The effects of novel and synthetic estrogens on liver health and microbiome crosstalk

estrogen;liver;NAFLD;microbiome

Chen, Karen Lee Ann ; Jeffery, Elizabeth H., ; ,Miller, Michael J. ; Madak-Erdogan ; Zeynep

关键词: estrogen;    liver;    NAFLD;    microbiome;   

Others  :  https://www.ideals.illinois.edu/bitstream/handle/2142/99478/CHEN-THESIS-2017.pdf?sequence=1&isAllowed=y

美国|英语

来源: The Illinois Digital Environment for Access to Learning and Scholarship

【 摘 要 】

Postmenopausal women have increased risk of metabolic diseases including non-alcoholic fatty liver disease (NAFLD). Hormone replacement therapies (HRT) reverse some of the risk factors associated with metabolic disease but increases the risk of reproductive cancers. Novel and synthetic estrogens may have the beneficial effects of HRT on metabolic health but do not increase the risk of cancers. The objective of these studies is to evaluate the effects of novel and synthetic estrogens on metabolism by analyzing transcriptomic, metabolomics, and microbiome data in mouse and cell line models. Additionally, a potential mechanism of interaction between estrogens and the gut microbiome is explored. Pathway preferential estrogen 1 (PaPE-1) is a promising novel estrogen receptor ligand that has been shown to favorably target tissues through selective activity. Though its effects on weight gain and fat accumulation have been previously investigated, its effects on liver transcriptome and plasma metabolites have yet to be determined. We use several genomics and postgenomics technologies to characterize the effects of various estrogens on the health of the liver. Additionally we tested the effects of PaPE-1 on two different mouse models: diet induced obesity (DIO) and leptin deficient (ob/ob) mice. PaPE-1 significantly decreased liver weight in both DIO and ob/ob models. H&E staining show that lipid accumulation decrease in animals who receive PaPE-1 treatment and this phenotype is also confirmed in HepG2 cells. Integrated pathway analysis using transcriptomics and metabolomics identified lower inflammation and fatty acid metabolic pathways to be modulated by PaPE-1 treatment. Our results show that PaPE-1 showed significant changes in inflammation and lipid synthesis and deposition-related metabolic pathways in two different mouse models that simulate metabolic dysfunction due to loss of estrogen cycling in combination with genetic background (ob/ob mice) and high-fat diet. In both models PaPE-1 is protective against steatosis and NAFLD.Bazedoxifene and conjugated estrogens (CE+BZA) combination has been shown to prevent visceral adiposity and weight gain after menopause. However, its interaction with the liver and prevention of steatosis has yet to be examined. As reported in previous studies, CE+BZA combination is very effective at preventing ovariectomy-induced weight gain in mice fed a high-fat diet (HFD). H&E and Oil Red O staining show that lipid droplet size is significantly reduced in CE+BZA treated animals after ovariectomy and HFD. Additionally, CE+BZA induces unique liver transcriptomic profiles compared to estradiol, conjugated estrogens alone, or bazedoxifene alone. Integrated pathway analysis shows that the most significant pathways influenced are associated with lower rates of inflammation and unsaturated fatty acid biosynthesis. These results point to overall benefits to liver health by CE+BZA treatment. Recent advances have enriched our understanding of the microbiome and have provided evidence that estrogens and gut microbiota might synergize to influence pathophysiologic conditions such as NAFLD. A better understanding of underlying mechanisms in estrogen and microbiota crosstalk might offer new approaches to influence this crosstalk and improve metabolic outcomes. Microbiome analysis in animals who received CE+BZA treatment show that there are no significant differences in the diversity of bacteria genera in the gut compared to vehicle treated animals. To identify changes in different genera of bacteria that are associated with weight gain after ovariectomy, we utilized Extended Random Forest (ERF) approach. This analysis identified Dehalobacteria, Akkermansia, and Anaerotruncus genera. There may be a potential for these genera to influence estrogen metabolism in the body by increasing the half-life of estrogens in the body. Further future studies will be performed to assess various metabolic activities associated with these bacteria that might influence half-life and fate of synthetic estrogens in the body.