Lopez, D., & McLean, M. P. (2006). Estrogen regulation of the scavenger receptor class B gene: Anti-atherogenic or steroidogenic, is there a priority? Molecular and Cellular Endocrinology, 247(1–2), 22–33.  https://doi.org/10.1016/j.mce.2005.10.005.CrossRefPubMedGoogle Scholar
  85. Ma, P. T., Yamamoto, T., Goldstein, J. L., & Brown, M. S. (1986). Increased mRNA for low density lipoprotein receptor in livers of rabbits treated with 17 alpha-ethinyl estradiol. Proceedings of the National Academy of Sciences of the United States of America, 83(3), 792–796.PubMedCentralCrossRefPubMedGoogle Scholar
  86. Maffei, L., Murata, Y., Rochira, V., Tubert, G., Aranda, C., Vazquez, M., Clyne, C. D., Davis, S., Simpson, E. R., & Carani, C. (2004). Dysmetabolic syndrome in a man with a novel mutation of the aromatase gene: Effects of testosterone, alendronate, and estradiol treatment. The Journal of Clinical Endocrinology and Metabolism, 89(1), 61–70.  https://doi.org/10.1210/jc.2003-030313.CrossRefPubMedGoogle Scholar
  87. Magkos, F., & Mittendorfer, B. (2009). Gender differences in lipid metabolism and the effect of obesity. Obstetrics and Gynecology Clinics of North America, 36(2), 245–265., vii.  https://doi.org/10.1016/j.ogc.2009.03.001.CrossRefPubMedGoogle Scholar
  88. Magkos, F., Patterson, B. W., & Mittendorfer, B. (2006). No effect of menstrual cycle phase on basal very-low-density lipoprotein triglyceride and apolipoprotein B-100 kinetics. American Journal of Physiology Endocrinology and Metabolism, 291(6), E1243–E1249.  https://doi.org/10.1152/ajpendo.00246.2006.CrossRefPubMedGoogle Scholar
  89. Magkos, F., Patterson, B. W., & Mittendorfer, B. (2007a). Reproducibility of stable isotope-labeled tracer measures of VLDL-triglyceride and VLDL-apolipoprotein B-100 kinetics. Journal of Lipid Research, 48(5), 1204–1211.  https://doi.org/10.1194/jlr.D600048-JLR200.CrossRefPubMedGoogle Scholar
  90. Magkos, F., Patterson, B. W., Mohammed, B. S., Klein, S., & Mittendorfer, B. (2007b). Women produce fewer but triglyceride-richer very low-density lipoproteins than men. The Journal of Clinical Endocrinology and Metabolism, 92(4), 1311–1318.  https://doi.org/10.1210/jc.2006-2215.CrossRefPubMedGoogle Scholar
  91. Manson, J. E., Hsia, J., Johnson, K. C., Rossouw, J. E., Assaf, A. R., Lasser, N. L., Trevisan, M., Black, H. R., Heckbert, S. R., Detrano, R., Strickland, O. L., Wong, N. D., Crouse, J. R., Stein, E., Cushman, M., & Women’s Health Initiative I. (2003). Estrogen plus progestin and the risk of coronary heart disease. The New England Journal of Medicine, 349(6), 523–534.  https://doi.org/10.1056/NEJMoa030808.CrossRefPubMedGoogle Scholar
  92. Manson, J. E., Allison, M. A., Rossouw, J. E., Carr, J. J., Langer, R. D., Hsia, J., Kuller, L. H., Cochrane, B. B., Hunt, J. R., Ludlam, S. E., Pettinger, M. B., Gass, M., Margolis, K. L., Nathan, L., Ockene, J. K., Prentice, R. L., Robbins, J., Stefanick, M. L., WHI, & Investigators W-C. (2007). Estrogen therapy and coronary-artery calcification. The New England Journal of Medicine, 356(25), 2591–2602.  https://doi.org/10.1056/NEJMoa071513.CrossRefPubMedGoogle Scholar
  93. Marino, M., Pallottini, V., & Trentalance, A. (1998). Estrogens cause rapid activation of IP3-PKC-alpha signal transduction pathway in HEPG2 cells. Biochemical and Biophysical Research Communications, 245(1), 254–258.  https://doi.org/10.1006/bbrc.1998.8413.CrossRefPubMedGoogle Scholar
  94. Marino, M., Distefano, E., Pallottini, V., Caporali, S., Bruscalupi, G., & Trentalance, A. (2001). Activation of IP(3)-protein kinase C-alpha signal transduction pathway precedes the changes of plasma cholesterol, hepatic lipid metabolism and induction of low-density lipoprotein receptor expression in 17-beta-oestradiol-treated rats. Experimental Physiology, 86(1), 39–45.CrossRefPubMedGoogle Scholar
  95. Marino, M., Galluzzo, P., & Ascenzi, P. (2006). Estrogen signaling multiple pathways to impact gene transcription. Current Genomics, 7(8), 497–508.PubMedCentralCrossRefPubMedGoogle Scholar
  96. Marotti, K. R., Castle, C. K., Boyle, T. P., Lin, A. H., Murray, R. W., & Melchior, G. W. (1993). Severe atherosclerosis in transgenic mice expressing simian cholesteryl ester transfer protein. Nature, 364(6432), 73–75.  https://doi.org/10.1038/364073a0.CrossRefPubMedGoogle Scholar
  97. Marsh, M. M., Walker, V. R., Curtiss, L. K., & Banka, C. L. (1999). Protection against atherosclerosis by estrogen is independent of plasma cholesterol levels in LDL receptor-deficient mice. Journal of Lipid Research, 40(5), 893–900.PubMedGoogle Scholar
  98. Matsuo, K., Gualtieri, M. R., Cahoon, S. S., Jung, C. E., Paulson, R. J., Shoupe, D., Muderspach, L. I., Wakatsuki, A., Wright, J. D., & Roman, L. D. (2016). Surgical menopause and increased risk of nonalcoholic fatty liver disease in endometrial cancer. Menopause, 23(2), 189–196.  https://doi.org/10.1097/GME.0000000000000500.CrossRefPubMedGoogle Scholar
  99. Matthan, N. R., Jalbert, S. M., Barrett, P. H., Dolnikowski, G. G., Schaefer, E. J., & Lichtenstein, A. H. (2008). Gender-specific differences in the kinetics of nonfasting TRL, IDL, and LDL apolipoprotein B-100 in men and premenopausal women. Arteriosclerosis, Thrombosis, and Vascular Biology, 28(10), 1838–1843.  https://doi.org/10.1161/ATVBAHA.108.163931.PubMedCentralCrossRefPubMedGoogle Scholar
  100. McKenzie, J., Fisher, B. M., Jaap, A. J., Stanley, A., Paterson, K., & Sattar, N. (2006). Effects of HRT on liver enzyme levels in women with type 2 diabetes: A randomized placebo-controlled trial. Clinical Endocrinology, 65(1), 40–44.  https://doi.org/10.1111/j.1365-2265.2006.02543.x.CrossRefPubMedGoogle Scholar
  101. Meyer, M. R., Fredette, N. C., Howard, T. A., Hu, C., Ramesh, C., Daniel, C., Amann, K., Arterburn, J. B., Barton, M., & Prossnitz, E. R. (2014). G Protein-coupled estrogen receptor protects from atherosclerosis. Scientific Reports, 4, 7564.  https://doi.org/10.1038/srep07564. https://www.nature.com/articles/srep07564-supplementary-information.PubMedCentralCrossRefPubMedGoogle Scholar
  102. Mittendorfer, B., Patterson, B. W., & Klein, S. (2003). Effect of sex and obesity on basal VLDL-triacylglycerol kinetics. The American Journal of Clinical Nutrition, 77(3), 573–579.CrossRefPubMedGoogle Scholar
  103. Murata, Y., Ogawa, Y., Saibara, T., Nishioka, A., Fujiwara, Y., Fukumoto, M., Inomata, T., Enzan, H., Onishi, S., & Yoshida, S. (2000). Unrecognized hepatic steatosis and non-alcoholic steatohepatitis in adjuvant tamoxifen for breast cancer patients. Oncology Reports, 7(6), 1299–1304.PubMedGoogle Scholar
  104. Nilsson, B. O., Olde, B., & Leeb-Lundberg, L. M. (2011). G protein-coupled oestrogen receptor 1 (GPER1)/GPR30: A new player in cardiovascular and metabolic oestrogenic signalling. British Journal of Pharmacology, 163(6), 1131–1139.  https://doi.org/10.1111/j.1476-5381.2011.01235.x.PubMedCentralCrossRefPubMedGoogle Scholar
  105. Nishino, M., Hayakawa, K., Nakamura, Y., Morimoto, T., & Mukaihara, S. (2003). Effects of tamoxifen on hepatic fat content and the development of hepatic steatosis in patients with breast cancer: High frequency of involvement and rapid reversal after completion of tamoxifen therapy. AJR American Journal of Roentgenology, 180(1), 129–134.  https://doi.org/10.2214/ajr.180.1.1800129.CrossRefPubMedGoogle Scholar
  106. O’Sullivan, A. J., Crampton, L. J., Freund, J., & Ho, K. K. (1998). The route of estrogen replacement therapy confers divergent effects on substrate oxidation and body composition in postmenopausal women. The Journal of Clinical Investigation, 102(5), 1035–1040.  https://doi.org/10.1172/JCI2773.PubMedCentralCrossRefPubMedGoogle Scholar
  107. Ohlsson, C., Hellberg, N., Parini, P., Vidal, O., Bohlooly, Y. M., Rudling, M., Lindberg, M. K., Warner, M., Angelin, B., & Gustafsson, J. A. (2000). Obesity and disturbed lipoprotein profile in estrogen receptor-alpha-deficient male mice. Biochemical and Biophysical Research Communications, 278(3), 640–645.  https://doi.org/10.1006/bbrc.2000.3827.CrossRefPubMedGoogle Scholar
  108. Oien, K. A., Moffat, D., Curry, G. W., Dickson, J., Habeshaw, T., Mills, P. R., & MacSween, R. N. (1999). Cirrhosis with steatohepatitis after adjuvant tamoxifen. Lancet, 353(9146), 36–37.  https://doi.org/10.1016/S0140-6736(05)74872-8.CrossRefPubMedGoogle Scholar
  109. Osborne, C. K., & Schiff, R. (2005). Estrogen-receptor biology: Continuing progress and therapeutic implications. Journal of Clinical Oncology, 23(8), 1616–1622.  https://doi.org/10.1200/JCO.2005.10.036.CrossRefPubMedGoogle Scholar
  110. Otero, Y. F., Stafford, J. M., & McGuinness, O. P. (2014). Pathway-selective insulin resistance and metabolic disease: The importance of nutrient flux. The Journal of Biological Chemistry, 289(30), 20462–20469.  https://doi.org/10.1074/jbc.R114.576355.PubMedCentralCrossRefPubMedGoogle Scholar
  111. Owman, C., Blay, P., Nilsson, C., & Lolait, S. J. (1996). Cloning of human cDNA encoding a novel heptahelix receptor expressed in Burkitt’s lymphoma and widely distributed in brain and peripheral tissues. Biochemical and Biophysical Research Communications, 228(2), 285–292.  https://doi.org/10.1006/bbrc.1996.1654.
  112. Paech, K., Webb, P., Kuiper, G. G. J. M., Nilsson, S., Gustafsson, J.-Å., Kushner, P. J., & Scanlan, T. S. (1997). Differential ligand activation of estrogen receptors ERα and ERβ at AP1 sites. Science, 277(5331), 1508.CrossRefPubMedGoogle Scholar
  113. Palmisano, B. T., Le, T. D., Zhu, L., Lee, Y. K., & Stafford, J. M. (2016). Cholesteryl ester transfer protein alters liver and plasma triglyceride metabolism through two liver networks in female mice. Journal of Lipid Research, 57(8), 1541–1551.  https://doi.org/10.1194/jlr.M069013.PubMedCentralCrossRefPubMedGoogle Scholar
  114. Paquette, A., Shinoda, M., Rabasa Lhoret, R., Prud'homme, D., & Lavoie, J. M. (2007). Time course of liver lipid infiltration in ovariectomized rats: Impact of a high-fat diet. Maturitas, 58(2), 182–190.  https://doi.org/10.1016/j.maturitas.2007.08.002.CrossRefPubMedGoogle Scholar
  115. Park, C. J., Zhao, Z., Glidewell-Kenney, C., Lazic, M., Chambon, P., Krust, A., Weiss, J., Clegg, D. J., Dunaif, A., Jameson, J. L., & Levine, J. E. (2011). Genetic rescue of nonclassical ERalpha signaling normalizes energy balance in obese Eralpha-null mutant mice. The Journal of Clinical Investigation, 121(2), 604–612.  https://doi.org/10.1172/JCI41702.PubMedCentralCrossRefPubMedGoogle Scholar
  116. Parks, B. W., Sallam, T., Mehrabian, M., Psychogios, N., Hui, S. T., Norheim, F., Castellani, L. W., Rau, C. D., Pan, C., Phun, J., Zhou, Z., Yang, W. P., Neuhaus, I., Gargalovic, P. S., Kirchgessner, T. G., Graham, M., Lee, R., Tontonoz, P., Gerszten, R. E., Hevener, A. L., & Lusis, A. J. (2015). Genetic architecture of insulin resistance in the mouse. Cell Metabolism, 21(2), 334–346.  https://doi.org/10.1016/j.cmet.2015.01.002.PubMedCentralCrossRefPubMedGoogle Scholar
  117. Pasqualini, J. R., Chetrite, G., Blacker, C., Feinstein, M. C., Delalonde, L., Talbi, M., & Maloche, C. (1996). Concentrations of estrone, estradiol, and estrone sulfate and evaluation of sulfatase and aromatase activities in pre- and postmenopausal breast cancer patients. The Journal of Clinical Endocrinology and Metabolism, 81(4), 1460–1464.  https://doi.org/10.1210/jcem.81.4.8636351.PubMedGoogle Scholar
  118. Pedram, A., Razandi, M., O’Mahony, F., Harvey, H., Harvey, B. J., & Levin, E. R. (2013). Estrogen reduces lipid content in the liver exclusively from membrane receptor signaling. Science Signaling, 6(276), ra36.  https://doi.org/10.1126/scisignal.2004013.CrossRefPubMedGoogle Scholar
  119. Petitti, D. B., Perlman, J. A., & Sidney, S. (1987). Noncontraceptive estrogens and mortality: Long-term follow-up of women in the Walnut Creek Study. Obstetrics and Gynecology, 70(3 Pt 1), 289–293.PubMedGoogle Scholar
  120. Qian, Y. M., Sun, X. J., Tong, M. H., Li, X. P., Richa, J., & Song, W. C. (2001). Targeted disruption of the mouse estrogen sulfotransferase gene reveals a role of estrogen metabolism in intracrine and paracrine estrogen regulation. Endocrinology, 142(12), 5342–5350.  https://doi.org/10.1210/endo.142.12.8540.CrossRefPubMedGoogle Scholar
  121. Rader, D. J., & Tall, A. R. (2012). The not-so-simple HDL story: Is it time to revise the HDL cholesterol hypothesis? Nature Medicine, 18(9), 1344–1346.  https://doi.org/10.1038/nm.2937.CrossRefPubMedGoogle Scholar
  122. Rader, D. J., Alexander, E. T., Weibel, G. L., Billheimer, J., & Rothblat, G. H. (2009). The role of reverse cholesterol transport in animals and humans and relationship to atherosclerosis. Journal of Lipid Research, 50 Suppl, S189–194.  https://doi.org/10.1194/jlr.R800088-JLR200.
  123. Reaven, G. M., & Bernstein, R. M. (1978). Effect of obesity on the relationship between very low density lipoprotein production rate and plasma triglyceride concentration in normal and hypertriglyceridemic subjects. Metabolism, 27(9), 1047–1054.CrossRefPubMedGoogle Scholar
  124. Ribas, V., Nguyen, M. T., Henstridge, D. C., Nguyen, A. K., Beaven, S. W., Watt, M. J., & Hevener, A. L. (2010). Impaired oxidative metabolism and inflammation are associated with insulin resistance in ERalpha-deficient mice. American Journal of Physiology. Endocrinology and Metabolism, 298(2), E304–E319.  https://doi.org/10.1152/ajpendo.00504.2009.CrossRefPubMedGoogle Scholar
  125. Ribas, V., Drew, B. G., Zhou, Z., Phun, J., Kalajian, N. Y., Soleymani, T., Daraei, P., Widjaja, K., Wanagat, J., de Aguiar Vallim, T. Q., Fluitt, A. H., Bensinger, S., Le, T., Radu, C., Whitelegge, J. P., Beaven, S. W., Tontonoz, P., Lusis, A. J., Parks, B. W., Vergnes, L., Reue, K., Singh, H., Bopassa, J. C., Toro, L., Stefani, E., Watt, M. J., Schenk, S., Akerstrom, T., Kelly, M., Pedersen, B. K., Hewitt, S. C., Korach, K. S., & Hevener, A. L. (2016). Skeletal muscle action of estrogen receptor α is critical for the maintenance of mitochondrial function and metabolic homeostasis in females. Science Translational Medicine, 8(334), 334ra354.CrossRefGoogle Scholar
  126. Rochira, V., Madeo, B., Zirilli, L., Caffagni, G., Maffei, L., & Carani, C. (2007). Oestradiol replacement treatment and glucose homeostasis in two men with congenital aromatase deficiency: Evidence for a role of oestradiol and sex steroids imbalance on insulin sensitivity in men. Diabetic Medicine, 24(12), 1491–1495.  https://doi.org/10.1111/j.1464-5491.2007.02304.x.CrossRefPubMedGoogle Scholar
  127. Roe, A., Hillman, J., Butts, S., Smith, M., Rader, D., Playford, M., Mehta, N. N., & Dokras, A. (2014). Decreased cholesterol efflux capacity and atherogenic lipid profile in young women with PCOS. The Journal of Clinical Endocrinology and Metabolism, 99(5), E841–E847.  https://doi.org/10.1210/jc.2013-3918.PubMedCentralCrossRefPubMedGoogle Scholar
  128. Roger, V. L., Go, A. S., Lloyd-Jones, D. M., Adams, R. J., Berry, J. D., Brown, T. M., Carnethon, M. R., Dai, S., de Simone, G., Ford, E. S., Fox, C. S., Fullerton, H. J., Gillespie, C., Greenlund, K. J., Hailpern, S. M., Heit, J. A., Ho, P. M., Howard, V. J., Kissela, B. M., Kittner, S. J., Lackland, D. T., Lichtman, J. H., Lisabeth, L. D., Makuc, D. M., Marcus, G. M., Marelli, A., Matchar, D. B., McDermott, M. M., Meigs, J. B., Moy, C. S., Mozaffarian, D., Mussolino, M. E., Nichol, G., Paynter, N. P., Rosamond, W. D., Sorlie, P. D., Stafford, R. S., Turan, T. N., Turner, M. B., Wong, N. D., & Wylie-Rosett, J. (2011). Heart disease and stroke statistics–2011 update: A report from the American Heart Association. Circulation, 123(4), e18–e209.  https://doi.org/10.1161/CIR.0b013e3182009701.CrossRefPubMedGoogle Scholar
  129. Rogers, N. H., Perfield, J. W., 2nd, Strissel, K. J., Obin, M. S., & Greenberg, A. S. (2009). Reduced energy expenditure and increased inflammation are early events in the development of ovariectomy-induced obesity. Endocrinology, 150(5), 2161–2168.  https://doi.org/10.1210/en.2008-1405.PubMedCentralCrossRefPubMedGoogle Scholar
  130. Romero-Aleshire, M. J., Diamond-Stanic, M. K., Hasty, A. H., Hoyer, P. B., & Brooks, H. L. (2009). Loss of ovarian function in the VCD mouse-model of menopause leads to insulin resistance and a rapid progression into the metabolic syndrome. American Journal of Physiology. Regulatory, Integrative and Comparative Physiology, 297(3), R587–R592.  https://doi.org/10.1152/ajpregu.90762.2008.PubMedCentralCrossRefPubMedGoogle Scholar
  131. Rosenson, R. S., Brewer, H. B., Jr., Davidson, W. S., Fayad, Z. A., Fuster, V., Goldstein, J., Hellerstein, M., Jiang, X. C., Phillips, M. C., Rader, D. J., Remaley, A. T., Rothblat, G. H., Tall, A. R., & Yvan-Charvet, L. (2012). Cholesterol efflux and atheroprotection: Advancing the concept of reverse cholesterol transport. Circulation, 125(15), 1905–1919.  https://doi.org/10.1161/CIRCULATIONAHA.111.066589.PubMedCentralCrossRefPubMedGoogle Scholar
  132. Rossi, R., Origliani, G., & Modena, M. G. (2004). Transdermal 17-beta-estradiol and risk of developing type 2 diabetes in a population of healthy, nonobese postmenopausal women. Diabetes Care, 27(3), 645–649.CrossRefPubMedGoogle Scholar
  133. Rudling, M., Norstedt, G., Olivecrona, H., Reihner, E., Gustafsson, J. A., & Angelin, B. (1992). Importance of growth hormone for the induction of hepatic low density lipoprotein receptors. Proceedings of the National Academy of Sciences of the United States of America, 89(15), 6983–6987.PubMedCentralCrossRefPubMedGoogle Scholar
  134. Ryu, S., Suh, B. S., Chang, Y., Kwon, M. J., Yun, K. E., Jung, H. S., Kim, C. W., Kim, B. K., Kim, Y. J., Choi, Y., Ahn, J., Cho, Y. K., Kim, K. H., Ahn, Y., Park, H. Y., Chung, E. C., Shin, H., & Cho, J. (2015). Menopausal stages and non-alcoholic fatty liver disease in middle-aged women. European Journal of Obstetrics, Gynecology, and Reproductive Biology, 190, 65–70.  https://doi.org/10.1016/j.ejogrb.2015.04.017.CrossRefPubMedGoogle Scholar
  135. Sanada, M., Tsuda, M., Kodama, I., Sakashita, T., Nakagawa, H., & Ohama, K. (2004). Substitution of transdermal estradiol during oral estrogen-progestin therapy in postmenopausal women: Effects on hypertriglyceridemia. Menopause, 11(3), 331–336.CrossRefPubMedGoogle Scholar
  136. Schaefer, E. J., Foster, D. M., Zech, L. A., Lindgren, F. T., Brewer, H. B., Jr., & Levy, R. I. (1983). The effects of estrogen administration on plasma lipoprotein metabolism in premenopausal females. The Journal of Clinical Endocrinology and Metabolism, 57(2), 262–267.  https://doi.org/10.1210/jcem-57-2-262.CrossRefPubMedGoogle Scholar
  137. Semenkovich, C. F., & Ostlund, R. E., Jr. (1987). Estrogens induce low-density lipoprotein receptor activity and decrease intracellular cholesterol in human hepatoma cell line Hep G2. Biochemistry, 26(16), 4987–4992.CrossRefPubMedGoogle Scholar
  138. Sharma, G., Mauvais-Jarvis, F., & Prossnitz, E. R. (2017). Roles of G protein-coupled estrogen receptor GPER in metabolic regulation. The Journal of Steroid Biochemistry and Molecular Biology.  https://doi.org/10.1016/j.jsbmb.2017.02.012.
  139. Smith, E. P., Boyd, J., Frank, G. R., Takahashi, H., Cohen, R. M., Specker, B., Williams, T. C., Lubahn, D. B., & Korach, K. S. (1994). Estrogen resistance caused by a mutation in the estrogen-receptor gene in a man. The New England Journal of Medicine, 331(16), 1056–1061.  https://doi.org/10.1056/NEJM199410203311604.CrossRefPubMedGoogle Scholar
  140. Smith, G. I., Reeds, D. N., Okunade, A. L., Patterson, B. W., & Mittendorfer, B. (2014). Systemic delivery of estradiol, but not testosterone or progesterone, alters very low density lipoprotein-triglyceride kinetics in postmenopausal women. The Journal of Clinical Endocrinology and Metabolism, 99(7), E1306–E1310.  https://doi.org/10.1210/jc.2013-4470.PubMedCentralCrossRefPubMedGoogle Scholar
  141. Stampfer, M. J., Willett, W. C., Colditz, G. A., Rosner, B., Speizer, F. E., & Hennekens, C. H. (1985). A prospective study of postmenopausal estrogen therapy and coronary heart disease. The New England Journal of Medicine, 313(17), 1044–1049.  https://doi.org/10.1056/NEJM198510243131703.CrossRefPubMedGoogle Scholar
  142. Starr, A. E., Lemieux, V., Noad, J., Moore, J. I., Dewpura, T., Raymond, A., Chretien, M., Figeys, D., & Mayne, J. (2015). Beta-estradiol results in a proprotein convertase subtilisin/kexin type 9-dependent increase in low-density lipoprotein receptor levels in human hepatic HuH7 cells. The FEBS Journal, 282(14), 2682–2696.  https://doi.org/10.1111/febs.13309.PubMedCentralCrossRefPubMedGoogle Scholar
  143. Steinberg, M., Tolksdorf, S., & Gordon, A. S. (1967). Relation of the adrenal and pituitary to the hypocholesterolemic effect of estrogen in rats. Endocrinology, 81(2), 340–344.  https://doi.org/10.1210/endo-81-2-340.CrossRefPubMedGoogle Scholar
  144. Strandberg, T. E., Ylikorkala, O., & Tikkanen, M. J. (2003). Differing effects of oral and transdermal hormone replacement therapy on cardiovascular risk factors in healthy postmenopausal women. The American Journal of Cardiology, 92(2), 212–214.CrossRefPubMedGoogle Scholar
  145. Sullivan, J. M., Vander Zwaag, R., Hughes, J. P., Maddock, V., Kroetz, F. W., Ramanathan, K. B., & Mirvis, D. M. (1990). Estrogen replacement and coronary artery disease. Effect on survival in postmenopausal women. Archives of Internal Medicine, 150(12), 2557–2562.CrossRefPubMedGoogle Scholar
  146. Svendsen, O. L., Hassager, C., & Christiansen, C. (1995). Age- and menopause-associated variations in body composition and fat distribution in healthy women as measured by dual-energy X-ray absorptiometry. Metabolism, 44(3), 369–373.CrossRefPubMedGoogle Scholar
  147. Tato, F., Vega, G. L., & Grundy, S. M. (1995). Bimodal distribution of cholesteryl ester transfer protein activities in normotriglyceridemic men with low HDL cholesterol concentrations. Arteriosclerosis, Thrombosis, and Vascular Biology, 15(4), 446–451.  https://doi.org/10.1161/01.atv.15.4.446.CrossRefPubMedGoogle Scholar
  148. Trial TWGftP. (1995). Effects of estrogen or estrogen/progestin regimens on heart disease risk factors in postmenopausal women. The postmenopausal estrogen/progestin interventions (PEPI) trial. The Writing Group for the PEPI Trial. JAMA, 273(3), 199–208.CrossRefGoogle Scholar
  149. Tuazon, M. A., McConnell, T. R., Wilson, G. J., Anthony, T. G., & Henderson, G. C. (2015). Intensity-dependent and sex-specific alterations in hepatic triglyceride metabolism in mice following acute exercise. Journal of Applied Physiology. (1985, 118(1), 61–70.  https://doi.org/10.1152/japplphysiol.00440.2014.CrossRefPubMedGoogle Scholar
  150. Ulloa, N., Arteaga, E., Bustos, P., Duran-Sandoval, D., Schulze, K., Castro, G., Jauhiainen, M., Fruchart, J. C., & Calvo, C. (2002). Sequential estrogen-progestin replacement therapy in healthy postmenopausal women: Effects on cholesterol efflux capacity and key proteins regulating high-density lipoprotein levels. Metabolism, 51(11), 1410–1417.CrossRefPubMedGoogle Scholar
  151. Vague, J. (1947). La différenciation sexuelle; facteur déterminant des formes de l'obésité. Presse Médicale, 55(30), 339.PubMedGoogle Scholar
  152. van der Schouw, Y. T., van der Graaf, Y., Steyerberg, E. W., Eijkemans, J. C., & Banga, J. D. (1996). Age at menopause as a risk factor for cardiovascular mortality. Lancet, 347(9003), 714–718.CrossRefPubMedGoogle Scholar
  153. Villa, A., Della Torre, S., Stell, A., Cook, J., Brown, M., & Maggi, A. (2012). Tetradian oscillation of estrogen receptor alpha is necessary to prevent liver lipid deposition. Proceedings of the National Academy of Sciences of the United States of America, 109(29), 11806–11811.  https://doi.org/10.1073/pnas.1205797109.PubMedCentralCrossRefPubMedGoogle Scholar
  154. Walsh, B. W., Schiff, I., Rosner, B., Greenberg, L., Ravnikar, V., & Sacks, F. M. (1991). Effects of postmenopausal estrogen replacement on the concentrations and metabolism of plasma lipoproteins. The New England Journal of Medicine, 325(17), 1196–1204.  https://doi.org/10.1056/NEJM199110243251702.CrossRefPubMedGoogle Scholar
  155. Wang, H. H., Afdhal, N. H., & Wang, D. Q. (2004). Estrogen receptor alpha, but not beta, plays a major role in 17beta-estradiol-induced murine cholesterol gallstones. Gastroenterology, 127(1), 239–249.CrossRefPubMedGoogle Scholar
  156. Wang, H. H., Afdhal, N. H., & Wang, D. Q. H. (2006). Overexpression of estrogen receptor a increases hepatic cholesterogenesis, leading to biliary hypersecretion in mice. Journal of Lipid Research, 47(4), 778–786.  https://doi.org/10.1194/Jlr.M500454-Jlr200.CrossRefPubMedGoogle Scholar
  157. Wang, X., Lu, Y., Wang, E., Zhang, Z., Xiong, X., Zhang, H., Lu, J., Zheng, S., Yang, J., Xia, X., Yang, S., & Li, X. (2015). Hepatic estrogen receptor alpha improves hepatosteatosis through upregulation of small heterodimer partner. Journal of Hepatology, 63(1), 183–190.  https://doi.org/10.1016/j.jhep.2015.02.029.CrossRefPubMedGoogle Scholar
  158. Wiegratz, I., Jung-Hoffmann, C., Gross, W., & Kuhl, H. (1998). Effect of two oral contraceptives containing ethinyl estradiol and gestodene or norgestimate on different lipid and lipoprotein parameters. Contraception, 58(2), 83–91.  https://doi.org/10.1016/S0010-7824(98)00074-2.CrossRefPubMedGoogle Scholar
  159. Wilmot, K. A., O’Flaherty, M., Capewell, S., Ford, E. S., & Vaccarino, V. (2015). <span hwp:id=&quot;article-title-1&quot; class=&quot;article-title&quot;>Coronary Heart Disease Mortality Declines in the United States From 1979 Through 2011</span><span hwp:id=&quot;article-title-50&quot; class=&quot;sub-article-title&quot;>CLINICAL PERSPECTIVE</span&gt. Circulation 132(11), 997.Google Scholar
  160. Wilson, P. W., Garrison, R. J., & Castelli, W. P. (1985). Postmenopausal estrogen use, cigarette smoking, and cardiovascular morbidity in women over 50. The Framingham Study. The New England Journal of Medicine, 313(17), 1038–1043.  https://doi.org/10.1056/NEJM198510243131702.CrossRefPubMedGoogle Scholar
  161. Windler, E. E., Kovanen, P. T., Chao, Y. S., Brown, M. S., Havel, R. J., & Goldstein, J. L. (1980). The estradiol-stimulated lipoprotein receptor of rat liver. A binding site that membrane mediates the uptake of rat lipoproteins containing apoproteins B and E. The Journal of Biological Chemistry, 255(21), 10464–10471.PubMedGoogle Scholar
  162. Wolf, P. H., Madans, J. H., Finucane, F. F., Higgins, M., & Kleinman, J. C. (1991). Reduction of cardiovascular disease-related mortality among postmenopausal women who use hormones: Evidence from a national cohort. American Journal of Obstetrics and Gynecology, 164(2), 489–494.CrossRefPubMedGoogle Scholar
  163. Yamamoto, Y., Moore, R., Hess, H. A., Guo, G. L., Gonzalez, F. J., Korach, K. S., Maronpot, R. R., & Negishi, M. (2006). Estrogen receptor alpha mediates 17alpha-ethynylestradiol causing hepatotoxicity. The Journal of Biological Chemistry, 281(24), 16625–16631.  https://doi.org/10.1074/jbc.M602723200.CrossRefPubMedGoogle Scholar
  164. Yang, J. D., Abdelmalek, M. F., Pang, H., Guy, C. D., Smith, A. D., Diehl, A. M., & Suzuki, A. (2014). Gender and menopause impact severity of fibrosis among patients with nonalcoholic steatohepatitis. Hepatology, 59(4), 1406–1414.  https://doi.org/10.1002/hep.26761.PubMedCentralCrossRefPubMedGoogle Scholar
  165. Yusuf, S., Hawken, S., Ounpuu, S., Bautista, L., Franzosi, M. G., Commerford, P., Lang, C. C., Rumboldt, Z., Onen, C. L., Lisheng, L., Tanomsup, S., Wangai, P., Jr., Razak, F., Sharma, A. M., Anand, S. S., & Investigators IS. (2005). Obesity and the risk of myocardial infarction in 27,000 participants from 52 countries: A case-control study. Lancet, 366(9497), 1640–1649.  https://doi.org/10.1016/S0140-6736(05)67663-5.CrossRefPubMedGoogle Scholar
  166. Zegura, B., Guzic-Salobir, B., Sebestjen, M., & Keber, I. (2006). The effect of various menopausal hormone therapies on markers of inflammation, coagulation, fibrinolysis, lipids, and lipoproteins in healthy postmenopausal women. Menopause, 13(4), 643–650.  https://doi.org/10.1097/01.gme.0000198485.70703.7a.CrossRefPubMedGoogle Scholar
  167. Zhang, Y., Howard, B. V., Cowan, L. D., Yeh, J., Schaefer, C. F., Wild, R. A., Wang, W., & Lee, E. T. (2002). The effect of estrogen use on levels of glucose and insulin and the risk of type 2 diabetes in American Indian postmenopausal women: The strong heart study. Diabetes Care, 25(3), 500–504.Google Scholar
  168. Zhang, Y., Da Silva, J. R., Reilly, M., Billheimer, J. T., Rothblat, G. H., & Rader, D. J. (2005). Hepatic expression of scavenger receptor class B type I (SR-BI) is a positive regulator of macrophage reverse cholesterol transport in vivo. The Journal of Clinical Investigation, 115(10), 2870–2874.  https://doi.org/10.1172/JCI25327.PubMedCentralCrossRefPubMedGoogle Scholar
  169. Zhang, Y., Klein, K., Sugathan, A., Nassery, N., Dombkowski, A., Zanger, U. M., & Waxman, D. J. (2011). Transcriptional profiling of human liver identifies sex-biased genes associated with polygenic dyslipidemia and coronary artery disease. PLoS One, 6(8), e23506.  https://doi.org/10.1371/journal.pone.0023506.PubMedCentralCrossRefPubMedGoogle Scholar
  170. Zhang, H., Liu, Y., Wang, L., Li, Z., Zhang, H., Wu, J., Rahman, N., Guo, Y., Li, D., Li, N., Huhtaniemi, I., Tsang, S. Y., Gao, G. F., & Li, X. (2013). Differential effects of estrogen/androgen on the prevention of nonalcoholic fatty liver disease in the male rat. Journal of Lipid Research, 54(2), 345–357.  https://doi.org/10.1194/jlr.M028969.PubMedCentralCrossRefPubMedGoogle Scholar
  171. Zhang, Z. C., Liu, Y., Xiao, L. L., Li, S. F., Jiang, J. H., Zhao, Y., Qian, S. W., Tang, Q. Q., & Li, X. (2015). Upregulation of miR-125b by estrogen protects against non-alcoholic fatty liver in female mice. Journal of Hepatology, 63(6), 1466–1475.  https://doi.org/10.1016/j.jhep.2015.07.037.CrossRefPubMedGoogle Scholar
  172. Zhu, L., Brown, W. C., Cai, Q., Krust, A., Chambon, P., McGuinness, O. P., & Stafford, J. M. (2013). Estrogen treatment after ovariectomy protects against fatty liver and may improve pathway-selective insulin resistance. Diabetes, 62(2), 424–434.  https://doi.org/10.2337/db11-1718.PubMedCentralCrossRefPubMedGoogle Scholar
  173. Zhu, L., Martinez, M. N., Emfinger, C. H., Palmisano, B. T., & Stafford, J. M. (2014). Estrogen signaling prevents diet-induced hepatic insulin resistance in male mice with obesity. American Journal of Physiology. Endocrinology and Metabolism, 306(10), E1188–E1197.  https://doi.org/10.1152/ajpendo.00579.2013.PubMedCentralCrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  • Brian T. Palmisano
    • 1
    • 2
    • 3
  • Lin Zhu
    • 1
    • 2
  • John M. Stafford
    • 1
    • 2
    • 3
  1. 1.Tennessee Valley Healthcare System, Veterans AffairsNashvilleUSA
  2. 2.Department of Molecular Physiology and BiophysicsVanderbilt UniversityNashvilleUSA
  3. 3.Division of Endocrinology, Diabetes and MetabolismVanderbilt University Medical CenterNashvilleUSA

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