Pathway preferential estrogens prevent hepatosteatosis due to ovariectomy and high−fat diets

About 20–30% of premenopausal women have metabolic syndrome, and the number is almost double in postmenopausal women, and these women have an increased risk of hepatoste-atosis. Postmenopausal women with metabolic syndrome are often treated with hormone replace-ment therapy (HRT), but estrogens in currently available HRTs increase the risk of breast and en-dometrial cancers and Cardiovascular Disease. Therefore, there is a critical need to find safer alter-natives to HRT to improve postmenopausal metabolic health. Pathway preferential estrogen 1 (PaPE−1) is a novel estrogen receptor ligand that has been shown to favorably affect metabolic tissues without adverse effects on reproductive tissues. In this study, we have examined the effects of PaPE−1 on metabolic health, in particular, examining its effects on the liver transcriptome and on plasma metabolites 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 and lowered the expression of genes associated with fatty acid metabolism and colla-gen deposition. In addition, PaPE−1 significantly increased the expression of mitochondrial genes, particularly ones associated with the electron transport chain, suggesting an increase in energy ex-penditure. Integrated pathway analysis using transcriptomics and metabolomics data showed that PaPE−1 treatment lowered inflammation, collagen deposition, and pathways regulating fatty acid metabolism and increased metabolites associated with glutathione metabolism. Overall, our findings support a beneficial metabolic role for PaPE−1 and suggest that PaPE−1 may protect postmen-opausal women from fatty liver disease without increasing reproductive cancer risk.