Staels B, Schoonjans K, Fruchart J C, Auwerx J
U325 INSERM, Département d'Athérosclérose, Institut Pasteur, Lille, France.
Biochimie. 1997 Feb-Mar;79(2-3):95-9. doi: 10.1016/s0300-9084(97)81497-6.
The hypolipidemic fibrates and antidiabetic thiazolidinediones display potent triglyceride-lowering activities. Studies on the molecular action mechanisms of these compounds indicate that thiazolidinediones and fibrates exert their action by activating distinct transcription factors of the peroxisome proliferator activated receptor (PPAR) family, resulting in increased expression of lipoprotein lipase (LPL) and decreased expression of apolipoprotein (apo) C-III, both key-players in plasma triglyceride metabolism. Fibrates, on the one hand, are PPAR alpha activators, which selectively induce LPL mRNA levels and activity in the liver. Furthermore, hepatic apo C-III mRNA levels and protein production strongly decrease after fibrate treatment. On the other hand, thiazolidinediones, which are high affinity ligands for PPAR gamma, have no effect in the liver, but act primarily on adipose tissue, where they induce LPL mRNA levels and activity. The modulation of the expression of the LPL and apo C-III genes in liver and adipose tissue is correlated with the tissue-specific distribution of the respective PPARs (PPAR gamma expression being restricted to adipose tissue, whereas PPAR alpha is expressed predominantly in liver) confirming that fibrates and thiazolidinediones exert their effects primarily through PPAR alpha and PPAR gamma respectively. This distinct tissue-specific transcriptional regulation of genes involved in lipid metabolism by fibrates and thiazolidinediones indicates that research of compounds displaying combined PPAR alpha and PPAR gamma activation potential should lead to the discovery of more potent triglyceride-lowering drugs, which may be of use in the treatment of hypertriglyceridemia.
降血脂的贝特类药物和抗糖尿病的噻唑烷二酮类药物具有显著的降低甘油三酯的活性。对这些化合物分子作用机制的研究表明，噻唑烷二酮类药物和贝特类药物通过激活过氧化物酶体增殖物激活受体（PPAR）家族中不同的转录因子发挥作用，导致脂蛋白脂肪酶（LPL）表达增加和载脂蛋白（apo）C-III表达降低，这两者都是血浆甘油三酯代谢的关键参与者。一方面，贝特类药物是PPARα激活剂，可选择性诱导肝脏中LPL mRNA水平和活性。此外，贝特类药物治疗后肝脏中apo C-III mRNA水平和蛋白质产量会大幅下降。另一方面，作为PPARγ高亲和力配体的噻唑烷二酮类药物对肝脏无作用，但主要作用于脂肪组织，在脂肪组织中它们可诱导LPL mRNA水平和活性。肝脏和脂肪组织中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），这证实了贝特类药物和噻唑烷二酮类药物分别主要通过PPARα和PPARγ发挥作用。贝特类药物和噻唑烷二酮类药物对参与脂质代谢的基因进行的这种独特的组织特异性转录调节表明，对具有联合激活PPARα和PPARγ潜力的化合物进行研究，应该能够发现更有效的降低甘油三酯的药物，这些药物可能用于治疗高甘油三酯血症。
