@article{25afe8248d514223960321f4118fbfa3,
title = "Hepatic estrogen receptor α improves hepatosteatosis through upregulation of small heterodimer partner",
abstract = "Background & Aims Estrogen participates in the control of energy homeostasis and lipid metabolism. However the role of hepatic estrogen receptor α (ERα) in triglyceride (TG) homeostasis remains poorly understood. This study aims to investigate the roles of estrogen and ERα in the regulation of hepatic TG metabolism. Methods Liver TG metabolism was analyzed in female mice with ovariectomy or tamoxifen treatment, and in hepatic ERα knockdown or overexpression. Phenotypes and expression of genes were compared in male and female mice with farnesoid X receptor deficiency. The mechanism of ERα in the regulation of small heterodimer partner (SHP) expression was further investigated. Results Female mice receiving ovariectomy or tamoxifen treatment exhibited hepatic TG accumulation. Ablation of ERα using adenoviral shRNA markedly increased hepatic TG accumulation, while overexpression of ERα ameliorated hepatosteatosis in obese mice. At the molecular level, estrogen upregulated hepatic SHP expression through binding to its proximal promoter. In addition, the roles of estrogen were largely blunted in mice with SHP deficiency. Conclusion These findings reveal a novel role of estrogen in improving hepatosteatosis through upregulation of SHP expression.",
keywords = "ERa, Estrogen, FXR, Hepatosteatosis, SHP",
author = "Xiaolin Wang and Yan Lu and E. Wang and Zhijian Zhang and Xuelian Xiong and Huijie Zhang and Jieli Lu and Sheng Zheng and Jian Yang and Xuefeng Xia and Shuyu Yang and Xiaoying Li",
note = "Funding Information: It has been shown that estrogen plays a role in glucose and lipid homeostasis involved in multiple tissues or organs. For instance, menopause is associated with an increase in obesity incidence in women [23] , while estrogen treatment reduces adipocyte size and mass in rodents [24] . Besides, estrogen has a leptin-like effect in activation of intracellular signals in the hypothalamus [25] . As a result, deletion or silencing of ERα in the hypothalamus leads to obesity and metabolic defects in rodents [5,26] . In addition, recent studies demonstrate that estrogen reduces lipid synthesis in pancreatic islets and prevents β-cell failure in rodent models of type 2 diabetes, through upregulation of Stat3 [27] . In addition, Zhu et al. reported that estrogen treatment may improve insulin resistance by promoting insulin action on glucose metabolism and inhibiting hepatic lipid retention [28] . Here, we reveal that estrogen could directly suppress hepatic TG synthesis through activation of ERα. This is supported by several evidence. First, estrogen treatment reduces TG accumulation in cultured MPH. Second, liver specific ablation of ERα promotes hepatosteatosis under high-fat diet conditions, while ERα overexpression ameliorates TG accumulation in obese mice. Therefore, we conclude that estrogen activated ERα in liver is critical to inhibit hepatic TG synthesis and accumulation, independent of the effect of estrogen in other tissues, such as white adipose tissue and central nervous system. Publisher Copyright: {\textcopyright} 2015 European Association for the Study of the Liver.",
year = "2015",
month = jul,
day = "1",
doi = "10.1016/j.jhep.2015.02.029",
language = "English (US)",
volume = "63",
pages = "183--190",
journal = "Journal of Hepatology",
issn = "0168-8278",
publisher = "Elsevier B.V.",
number = "1",
}