Role of PPAR in the pharmacological regulation of lipoprotein metabolism by fibrates and thiazolidinediones

The peroxisome proliferator activated receptors or PPARs constitute a subfamily of the nuclear hormone receptor superfamily of transcription factors. PPARs form heterodimeric complexes with the 9-cis retinoic acid receptor (RXR), which bind to specific response elements, termed peroxisome proliferator response element (PPRE), located in the regulatory regions of target genes. As such they modulate the transcriptional activity of genes, the majority of which are involved in lipid and lipoprotein metabolism. To date three PPAR variants, α, β (δ) and γ, have been identified, each displaying a specific tissue distribution pattern. Although the function of the PPARδ variant remains unknown, evidence coming from different rodent model systems indicates that the PPARα plays a crucial role in hepatic lipid metabolism, whereas PPARγ participates in adipocyte differentiation and function. Although only for PPARγ natural (prostaglandin J2) and synthetic (the thiazolidinedione BRL 49653) ligands have been identified so far, all PPARs are activated by a wide variety of chemicals amongst which the hypolipidemic drugs fibrates and the antidiabetic thiazolidinediones. Evidence is now accumulating that the hypotriglyceridemic action of fibrates in humans is primarily mediated via activation of PPARα in liver resulting in the repression of the expression of apo C-III, a key-player in plasma triglyceride metabolism. In addition the high density lipoprotein (HDL)-raising activity of fibrates is linked to a PPARα-mediated induction of the major HDL apolipoproteins, apo A-I and apo A-II in liver. By contrast, whereas the link between PPARγ activation and glucose metabolism is still unclear, the antidiabetic thiazolidinediones exert a potent hypotriglyceridemic action via the induction of lipoprotein lipase (LPL) expression in adipose tissue. Due to the involvement of different PPAR variants, fibrates and thiazolidinediones act through distinct and complementary mechanisms on plasma triglyceride metabolism. The identification of the molecular mechanism of action of these pharmacological agents, and the role distinct transcription factors of the PPAR family play therein, suggests that compounds activating both PPARα and PPARγ should be very potent hypotriglyceridemic drugs, which may be of use in the treatment of the dyslipidemia associated with atherosclerosis and non-insulin dependent diabetes mellitus

PPARalpha and PPARgamma activators direct a distinct tissue-specific transcriptional response via a PPRE in the lipoprotein lipase gene

Johan Auwerx, Kristina Schoonjans

Increased activity of lipoprotein lipase (LPL) may explain the hypotriglyceridemic effects of fibrates, thiazolidinediones and fatty acids, which are known activators (and/or ligands) of the various peroxisome proliferator-activated receptors (PPARs). Treatment with compounds which activate preferentially PPARalpha, such as fenofibrate, induced LPL expression exclusively in rat liver. In contrast, the antidiabetic thiazolidinedione BRL 49653, a high affinity ligand for PPARgamma, 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 PPARgamma 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 PPARalpha or gamma activators, correlated with the tissue distribution of the respective PPARs: an adipocyte-restricted expression of PPARgamma, whereas PPARalpha was expressed predominantly in liver. A sequence element was identified in the human LPL promoter that mediates the functional responsiveness to fibrates and thiazolidinediones. Methylation interference and gel retardation assays demonstrated that a PPARalpha 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 PPARgamma, fibrates exert their effects mainly in the liver via activation of PPARalpha.

1996

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

Johan Auwerx, Kristina Schoonjans

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.

1996

The effects of fibrates and thiazolidinediones on plasma triglyceride metabolism are mediated by distinct peroxisome proliferator activated receptors (PPARs)

Johan Auwerx, Kristina Schoonjans

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.

1997

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

Johan Auwerx, Kristina Schoonjans

1996