ABSTRACT
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 hepatosteatosis. Postmenopausal women with metabolic syndrome are often treated with hormone replacement therapy (HRT), but estrogens in currently available HRTs increase the risk of breast and endometrial cancers and Cardiovascular Disease. Therefore, there is a critical need to find safer alternatives 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 collagen 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 expenditure. 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 postmenopausal women from fatty liver disease without increasing reproductive cancer risk.
Subject(s)
Diet, High-Fat , Estrogens/therapeutic use , Fatty Liver/etiology , Fatty Liver/prevention & control , Ovariectomy , Animals , Body Weight/drug effects , Collagen/metabolism , Estrogen Receptor alpha/metabolism , Estrogens/pharmacology , Fatty Liver/complications , Fatty Liver/genetics , Hep G2 Cells , Hepatocytes/metabolism , Humans , Inflammation/pathology , Ligands , Lipid Metabolism , Liver/metabolism , Metabolomics , Mice, Inbred C57BL , Mice, Obese , Obesity/complications , Obesity/genetics , Organ Size/drug effects , Transcriptome/genetics , Weight GainABSTRACT
Due to declining estrogen levels during menopause, NAFLD prevalence is higher in postmenopausal women compared to in premenopausal women or in men. Postmenopausal women are more susceptible to weight gain, fat redistribution and dyslipidemia, all major hallmarks of metabolic syndrome associated with increased NAFLD risk. Gut microbiota plays important roles in development of gastrointestinal tract, metabolism and immunity. Host-microbe interactions allows regulation of a wide range of pathways that affect healthy and diseased physiology. Recent advances in - omics technologies, such as microbiome, transcriptome and metabolome analysis, provided evidence that estrogens and intestinal microbiota (IM) can collectively influence obesity, inflammatory disease, diabetes, and cancers. By understanding underlying mechanisms of estrogens and microbiota crosstalk, we might design dietary and pharmacological interventions to alleviate the metabolic syndrome and NAFLD.
Subject(s)
Estrogens/metabolism , Liver , Sex Characteristics , Animals , Female , Humans , Liver/metabolism , Microbiota , Non-alcoholic Fatty Liver Disease/metabolism , Non-alcoholic Fatty Liver Disease/physiopathologyABSTRACT
Diet and nutrition are undeniably two factors that have a major impact on the prevention, progression, and treatment of various cancers. In this review, we will discuss how bioactives from diet and nutritional status affect each of the hallmarks of cancer. We will present recent research and discuss using diet and nutrition as a means to prevent and treat cancer.
ABSTRACT
Recent advances have suggested that steroid hormones such as estrogens, and gut microbiota might synergize to influence obesity, diabetes, and cancer. We discuss recent knowledge of the interactions between estrogens and gut microbiota, and new insights that might offer new approaches to influence this crosstalk and improve metabolic outcomes.
