Coordinate regulation of the expression of the fatty acid transport protein and acyl-CoA synthetase genes by PPAR alpha and PPAR gamma activators
Coordinate regulation of the expression of the fatty acid transport protein and acyl-CoA synthetase genes by PPAR alpha and PPAR gamma activators
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DOI：
10.1074/jbc.272.45.28210
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发表时间：
1997-11-07
影响因子：
4.8
通讯作者：
Auwerx, J
中科院分区：
文献类型：
--
作者：
Martin, G;Schoonjans, K;Auwerx, J
细胞内脂肪酸(FA)的浓度在一定程度上由一个受调控的输入/输出系统决定，该系统由两个关键蛋白质组成，即脂肪酸转运蛋白(FATP)和酰基辅酶A合成酶(ACS)，这两个蛋白质分别促进FA的跨细胞膜运输和酯化以防止其外流。本研究的目的是分析FATP和ACS的表达模式，并确定它们的表达是否受到通过激活过氧体增殖物激活受体(PPAR)(如贝特类和噻唑烷二酮)而影响FA代谢的因素的改变。FATPmRNA在脂肪组织、心脏、脂肪组织中表达水平最高大脑和睾丸。已知的贝特治疗优先激活PPARγ，诱导大鼠肝脏和肠道的FATPmRNA水平，并诱导肝脏和肾脏的ACSmRNA水平；抗糖尿病的噻唑烷二酮BRL 49653是脂肪细胞特异性PPARγ形式的高亲和力配体，对肌肉的诱导很小，但对脂肪组织的FATPmRNA水平有很强的诱导作用。BRL 49653不影响肝脏FATPmRNA的表达，并有降低心脏FATPmRNA水平的趋势。在BRL 49653后，ACSmRNA的表达水平总体上呈现出与FATP相似的模式，除了诱导ACSmRNA的肌肉外，这种由PPAR激活剂在转录水平上的调节，也可以在体外细胞培养系统中复制。在肝细胞系AML-12或Fa 32中，非诺贝酸，而不是BRL 49653，诱导了FATP和ACSmRNA的水平，而在3T3-L1前脂肪细胞系，PPARγ配体和诱导FATSmRNA水平的速度快于非诺贝酸。PPARα或γ激动剂诱导ACS和FATP mRNA的表达与各自PPAR的组织特异性分布相关，并进一步与FA摄取的增加相关，最有趣的是，噻唑烷二酮类抗糖尿病药物似乎比肌肉更有利于脂肪细胞特异性FA的摄取，这可能是这些药物对胰岛素介导的葡萄糖处置的有益影响的部分原因。
Intracellular fatty acid (FA) concentrations are in part determined by a regulated import/export system that is cent-rolled by two key proteins, i.e. fatty acid transport protein (FATP) and acyl-CoA synthetase (ACS), which respectively facilitate the transport of FAs across the cell membrane and their esterification to prevent their efflux, The aim of this investigation was to analyze the expression pattern of FATP and ACS and to determine whether their expression was altered by agents that affect FA metabolism through the activation of peroxisome proliferator-activated receptors (PPAR) such as the fibrates and thiazolidinediones, FATP mRNA was ubiquitously expressed, with highest levels being detected in adipose tissue, heart, brain, and testis. Fibrate treatment, which is known to preferentially activate PPAR gamma, induced FATP mRNA levels in rat liver and intestine and induced ACS mRNA levels in liver and kidney, The antidiabetic thiazolidinedione BRL 49653, which is a high-affinity ligand for the adipocyte-specific PPAR gamma form, caused a small induction of muscle but a robust induction of adipose tissue FATP mRNA levels. BRL 49653 did not affect liver FATP and had a tendency to decrease heart FATP mRNA levels, ACS mRNA levels in general showed a similar pattern after BRL 49653 as FATP except for the muscle where ACS mRNA was induced, This regulation of FATP and ACS expression by PPAR activators was shown to be at the transcriptional level and could also be reproduced in vitro in cell culture systems, In the hepatocyte cell lines AML-12 or Fa 32, fenofibric acid, but not BRL 49653, induced FATP and ACS mRNA levels, whereas in the 3T3-L1 preadipocyte cell line, the PPAR gamma ligand induced FATP and ACS mRNA levels quicker than fenofibric acid, Inducibility of ACS and FATP mRNA by PPAR alpha or gamma activators correlated with the tissue-specific distribution of the respective PPARs and was furthermore associated with a concomitant increase in FA uptake, Most interestingly, thiazolidinedione antidiabetic agents seem to favor adipocyte-specific FA uptake relative to muscle, perhaps underlying in part the beneficial effects of these agents on insulin-mediated glucose disposal.