The PPARβ/δ Activator GW501516 Prevents the Down-Regulation of AMPK Caused by a High-Fat Diet in Liver and Amplifies the PGC-1α-Lipin 1-PPARα Pathway Leading to Increased Fatty Acid Oxidation
The PPARβ/δ Activator GW501516 Prevents the Down-Regulation of AMPK Caused by a High-Fat Diet in Liver and Amplifies the PGC-1α-Lipin 1-PPARα Pathway Leading to Increased Fatty Acid Oxidation
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DOI：
10.1210/en.2010-1468
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发表时间：
2011-05-01
期刊：
影响因子：
4.8
通讯作者：
Vazquez-Carrera, Manuel
中科院分区：
文献类型：
--
作者：
Barroso, Emma;Rodriguez-Calvo, Ricardo;Vazquez-Carrera, Manuel
代谢综合征相关的血脂异常主要由携带甘油三酯的血浆脂蛋白的肝脏过度产生引发。在这里，我们研究了过氧化物酶体增殖物激活受体（PPAR）-β/δ激活剂GW 501516对高脂饮食（HFD）诱导的高脂血症和肝脂肪酸氧化的影响。暴露于HFD引起高脂血症，伴随着肝脏PPAR-γ共激活因子1（PGC-1）-α和脂蛋白1 mRNA水平的降低，这些作用可被GW 501516治疗预防。GW 501516处理还增加了核脂蛋白1蛋白水平，导致PGC-1 α-PPAR α信号传导系统的扩增，如通过PPAR α水平和PPAR α-DNA结合活性的增加以及参与脂肪酸氧化的PPAR α靶基因的表达增加所证明的。GW 501516的这些作用伴随着血浆β-羟基丁酸水平的增加，表明肝脂肪酸氧化增强。此外，GW 501516增加了肝脏内源性配体PPAR α，16：0/18：1-磷脂酰胆碱的水平，并显着增强肝脏Vldl受体的表达。有趣的是，GW 501516阻止了HFD引起的AMP活化蛋白激酶（AMPK）磷酸化的减少和ERK 1/2磷酸化水平的增加。此外，我们的数据表明，在GW 501516处理后，在喂食HFD的小鼠中AMPK的活化可能是肝细胞中AMP与ATP比率增加的结果。这些发现表明，GW 501516在HFD喂养的小鼠中的降血糖作用伴随着磷酸化AMPK水平的增加和PGC-1 α-脂蛋白1-PPAR α途径的扩增。（内分泌学152：1848-1859，2011）
Metabolic syndrome-associated dyslipidemia is mainly initiated by hepatic overproduction of the plasma lipoproteins carrying triglycerides. Here we examined the effects of the peroxisome proliferator-activated receptors (PPAR)-beta/delta activator GW501516 on high-fat diet (HFD)-induced hypertriglyceridemia and hepatic fatty acid oxidation. Exposure to the HFD caused hypertriglyceridemia that was accompanied by reduced hepatic mRNA levels of PPAR-gamma coactivator 1 (PGC-1)-alpha and lipin 1, and these effects were prevented by GW501516 treatment. GW501516 treatment also increased nuclear lipin 1 protein levels, leading to amplification in the PGC-1 alpha-PPAR alpha signaling system, as demonstrated by the increase in PPAR alpha levels and PPAR alpha-DNA binding activity and the increased expression of PPAR alpha-target genes involved in fatty acid oxidation. These effects of GW501516 were accompanied by an increase in plasma beta-hydroxybutyrate levels, demonstrating enhanced hepatic fatty acid oxidation. Moreover, GW501516 increased the levels of the hepatic endogenous ligand for PPAR alpha, 16:0/18:1-phosphatidilcholine and markedly enhanced the expression of the hepatic Vldl receptor. Interestingly, GW501516 prevented the reduction in AMP-activated protein kinase (AMPK) phosphorylation and the increase in phosphorylated levels of ERK1/2 caused by HFD. In addition, our data indicate that the activation of AMPK after GW501516 treatment in mice fed HFD might be the result of an increase in the AMP to ATP ratio in hepatocytes. These findings indicate that the hypotriglyceridemic effect of GW501516 in HFD-fed mice is accompanied by an increase in phospho-AMPK levels and the amplification of the PGC-1 alpha-lipin 1-PPAR alpha pathway. (Endocrinology 152: 1848-1859, 2011)