Auwerx J, Schoonjans K, Fruchart J C, Staels B
U. 325 INSERM, Département d'Atherosclérose, Institut Pasteur, Lille, France.
J Atheroscler Thromb. 1996;3(2):81-9. doi: 10.5551/jat1994.3.81.
The molecular mechanism by which hypolipidemic fibrates and antidiabetic thiazolidinediones exert their hypotriglyceridemic action are discussed. Increased activity of lipoprotein lipase (LPL), a key lipolytic enzyme, and decreased levels of apolipoprotein C-III (apo C-III) seem to explain the hypotriglyceridemic effects of compounds. Both fibrates and thiazolidinediones exert their action by activating transcription factors of the peroxisome proliferator activated receptor (PPAR) family, thereby modulating the expression of the LPL and apo C-II genes. First, treatment of rats with PPAR alpha activators, such as fibrates induced LPL mRNA and activity selectively in the liver. In contrast, the thiazolidinediones, which are high affinity ligands for PPAR gamma, have no effect on liver, but induce LPL mRNA and activity levels in adipose tissue. In hepatocytes, fibrates, unlike the thiazolidinediones, induce LPL mRNA levels, whereas in preadipocyte cell lines the PPAR gamma ligand induces LPL mRNA levels much quicker and to a higher extent than fibrates. Second, apo C-III mRNA and protein production strongly decrease in livers of fibrate but not thiazolidinedione-treated animals. Fibrates also reduced apo C-III production in primary cultures of rat and human hepatocytes. The modulation of the expression of the LPL and apo C-III genes by either PPAR alpha or gamma activators, correlates with the tissue-specific distribution of the respective PPARs: PPAR gamma expression is restricted to adipose tissues, whereas PPAR alpha is expressed predominantly in liver. In both the LPL and apo C-III genes, sequence elements responsible for the modulation of their expression by activated PPARs have been identified which supports that the transcriptional regulation of these genes by fibrates and thiazolidinediones 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 a PPAR alpha-mediated reduction in apo C-III production. This tissue specific transcriptional regulation of genes involved in lipid metabolism by PPAR activators and/or ligands might have important therapeutic implications.
本文讨论了降血脂贝特类药物和抗糖尿病噻唑烷二酮类药物发挥其降甘油三酯作用的分子机制。关键脂解酶脂蛋白脂肪酶（LPL）活性增加以及载脂蛋白C-III（apo C-III）水平降低似乎可以解释这些化合物的降甘油三酯作用。贝特类药物和噻唑烷二酮类药物均通过激活过氧化物酶体增殖物激活受体（PPAR）家族的转录因子来发挥作用，从而调节LPL和apo C-II基因的表达。首先，用PPARα激活剂（如贝特类药物）处理大鼠，可选择性地诱导肝脏中LPL mRNA和活性。相比之下，作为PPARγ高亲和力配体的噻唑烷二酮类药物对肝脏无影响，但可诱导脂肪组织中LPL mRNA和活性水平。在肝细胞中，与噻唑烷二酮类药物不同，贝特类药物可诱导LPL mRNA水平，而在脂肪前体细胞系中，PPARγ配体诱导LPL mRNA水平的速度比贝特类药物更快，程度更高。其次，在接受贝特类药物治疗而非噻唑烷二酮类药物治疗的动物肝脏中，apo C-III mRNA和蛋白产量显著降低。贝特类药物还可降低大鼠和人原代肝细胞培养物中apo C-III的产量。PPARα或γ激活剂对LPL和apo C-III基因表达的调节与各自PPAR的组织特异性分布相关：PPARγ表达仅限于脂肪组织，而PPARα主要在肝脏中表达。在LPL和apo C-III基因中，已鉴定出负责其表达受激活PPAR调节的序列元件，这支持了贝特类药物和噻唑烷二酮类药物对这些基因的转录调控在体内对其降甘油三酯作用有显著贡献。虽然噻唑烷二酮类药物主要通过激活PPARγ来影响脂肪细胞LPL的产生，但贝特类药物主要通过PPARα介导降低apo C-III的产生在肝脏中发挥作用。PPAR激活剂和/或配体对参与脂质代谢的基因进行的这种组织特异性转录调控可能具有重要的治疗意义。
