Treatment with estrogen protects against ovariectomy-induced hepatic steatosis by increasing AQP7 expression

Fu,Xiaohua; Xing,Lili; Xu,Weihai; Shu,Jing

doi:10.3892/mmr.2016.5236

Treatment with estrogen protects against ovariectomy-induced hepatic steatosis by increasing AQP7 expression

Authors:
- Xiaohua Fu
- Lili Xing
- Weihai Xu
- Jing Shu
View Affiliations

Affiliations: Department of Reproductive Endocrinology, Zhejiang Provincial People's Hospital, Hangzhou, Zhejiang 310014, P.R. China
Published online on: May 10, 2016 https://doi.org/10.3892/mmr.2016.5236
Pages: 425-431

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Recent evidence has suggested that the marked decrease in ovarian secretion of estrogens in postmenopausal women may be associated with the development of non-alcoholic fatty liver disease. The present study aimed to elucidate the mechanisms by which low levels of estrogen induce fatty liver disease using an ovariectomized (OVX) mouse model and an in vitro cell model. A total of 24 female C57/BL6 mice were divided into four groups: Sham operation, sham operation plus subcutaneous implantation of tamoxifen (TAM), bilateral OVX, and OVX plus subcutaneous implantation of 17β-estradiol (E2). Marked hepatic steatosis and increased expression of lipogenic genes (acetyl‑CoA carboxylase, fatty acid synthase and glycerol-3-phosphate acyltransferase) was observed in the estrogen‑depleted mice (TAM and OVX groups), as compared with in the sham operation group. Treatment with E2 significantly improved hepatic steatosis by decreasing the expression of the aforementioned lipogenic genes. Furthermore, hepatic aquaporin 7 (AQP7) expression was decreased in the estrogen‑depleted mice, but was increased in the OVX + E2 treatment group, as compared with in the sham operation group. These results suggested an association between AQP7 and low estrogen‑induced hepatic steatosis. Subsequently, the functions of AQP7 in hepatic steatosis were investigated using an oleic acid‑induced HepG2 cell model of steatosis. Treatment with E2 alleviated lipid accumulation and decreased the expression of lipogenic genes in vitro; however, such effects were attenuated following transfection with AQP7 small interfering RNA. The present study suggested a mechanism by which low levels of estrogen induce fatty liver disease, and may provide useful information regarding the prevention and treatment of fatty liver disease in postmenopausal women.

View Figures

View References

1	Winkler UH: Menopause, hormone replacement therapy and cardiovascular disease: A review of haemostaseological findings. Fibrinolysis. 6:5–10. 1992. View Article : Google Scholar
2	Carr MC: The emergence of the metabolic syndrome with menopause. J Clin Endocrinol Metab. 88:2404–2411. 2003. View Article : Google Scholar : PubMed/NCBI
3	Marchesini G, Brizi M, Bianchi G, Tomassetti S, Bugianesi E, Lenzi M, McCullough AJ, Natale S, Forlani G and Melchionda N: Nonalcoholic fatty liver disease: A feature of the metabolic syndrome. Diabetes. 50:1844–1850. 2001. View Article : Google Scholar : PubMed/NCBI
4	Suzuki A and Abdelmalek MF: Nonalcoholic fatty liver disease in women. Womens Health (Lond Engl). 5:191–203. 2009. View Article : Google Scholar
5	Lonardo A, Carani C, Carulli N and Loria P: 'Endocrine NAFLD' a hormonocentric perspective of nonalcoholic fatty liver disease pathogenesis. J Hepatol. 44:1196–1207. 2006. View Article : Google Scholar : PubMed/NCBI
6	Zhu L, Brown WC, Cai Q, Krust A, Chambon P, McGuinness OP and Stafford JM: Estrogen treatment after ovariectomy protects against fatty liver and may improve pathway-selective insulin resistance. Diabetes. 62:424–434. 2013. View Article : Google Scholar :
7	Farrell GC and Larter CZ: Nonalcoholic fatty liver disease: From steatosis to cirrhosis. Hepatology. 43(2 Suppl 1): S99–S112. 2006. View Article : Google Scholar : PubMed/NCBI
8	Frühbeck G, Catalán V, Gómez-Ambrosi J and Rodríguez A: Aquaporin-7 and glycerol permeability as novel obesity drug-target pathways. Trends Pharmacol Sci. 27:345–347. 2006. View Article : Google Scholar : PubMed/NCBI
9	Rodríguez A, Catálan V, Gómez-Ambrosi J and Frühbeck G: Role of aquaporin-7 in the pathophysiological control of fat accumulation in mice. FEBS Lett. 580:4771–4776. 2006. View Article : Google Scholar : PubMed/NCBI
10	Zou LB, Zhang RJ, Tan YJ, Ding GL, Shi S, Zhang D, He RH, Liu AX, Wang TT, Leung PC, et al: Identification of estrogen response element in the aquaporin-2 gene that mediates estrogen-induced cell migration and invasion in human endometrial carcinoma. J Clin Endocrinol Metab. 96:E1399–E1408. 2011. View Article : Google Scholar : PubMed/NCBI
11	Institute of Laboratory Animal Resources (US) Committee on Care, Use of Laboratory Animals, and National Institutes of Health (US): Division of Research Resources: Guide for the care and use of laboratory animals. 8th edition. National Academies Press; Washington, DC: 2011
12	Yuan H, Zhang H, Wu X, Zhang Z, Du D, Zhou W, Zhou S, Brakebusch C and Chen Z: Hepatocyte-specific deletion of Cdc42 results in delayed liver regeneration after partial hepatectomy in mice. Hepatology. 49:240–249. 2009. View Article : Google Scholar
13	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods. 25:402–408. 2001. View Article : Google Scholar
14	Ricchi M, Odoardi MR, Carulli L, Anzivino C, Ballestri S, Pinetti A, Fantoni LI, Marra F, Bertolotti M, Banni S, et al: Differential effect of oleic and palmitic acid on lipid accumulation and apoptosis in cultured hepatocytes. J Gastroenterol Hepatol. 24:830–840. 2009. View Article : Google Scholar : PubMed/NCBI
15	Mori-Okamoto J, Otawara-Hamamoto Y, Yamato H and Yoshimura H: Pomegranate extract improves a depressive state and bone properties in menopausal syndrome model ovariectomized mice. J Ethnopharmacol. 92:93–101. 2004. View Article : Google Scholar : PubMed/NCBI
16	Bekku N and Yoshimura H: Animal model of menopausal depressive-like state in female mice: Prolongation of immobility time in the forced swimming test following ovariectomy. Psychopharmacology (Berl). 183:300–307. 2005. View Article : Google Scholar
17	Shou J, Massarweh S, Osborne CK, Wakeling AE, Ali S, Weiss H and Schiff R: Mechanisms of tamoxifen resistance: Increased estrogen receptor-HER2/neu cross-talk in ER/HER2-positive breast cancer. J Natl Cancer Inst. 96:926–935. 2004. View Article : Google Scholar : PubMed/NCBI
18	Okamoto Y, Tanaka S and Haga Y: Enhanced GLUT2 gene expression in an oleic acid-induced in vitro fatty liver model. Hepatol Res. 23:138–144. 2002. View Article : Google Scholar : PubMed/NCBI
19	Pacifici R: Estrogen, cytokines, and pathogenesis of postmenopausal osteoporosis. J Bone Miner Res. 11:1043–1051. 1996. View Article : Google Scholar : PubMed/NCBI
20	Gloy V, Langhans W, Hillebrand JJ, Geary N and Asarian L: Ovariectomy and overeating palatable, energy-dense food increase subcutaneous adipose tissue more than intra-abdominal adipose tissue in rats. Biol Sex Differ. 2:62011. View Article : Google Scholar : PubMed/NCBI
21	Chung YH, Huang CC, Chiu SC, Lin YH and Yen TC: Evaluate non-alcoholic fatty liver disease in ovariectomized mice as a model of postmenopausal women using Tc-99m Disofenin scintigraphy and ultrasound imaging. J Nucl Med. 55(Suppl 1): p352014.
22	Lundholm L, Zang H, Hirschberg AL, Gustafsson JA, Arner P and Dahlman-Wright K: Key lipogenic gene expression can be decreased by estrogen in human adipose tissue. Fertil Steril. 90:44–48. 2008. View Article : Google Scholar : PubMed/NCBI
23	Paquette A, Wang D, Jankowski M, Gutkowska J and Lavoie JM: Effects of ovariectomy on PPAR alpha, SREBP-1c, and SCD-1 gene expression in the rat liver. Menopause. 15:1169–1175. 2008. View Article : Google Scholar : PubMed/NCBI
24	Carroll JS and Brown M: Estrogen receptor target gene: An evolving concept. Mol Endocrinol. 20:1707–1714. 2006. View Article : Google Scholar : PubMed/NCBI
25	Kobayashi M, Takahashi E, Miyagawa S, Watanabe H and Iguchi T: Chromatin immunoprecipitation-mediated target identification proved aquaporin 5 is regulated directly by estrogen in the uterus. Genes Cells. 11:1133–1143. 2006. View Article : Google Scholar : PubMed/NCBI