OR09-2 Pathway Preferential Estrogens Prevent Hepatosteatosis Due to Ovariectomy and High-Fat Diets

Non-alcoholic fatty liver disease (NAFLD) is the most common form of chronic liver diseases in the United States. Simple and benign steatosis can gradually develop into the more serious conditions of nonalcoholic steatohepatitis (NASH) and cirrhosis. Population studies have demonstrated that men and postmenopausal women have higher incidences of NAFLD compared to premenopausal women, suggesting a protective role for estrogens. The decrease in estrogens due to the onset of menopause make postmenopausal women more susceptible to weight gain, fat redistribution to abdominal areas, dyslipidemia, hypertension and insulin resistance, all of which are major hallmarks of metabolic syndrome and are associated with NAFLD. Pathway preferential estrogen 1 (PaPE-1) is a novel estrogen receptor ligand that has been shown to favorably affect metabolic tissues without stimulating reproductive tissues. 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 transcriptomics and metabolomics analysis to characterize the effects of PaPEs in two different mouse models: diet-induced obesity (DIO) and leptin-deficient (ob/ob) mice. PaPE-1 significantly decreased liver weight and lipid accumulation in both DIO and ob/ob models. Integrated pathway analysis using transcriptomics and metabolomics data showed that PaPE-1 treatment lowered genes associated with inflammation, collagen deposition, and fatty acid metabolism. On the other hand, PaPE-1 significantly increased expression of mitochondrial genes, particularly ones associated with electron transport chain and ribosome synthesis suggesting an increase in energy expenditure and mTOR signaling activity. In addition, PaPE-1 treatment restored insulin sensitivity in hepatocytes. Overall, our data show that PaPE-1 provides a metabolic benefit without stimulation of reproductive tissues.