Peroxisome proliferator activated receptor alpha (PPARalpha) and PPAR gamma coactivator (PGC-1alpha) induce carnitine palmitoyltransferase IA (CPT-1A) via independent gene elements.
Peroxisome proliferator activated receptor alpha (PPARalpha) and PPAR gamma coactivator (PGC-1alpha) induce carnitine palmitoyltransferase IA (CPT-1A) via independent gene elements.
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DOI：
10.1016/j.mce.2010.05.019
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发表时间：
2010-08-30
影响因子：
4.1
通讯作者：
Park, Edwards A.
中科院分区：
文献类型：
--
作者：
Song, Shulan;Attia, Ramy R.;Connaughton, Sara;Niesen, Melissa I.;Ness, Gene C.;Elam, Marshall B.;Hori, Roderick T.;Cook, George A.;Park, Edwards A.
关键词：
长链脂肪酸和过氧化物酶体增殖物激活受体α（PPARα）的药理学配体激活参与脂肪酸和葡萄糖氧化的基因表达，包括肉毒碱棕榈酰转移酶-1A（CPT-1A）和丙酮酸脱氢酶激酶4（PDK 4）。CPT-1A催化长链脂肪酸从酰基辅酶A转移到肉毒碱，以跨线粒体膜易位，并且是长链脂肪酸线粒体氧化的起始步骤。PDK 4磷酸化并抑制丙酮酸脱氢酶复合物（PDC），该复合物在葡萄糖氧化途径中催化丙酮酸转化为乙酰辅酶A。CPT-1A的活性受转录变化以及丙二酰辅酶A抑制的调节。在肝脏中，CPT-1A和PDK 4基因表达被饥饿、高脂饮食和PPARα配体诱导。在这里，我们的特点是在大鼠CPT-1A基因的第二个内含子的结合位点的过氧化物酶体增殖物激活受体α。我们的研究表明，WY 14643和长链脂肪酸诱导CPT-1A基因的表达通过这个元件。此外，我们发现PPARα结合位点的突变降低了CPT-1A-荧光素酶载体在禁食大鼠肝脏中的表达。我们以前已经证明，CPT-1A是由过氧化物酶体增殖物激活受体γ辅激活因子（PGC-1α）通过大鼠CPT-1A基因第一内含子序列刺激的。令人惊讶的是，PGC-1α并没有通过第二内含子中的PPARα结合位点增强CPT-1A的转录。在用短发夹RNA敲低PGC-1α后，CPT-1A和PDK 4基因仍然对WY 14643有反应。总之，我们的研究表明，PPARα和PGC-1α通过CPT-1A基因的不同区域刺激CPT-1A基因的转录。
Long chain fatty acids and pharmacologic ligands for the peroxisome proliferator activated receptor alpha (PPARα) activate expression of genes involved in fatty acid and glucose oxidation including carnitine palmitoyltransferase-1A (CPT-1A) and pyruvate dehydrogenase kinase 4 (PDK4). CPT-1A catalyzes the transfer of long chain fatty acids from acyl-CoA to carnitine for translocation across the mitochondrial membranes and is an initiating step in the mitochondrial oxidation of long chain fatty acids. PDK4 phosphorylates and inhibits the pyruvate dehydrogenase complex (PDC) which catalyzes the conversion of pyruvate to acetyl-CoA in the glucose oxidation pathway. The activity of CPT-1A is modulated both by transcriptional changes as well as by malonyl-CoA inhibition. In the liver, CPT-1A and PDK4 gene expression are induced by starvation, high fat diets and PPARα ligands. Here, we characterized a binding site for PPARα in the second intron of the rat CPT-1A gene. Our studies indicated that WY14643 and long chain fatty acids induce CPT-1A gene expression through this element. In addition, we found that mutation of the PPARα binding site reduced the expression of CPT-1A-luciferase vectors in the liver of fasted rats. We had demonstrated previously that CPT-1A was stimulated by the peroxisome proliferator activated receptor gamma coactivator (PGC-1α) via sequences in the first intron of the rat CPT-1A gene. Surprisingly, PGC-1α did not enhance CPT-1A transcription through the PPARα binding site in the second intron. Following knockdown of PGC-1α with short hairpin RNA, the CPT-1A and PDK4 genes remained responsive to WY14643. Overall, our studies indicated that PPARα and PGC-1α stimulate transcription of the CPT-1A gene through different regions of the CPT-1A gene.
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DOI：
10.1046/j.1440-1681.2002.03655.x
发表时间：
2002-04-01
影响因子：
2.9
作者：
Lehman, JJ;Kelly, DP
通讯作者：
Kelly, DP
影响因子：
64.5
作者：
Lin, JD;Wu, PH;Spiegelman, BM
通讯作者：
Spiegelman, BM
影响因子：
4.2
作者：
Le May, Cedric;Cauzac, Michele;Pegorier, Jean-Paul
通讯作者：
Pegorier, Jean-Paul
影响因子：
4.8
作者：
Jackson-Hayes, L;Song, SL;Park, EA
通讯作者：
Park, EA
影响因子：
4.1
作者：
COOK, GA;OTTO, DA;CORNELL, NW
通讯作者：
CORNELL, NW