Journal of Atherosclerosis and Thrombosis
Online ISSN : 1880-3873
Print ISSN : 1340-3478
ISSN-L : 1340-3478
Regulation of Triglyceride Metabolism by PPARs : Fibrates and Thiazolidinediones have Distinct Effects
Johan AuwerxKristina SchoonjansJean-Charles FruchartBart Staels
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1996 Volume 3 Issue 2 Pages 81-89

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Abstract

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 PPARα activators, such as fibrates induced LPL mRNA and activity selectively in the liver. In contrast, the thiazolidinediones, which are high affinity ligands for PPARγ, 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 PPARγ 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 PPARα or γ activators, correlates with the tissue-specific distribution of the respective PPARs : PPARγ expression is restricted to adipose tissues, whereas PPARα 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 PPARγ, fibrates exert their effects mainly in the liver via a PPARα-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. J Atheroscler Thromb, 1996; 3 : 81-89.

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© Japan Atherosclerosis Society
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