PPAR alpha and PPAR gamma activators direct a distinct tissue-specific transcriptional response via a PPRE in the lipoprotein lipase gene
PPAR alpha and PPAR gamma activators direct a distinct tissue-specific transcriptional response via a PPRE in the lipoprotein lipase gene
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DOI：
10.1002/j.1460-2075.1996.tb00918.x
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发表时间：
1996-10-01
期刊：
影响因子：
11.4
通讯作者：
Auwerx, J
中科院分区：
文献类型：
--
作者：
Schoonjans, K;PeinadoOnsurbe, J;Auwerx, J
脂蛋白脂酶（LPL）活性的增加可能是贝特类、噻唑啉二酮类和脂肪酸的降血脂作用，这些物质是各种过氧化物酶体增殖物激活受体（PPARs）的已知激活剂（和/或配体）。用优先激活PPAR α的化合物如非诺贝特治疗，仅在大鼠肝脏中诱导LPL表达。相反，抗糖尿病噻唑烷二酮BRL 49653，一种对PPAR γ具有高亲和力的配体，对肝脏没有影响，但在大鼠脂肪组织中诱导LPL表达。在肝细胞系AML-12中，非诺贝酸而非BRL 49653诱导LPL mRNA，而在3 T3-L1前脂肪细胞中，PPAR γ配体诱导LPL mRNA水平比非诺贝酸快得多，且程度更高。在体内和体外研究中，由PPAR α或γ激活剂诱导的LPL mRNA水平与相应PPAR的组织分布相关：脂肪细胞限制性表达的过氧化物酶体增殖物激活受体γ，而过氧化物酶体增殖物激活受体α主要在肝脏中表达。在人LPL启动子中鉴定了一个序列元件，其介导对贝特类和噻唑啉二酮类的功能性反应。甲基化干扰和凝胶阻滞试验表明，PPaR α或γ和9-顺式视黄酸受体（RXR）异二聚体结合到该序列-169 TGCCCTTTCCCCC-157上。这些数据提供了证据，表明贝特类和噻唑烷二酮类药物对LPL基因的转录激活是由PPAR-RXR异二聚体介导的，并显著有助于它们在体内的降血脂作用。而噻唑烷二酮类药物主要通过激活PPAR γ影响脂肪细胞LPL的产生：贝特类药物主要通过激活PPAR α在肝脏中发挥作用。
Increased activity of lipoprotein lipase (LPL) may er;plain the hypotriglyceridemic effects of fibrates, thiazolindinediones and fatty acids, which are known activators (and/or ligands) of the various peroxisome proliferator-activated receptors (PPARs). Treatment with compounds which activate preferentially PPAR alpha, such as fenofibrate, induced LPL expression exclusively in rat liver, In contrast, the antidiabetic thiazolidine-dione BRL 49653, a high affinity ligand for PPAR gamma, had no effect on liver, but induced LPL expression in rat adipose tissue. In the hepatocyte cell line AML-12, fenofibric acid, but not BRL 49653, induced LPL mRNA, whereas in 3T3-L1 preadipocytes, the PPAR gamma ligand induced LPL mRNA levels much quicker and to a higher extent than fenofibric acid, In both the in vivo and in vitro studies, inducibility by either PPAR alpha or gamma activators, correlated with the tissue distribution of the respective PPARs: an adipocyte-restricted expression of PPAR gamma, whereas PPAR alpha was expressed predominately in liver, A sequence element was identified in the human LPL promoter that mediates the functional responsiveness to fibrates and thiazolinediones. Methylation interference and gel retardation assays demonstrated that a PPaR alpha or gamma and the 9-cis retinoic acid receptor (RXR) heterodimers bind to this sequence -169 TGCCCTTTCCCCC -157, These data provide evidence that transcriptional activation of the LPL gene by fibrates and thiazolidinediones is mediated by PPAR-RXR heterodimers and contributes significantly to their hypotriglyceridemic effects in vivo, Whereas thiazolidinediones predominantly affect adipocyte LPL production through activation of PPAR gamma: fibrates exert their effects mainly in the liver via activation of PPAR alpha.