Estrogen Administration for the Treatment of NASH in Postmenopausal Women

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.