Regulation of triglyceride metabolism by PPARs: fibrates and thiazolidinediones have distinct effects.

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 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.