PPARα/β Activation Alleviates Age-Associated Renal Fibrosis in Sprague Dawley Rats.
Ppar α/β 活化减轻 Sprague Dawley 大鼠年龄相关性肾纤维化。
- 作者列表："Chung KW","Ha S","Kim SM","Kim DH","An HJ","Lee EK","Moon HR","Chung HY
:Age-associated renal fibrosis is commonly observed, with a decline in renal function during aging. Although peroxisome proliferator-activated receptors α/β (PPARα/β) activation has been shown to exert beneficial effects on age-associated renal changes, its effects on age-associated renal fibrosis have not been investigated yet. Here, we show that the PPARα/β activator, MHY2013, can significantly alter lipid metabolism in renal tubule epithelial cells and attenuate renal fibrosis in aged Sprague Dawley (SD) rats. We found that MHY2013 significantly increased nuclear translocation and activity of PPARα/β in NRK52E renal epithelial cells. Moreover, the enhanced PPARα/β activity increased the expression of fatty acid oxidation-associated PPARα/β target genes. In addition, transforming growth factor-β (TGF-β)- and oleic acid-induced lipid accumulation and fibrosis-associated gene expression were decreased in NRK52E cells by MHY2013 pretreatment. To evaluate the effects of MHY2013 on age-associated renal fibrosis, aged SD rates were orally administered MHY2013 (1 and 5 mg/kg) daily for 1 month. MHY2013 efficiently increased PPARα/β activation and reduced renal lipid accumulation in aged SD rat kidneys. Furthermore, renal fibrosis was significantly decreased by MHY2013, indicating the importance of renal lipid metabolism in age-associated renal fibrosis. Taken together, our results suggest that activation of PPARα/β signaling during aging prevents age-associated renal fibrosis.
: 通常观察到年龄相关的肾纤维化，在衰老过程中肾功能下降。尽管过氧化物酶体增殖物激活受体 α/β (ppar α/β) 激活已被证明对年龄相关的肾脏改变发挥有益作用, 其对年龄相关性肾纤维化的影响尚未研究。在此，我们发现 ppar α/β 激活剂 MHY2013 可显著改变老年 Sprague Dawley (SD) 大鼠肾小管上皮细胞的脂质代谢，减弱肾纤维化。我们发现 MHY2013 显著增加 NRK52E 肾上皮细胞 ppar α/β 的核转位和活性。此外，增强的 ppar α/β 活性增加了脂肪酸氧化相关 ppar α/β 靶基因的表达。此外，MHY2013 预处理可降低 NRK52E 细胞中转化生长因子-β (TGF-β) 和油酸诱导的脂质蓄积和纤维化相关基因表达。为了评估 MHY2013 对年龄相关性肾纤维化的影响，老年 SD 率每天口服 MHY2013 (1 和 5 mg/kg)，持续 1 个月。MHY2013 有效增加老年 SD 大鼠肾脏 ppar α/β 活化，减少肾脏脂质蓄积。此外，MHY2013 显著降低了肾纤维化，表明肾脂质代谢在年龄相关性肾纤维化中的重要性。总之，我们的结果表明，衰老过程中 ppar α/β 信号的激活可预防年龄相关性肾纤维化。
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.
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.
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.