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Modulation of the hepatic expression of miR-33 and miR-34a possibly mediates the metabolic effects of estrogen in ovariectomized female rats.

在去卵巢雌性大鼠中,调节肝脏 miR-33 和 miR-34a 的表达可能介导了雌激素的代谢作用。

  • 影响因子:3.24
  • DOI:10.1016/j.ejphar.2020.173006
  • 作者列表:"Ali MA","Kamel MA
  • 发表时间:2020-02-08

:Estrogen and the estrogen receptors (ERs) are well-known regulators of several aspects of glucose and lipid metabolism. Meanwhile, the underlying mechanistic role of estrogens in regulating metabolic health remains largely unknown. Hence, the study was designed to tackle the possible contribution of the hepatic expression of miR-33, miR-21 and miR-34a and their target genes as the underlying mechanism of the metabolic effects of estrogen in ovariectomized rats. Forty female rats were ovariectomized (OVX), treated with estrogen and/or fulvestrant for 28 days and compared with untreated or treated sham operated rats. Estradiol amended the metabolic abnormalities in the OVX rats, witnessed by decreasing blood sugar, insulin and HOMA-IR as well as correcting the disrupted serum and hepatic lipids. Estradiol increased the hepatic expression of miR-33 and inhibited that of miR-34a and miR-21, leading to adjusting the gene expression and the protein level of their targets, sterol regulatory element-binding proteins-1c (SREBP-1c), fatty acid synthase (FASN), high mobility group (HMG) Box Transcription Factor 1 (HBP1) and Sirtuin 1 (SIRT1), receptively. However, estrogen had no significant effects on HBP1 protein. These effects were almost completely inhibited by fulvestrant, an estrogen receptor blocker, to the extent that fulvestrant had similar metabolic disorders to that of ovariectomization. In conclusion, estrogen replacement therapy in OVX females significantly ameliorated the metabolic derangements of insulin resistance, dyslipidemia and hepatic fat accumulation possibly via corrections of hepatic expression of miR-33 and miR-34a; effects that were mediated through the receptor-mediated signaling of ERs as confirmed by fulvestrant.


: 雌激素和雌激素受体 (ERs) 是众所周知的葡萄糖和脂质代谢的几个方面的调节因子。同时,雌激素在调节代谢健康中的潜在机制作用在很大程度上仍然未知。因此,本研究旨在探讨肝脏表达 miR-33 、 miR-21 和 miR-34a 及其靶基因作为雌激素代谢作用的潜在机制。40 只雌性大鼠去卵巢 (OVX),用雌激素和/或氟维司群治疗 28 天,与未治疗或治疗的假手术大鼠进行比较。雌二醇通过降低血糖、胰岛素和 HOMA-IR 以及纠正破坏的血清和肝脏脂质来改善 OVX 大鼠的代谢异常。雌二醇增加了 miR-33 的肝脏表达,抑制了 miR-34a 和 miR-21 的肝脏表达,从而调节了它们的目标基因表达和蛋白质水平,固醇调节元件结合 proteins-1c (SREBP-1c), 脂肪酸合成酶 (FASN) 、高迁移率族蛋白 (HMG) 盒转录因子 1 (HBP1) 和 Sirtuin 1(SIRT1),接受性。而雌激素对 HBP1 蛋白无明显影响。这些作用几乎完全被雌激素受体阻滞剂 fulvestrant 抑制,达到 fulvestrant 与卵巢切除术类似的代谢紊乱的程度。总之,雌激素替代治疗可显著改善卵巢雌性动物胰岛素抵抗、血脂异常和肝脏脂肪堆积的代谢紊乱,可能是通过纠正肝脏 miR-33 和 miR-34a 的表达而实现的; 通过 fulvestrant 证实的受体介导的 ERs 信号介导的效应。



作者列表:["Hone M","Nugent AP","Walton J","McNulty BA","Egan B"]

METHODS:BACKGROUND:Given the importance of habitual dietary protein intake, distribution patterns and dietary sources in the aetiology of age-related declines of muscle mass and function, the present study examined these factors as a function of sex and age in Irish adults aged 18-90 years comprising The National Adult Nutrition Survey (NANS). METHODS:In total, 1051 (males, n = 523; females, n = 528) undertook a 4-day semi-weighed food diary. Total, body mass relative intake and percentage contribution to total energy intake of dietary protein were determined in addition to protein distribution scores (PDS), as well as the contribution of food groups, animal- and plant-based foods to total protein intake. RESULTS:Total and relative protein intake [mean (SD)] were highest in those aged 18-35 years [96 (3) g day , 1.32 (0.40) g kg day ], with lower protein intakes with increasing age (i.e. in adults aged ≥65 years [82 (22) g, 1.15 (0.34) g kg day , P < 0.001 for both]. Differences in protein intake between age groups were more pronounced in males compared to females. Protein distribution followed a skewed pattern for all age groups [breakfast, 15 (10) g; lunch, 30 (15) g; dinner, 44 (17) g]. Animal-based foods were the dominant protein source within the diet [63% (11%) versus 37% (11%) plant protein, P < 0.001]. CONCLUSIONS:Protein intake and the number of meals reaching the purported threshold for maximising post-prandial anabolism were highest in young adults, and lower with increasing age. For main meals, breakfast provided the lowest quantity of protein across all age categories and may represent an opportunity for improving protein distribution, whereas, in older adults, increasing the number of meals reaching the anabolic threshold regardless of distribution pattern may be more appropriate.

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作者列表:["Bonomi AG","Ten Hoor GA","De Morree HM","Plasqui G","Sartor F"]

METHODS:BACKGROUND:Low cardiorespiratory fitness (CRF) increases risk of all-cause mortality and cardiovascular events. Periodic CRF assessment can have an important preventive function. OBJECTIVE:To develop a protocol-free method to estimate CRF in daily life based on heart rate (HR) and body acceleration measurements. METHODS:Acceleration and HR data were collected from 37 subjects (M=49%) while performing a standardized laboratory activity protocol (sitting, walking, running, cycling) and during a 5-days free-living monitoring period. CRF was determined by oxygen uptake (VO2max) during maximal exercise testing. A doubly-labeled water validated equation was used to predict total energy expenditure (TEE) from acceleration data. A fitness index was defined as the ratio between TEE and HR (TEE-pulse). Activity recognition techniques were used to process acceleration features and classify sedentary, ambulatory and other activity types. Regression equations based on TEE-pulse data from each activity type were developed to predict VO2max. RESULTS:TEE-pulse measured within each activity type of the laboratory protocol was highly correlated to VO2max (r from 0.74 to 0.91). Averaging the outcome of each activity-type specific equation based on TEE-pulse from the laboratory data led to accurate estimates of VO2max (RMSE: 300.0 mlO2/min or 10%). The difference between laboratory and free-living determined TEE-pulse was 3.7 ± 11% (r =0.85). The prediction method preserved the prediction accuracy when applied to free-living data (RMSE: 367 mlO2/min or 12%). CONCLUSIONS:Measurements of body acceleration and HR can be used to predict VO2max in daily life. Activity-specific prediction equations are needed to achieve highly accurate estimates of CRF.

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作者列表:["Farr S","Stankovic B","Hoffman S","Masoudpoor H","Baker C","Taher J","Dean A","Anakk S","Adeli K"]

METHODS:OBJECTIVE:Postprandial dyslipidemia is a common feature of insulin resistant states and contributes to increased cardiovascular disease risk. Recently, bile acids have been recognized beyond their emulsification properties as important signaling molecules that promote energy expenditure, improve insulin sensitivity, and lower fasting lipemia. While bile acid receptors have become novel pharmaceutical targets, their effects on postprandial lipid metabolism remain unclear. Here we investigated the potential role of bile acids in regulation of postprandial chylomicron production and triglyceride excursion. Approach and Results: Healthy C57BL/6 mice were given an intraduodenal infusion of taurocholic acid (TA) under fat-loaded conditions and circulating lipids were measured. Targeting of bile acid receptors was achieved with GW4064, a synthetic agonist to the farnesoid X receptor (FXR), and with deoxycholic acid (DCA), an activator of the Takeda G-protein-coupled receptor 5. TA, GW4064, and DCA treatments all lowered postprandial lipemia. FXR agonism also reduced intestinal triglyceride content and activity of microsomal triglyceride transfer protein, involved in chylomicron assembly. Importantly, TA effects (but not DCA) were largely lost in FXR knockout mice. These bile acid effects are reminiscent of the anti-diabetic hormone glucagon-like peptide-1 (GLP-1). While the GLP-1 receptor agonist exendin-4 retained its ability to acutely lower postprandial lipemia during bile acid sequestration and FXR deficiency, it did raise hepatic expression of the rate limiting enzyme for bile acid synthesis. CONCLUSIONS:Bile acid signaling may be an important mechanism of controlling dietary lipid absorption and bile acid receptors may constitute novel targets for the treatment of postprandial dyslipidemia.

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