Department of Food Science and Human Nutrition, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
Division of Nutritional Sciences, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
Nutrients. 2021 Sep 23;13(10):3334. doi: 10.3390/nu13103334.
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.
约 20-30%的绝经前女性患有代谢综合征，而绝经后女性这一数字几乎翻了一番，这些女性患肝脂肪变性的风险增加。患有代谢综合征的绝经后女性通常接受激素替代疗法 (HRT) 治疗，但目前可用的 HRT 中的雌激素会增加乳腺癌和子宫内膜癌以及心血管疾病的风险。因此，迫切需要找到更安全的 HRT 替代品来改善绝经后女性的代谢健康。途径优先雌激素 1 (PaPE-1) 是一种新型雌激素受体配体，已被证明可对代谢组织产生有利影响，而对生殖组织无不良影响。在这项研究中，我们研究了 PaPE-1 对代谢健康的影响，特别是研究了它对两种不同小鼠模型（饮食诱导肥胖 (DIO) 和瘦素缺乏 (ob/ob) 小鼠）的肝脏转录组和血浆代谢物的影响。PaPE-1 可显著降低 DIO 和 ob/ob 模型中的肝脏重量和脂质积累，并降低与脂肪酸代谢和胶原蛋白沉积相关的基因表达。此外，PaPE-1 可显著增加与电子传递链相关的线粒体基因的表达，表明能量消耗增加。使用转录组学和代谢组学数据进行的综合途径分析表明，PaPE-1 治疗可降低炎症、胶原蛋白沉积以及调节脂肪酸代谢和增加与谷胱甘肽代谢相关的代谢物的途径。总的来说，我们的研究结果支持 PaPE-1 具有有益的代谢作用，并表明 PaPE-1 可能在不增加生殖癌症风险的情况下保护绝经后女性免受脂肪肝疾病的侵害。
