Estrogen Administration for the Treatment of NASH in Postmenopausal Women

项目摘要 非酒精性脂肪性肝病(NAFLD)是全球最常见的肝病原因；进展为 非酒精性脂肪性肝炎(NASH)肝硬变发生在一部分患者中，是第二大适应症 在美国进行肝脏移植。非酒精性脂肪性肝病发生发展的因素及进展 对非酒精性脂肪性肝炎(NASH)，包括炎症和纤维化，了解很少。此外， 这些疾病缺乏有效的治疗方法。对动物和人类的研究表明，雌激素 缺乏可能是NAFLD发生和进展为NASH的重要机制。 然而，没有前瞻性的、随机的、安慰剂对照的研究来检验雌激素的影响。 对绝经后NASH患者脂肪变性、炎症或纤维化的治疗。我们的整体 假说是低剂量的经皮雌激素注射将减少肝脏脂肪，炎症和 经活检证实为NASH的女性患者出现纤维化。进一步，我们将探索雌激素对免疫和代谢的影响 在肝脏，包括单细胞水平的变化。目标1将检验这样一种假设，即服用雌二醇 将减少肝纤维化，炎症和脂肪变性的妇女，活检证实的NASH。目标2将决定 雌激素对肝内代谢途径和肝内转录图谱的影响 免疫细胞。我们假设雌激素会减少纤维化形成，减少肝脏新生脂肪生成， 并增加脂质β氧化作用。这些假设将通过严格设计的双盲、 小剂量经皮雌激素替代疗法治疗慢性前列腺癌的安慰剂对照研究 患有NASH的绝经后妇女。最先进的肝脏成像，肝脏活检，全肝转录和 SeqWell的无偏见单细胞RNAseq将被用来研究这些假说。我们已经集合好了 在内分泌学(米勒博士)、NAFLD(科里博士)、 肝脏成像(Bredella博士)和肝脏免疫学(Lauer博士)，这是进行这项工作的独特位置 多学科提案。小剂量雌激素透皮给药对肝脏影响的研究 纤维化、炎症和脂肪变性有可能加深我们对这种疾病过程和 找出目前还不存在的新的治疗靶点。

PROJECT ABSTRACT Non-alcoholic fatty liver disease (NAFLD) is the most common cause of liver disease worldwide; progression to non-alcoholic steatohepatitis (NASH) cirrhosis occurs in a subset of patients and is the second leading indication for liver transplantation in the United States. The factors leading to the development of NAFLD and progression to nonalcoholic steatohepatitis (NASH), including inflammation and fibrosis, are poorly understood. Moreover, there is a lack of effective therapies for these disorders. Studies in animals and humans suggest that estrogen deficiency may be an important mechanism underlying the development of NAFLD and progression to NASH. However, no prospective, randomized, placebo-controlled studies have examined the impact of estrogen administration on steatosis, inflammation or fibrosis in postmenopausal women with NASH. Our overall hypothesis is that low-dose, transdermal estrogen administration will decrease hepatic fat, inflammation and fibrosis in women with biopsy-proven NASH. Further, we will explore estrogen’s immune and metabolic effects in the liver, including changes at the single-cell level. Aim 1 will test the hypothesis that estradiol administration will decrease fibrosis, inflammation and steatosis in women with biopsy-proven NASH. Aim 2 will determine the impact of estrogen on intrahepatic metabolic pathways and on the transcriptional landscape of intrahepatic immune cells. We hypothesize that estrogen will decrease fibrogenesis, decrease hepatic de novo lipogenesis, and increase lipid beta oxidation. These hypotheses will be tested with a rigorously designed, double-blind, placebo-controlled study of the effects of low-dose transdermal estrogen replacement therapy in postmenopausal women with NASH. State-of-the-art liver imaging, liver biopsies, whole liver transcriptomics and unbiased single cell RNAseq by SeqWell will be leveraged to investigate these hypotheses. We have assembled a team of investigators with extensive research experience in endocrinology (Dr. Miller), NAFLD (Dr. Corey), liver imaging (Dr. Bredella), and hepatic immunology (Dr. Lauer), which is uniquely positioned to carry out this multi-disciplinary proposal. Elucidating the effects of low-dose, transdermal estrogen administration on liver fibrosis, inflammation and steatosis has the potential to further our understanding of this disease process and identify new therapeutic targets where few currently exist.