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Bile acid treatment and FXR agonism lower postprandial lipemia in mice.

胆汁酸治疗和 FXR 激动降低小鼠餐后血脂。

  • 影响因子:3.76
  • DOI:10.1152/ajpgi.00386.2018
  • 作者列表:"Farr S","Stankovic B","Hoffman S","Masoudpoor H","Baker C","Taher J","Dean A","Anakk S","Adeli K
  • 发表时间:2020-01-31
Abstract

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.

摘要

目的: 餐后血脂异常是胰岛素抵抗状态的共同特征,有助于增加心血管疾病的风险。最近,胆汁酸被认为是促进能量消耗、改善胰岛素敏感性和降低空腹血脂的重要信号分子。虽然胆汁酸受体已经成为新的药物靶点,但它们对餐后脂代谢的影响仍不清楚。这里我们研究了胆汁酸在调节餐后乳糜微粒产生和甘油三酯漂移中的潜在作用。方法和结果: 在脂肪负荷条件下给予健康 C57BL/6 小鼠十二指肠内输注牛磺胆酸 (TA),并测量循环脂质。用法尼酯 X 受体 (FXR) 的合成激动剂 GW4064 和脱氧胆酸 (DCA) 实现胆汁酸受体的靶向, 武田 G 蛋白偶联受体 5 的激活剂。 TA 、 GW4064 和 DCA 治疗均降低餐后血脂。FXR 激动也降低了肠甘油三酯含量和微粒体甘油三酯转移蛋白的活性,参与乳糜微粒组装。重要的是,在 FXR 基因敲除小鼠中 TA 效应 (但不是 DCA) 大部分丧失。这些胆汁酸作用让人联想到抗糖尿病激素胰高血糖素样肽-1 (GLP-1)。虽然 GLP-1 受体激动剂 exendin-4 在胆汁酸隔离和 FXR 缺乏时保留了其急性降低餐后血脂的能力,但它确实提高了肝脏胆汁酸合成限速酶的表达。 结论: 胆汁酸信号可能是控制膳食脂质吸收的重要机制,胆汁酸受体可能是治疗餐后血脂异常的新靶点。

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影响因子:3.17
发表时间:2020-01-30
DOI:10.1111/jhn.12736
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.

翻译标题与摘要 下载文献
影响因子:2.76
发表时间:2020-01-30
DOI:10.1152/japplphysiol.00631.2019
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.

翻译标题与摘要 下载文献
影响因子:3.76
发表时间:2020-01-31
DOI:10.1152/ajpgi.00386.2018
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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