Concurrent activation of liver X receptor and peroxisome proliferator-activated receptor alpha exacerbates hepatic steatosis in high fat diet-induced obese mice.
Concurrent activation of liver X receptor and peroxisome proliferator-activated receptor alpha exacerbates hepatic steatosis in high fat diet-induced obese mice.
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DOI：
10.1371/journal.pone.0065641
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Liu D
中科院分区：
文献类型：
--
作者：
Gao M;Bu L;Ma Y;Liu D
肝脏X受体（LXR）激活改善肥胖患者的葡萄糖稳态。然而，这种改善与一些副作用有关，包括高脂血症和肝脂肪变性。另一方面，过氧化物酶体增殖物激活受体α (PPARα)的激活会增加脂肪酸氧化，导致高脂血症的减少。本研究的目的是探讨LXR/PPARα的同时激活是否能在治疗肥胖相关代谢紊乱中产生协同效应。用T0901317（一种LXR激活剂）或非诺贝特（一种PPARα激动剂）或联合用药治疗高脂饮食诱导的肥胖小鼠，可减轻胰岛素抵抗并改善葡萄糖耐量。联合治疗显著加重肝脂肪变性。肝脏基因表达分析显示，联合治疗增加了参与脂肪生成和脂肪酸运输的基因的表达，包括srebp-1c、chrebp、acc1、fas、scd1和cd36。组织化学和体外甘油释放试验表明，联合治疗加速脂肪组织的脂质动员。联合治疗还增加了glut4、hs1、atgl和脂联素的转录，降低了plin1、cd11c、ifnγ和瘦素的转录。联合治疗显著提高了fgf21在肝脏中的转录，而在脂肪组织中没有。这些结果表明，同时激活LXR和PPARα作为控制肥胖患者葡萄糖和脂质代谢的策略是有益的，但可能导致肝脏脂质积累升高。
Liver X receptor (LXR) activation improves glucose homeostasis in obesity. This improvement, however, is associated with several side effects including hyperlipidemia and hepatic steatosis. Activation of peroxisome proliferator-activated receptor alpha (PPARα), on the other hand, increases fatty acid oxidation, leading to a reduction of hyperlipidemia. The objective of this study was to investigate whether concurrent activation of LXR/PPARα can produce synergistic benefits in treating obesity-associated metabolic disorders. Treatment of high fat diet-induced obese mice with T0901317, an LXR activator, or fenofibrate, the PPARα agonist, or in combination alleviated insulin resistance and improved glucose tolerance. The combined treatment dramatically exacerbated hepatic steatosis. Gene expression analysis in the liver showed that combined treatment increased the expression of genes involved in lipogenesis and fatty acid transport, including srebp-1c, chrebp, acc1, fas, scd1 and cd36. Histochemistry and ex vivo glycerol releasing assay showed that combined treatment accelerated lipid mobilization in adipose tissue. Combined treatment also increased the transcription of glut4, hsl, atgl and adiponectin, and decreased that of plin1, cd11c, ifnγ and leptin. Combined treatment markedly elevated the transcription of fgf21 in liver but not in adipose tissue. These results suggest that concurrent activation of LXR and PPARα as a strategy to control glucose and lipid metabolism in obesity is beneficial but could lead to elevation of lipid accumulation in the liver.
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DOI：
10.1016/j.bbrc.2006.02.032
发表时间：
2006-04-21
影响因子：
3.1
作者：
Arsov, T;Larter, CZ;Farrell, GC
通讯作者：
Farrell, GC
影响因子：
4.8
作者：
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通讯作者：
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影响因子：
6.5
作者：
Chisholm, JW;Hong, J;Lawn, RM
通讯作者：
Lawn, RM
影响因子：
3.9
作者：
Darimont, C;Avanti, O;Macé, K
通讯作者：
Macé, K
影响因子：
--
作者：
Juvet, LK;Andresen, SM;Nebb, HI
通讯作者：
Nebb, HI