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

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.

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

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

Johan Auwerx

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

1997

Induction of the fatty acid transport protein 1 and acyl-CoA synthase genes by dimer-selective rexinoids suggests that the peroxisome proliferator-activated receptor-retinoid X receptor heterodimer is their molecular target

Johan Auwerx

The intracellular fatty acid content of insulin-sensitive target tissues determines in part their insulin sensitivity. Uptake of fatty acids into cells is a controlled process determined in part by a regulated import/export system that is controlled at least by two key groups of proteins, i.e. the fatty acid transport protein (FATP) and acyl-CoA synthetase (ACS), which facilitate, respectively, the transport of fatty acids across the cell membrane and catalyze their esterification to prevent their efflux. Previously it was shown that the expression of the FATP-1 and ACS genes was controlled by insulin and by peroxisome proliferator-activated receptor (PPAR) agonists in liver or in adipose tissue. The aim of this investigation was to determine the effects of retinoic acid derivatives on the expression of FATP-1 and ACS. In several cultured cell lines, it was shown that the expression of both the FATP-1 and ACS mRNAs was specifically induced at the transcriptional level by selective retinoid X receptor (RXR) but not by retinoic acid receptor (RAR) ligands. This effect was most pronounced in hepatoma cell lines. A similar induction of FATP-1 and ACS mRNA levels was also observed in vivo in Zucker diabetic fatty rats treated with the RXR agonist, LGD1069 (4-[1-(3,5,5,8,8-pentamethyl-5,6,7, 8-tetrahydro-2-naphthyl)ethenyl]benzoic acid). Through the use of heterodimer-selective compounds, it was demonstrated that the modulatory effect of these rexinoids on FATP-1 and ACS gene expression was mediated through activation of RXR in the context of the PPAR-RXR heterodimer. The observation that both RXR and PPAR agonists can stimulate the transcription of genes implicated in lipid metabolism, suggest that rexinoids may also act as lipid-modifying agents and support a role of the permissive PPAR-RXR heterodimer in the control of insulin sensitivity.

2000

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

Johan Auwerx

1997

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

Johan Auwerx, Kristina Schoonjans

1996

Johan Auwerx

2000