Role of the peroxisome proliferator-activated receptor (PPAR) in mediating the effects of fibrates and fatty acids on gene expression

The three types of peroxisome proliferator-activated receptors (PPAR), termed alpha, delta (or beta), and gamma, belong to the nuclear receptor superfamily. Although peroxisome proliferators, including fibrates and fatty acids, activate the transcriptional activity of these receptors, only prostaglandin J2 derivatives have been identified as natural ligands of the PPAR gamma subtype that also binds thiazolidinedione antidiabetic agents with high affinity. PPARs heterodimerize with retinoic X receptor (RXR) and alter the transcription of target genes after binding to response elements or PPREs, consisting of a direct repeat of the nuclear receptor hexameric DNA recognition motif (PuGGTCA) spaced by 1 nucleotide (DR-1). Upon activation by fatty acids (FAs) and drugs that affect lipid metabolism, PPARs control the expression of genes implicated in intra- and extracellular lipid metabolism, most notably those involved in peroxisomal beta-oxidation. PPARs partially mediate the inductive effects of fibrates and fatty acids on high density lipoprotein (HDL) cholesterol levels by regulating the transcription of the major HDL apolipoproteins, apoA-I and apoA-II. The hypotriglyceridemic action of fibrates and certain fatty acids also involves PPAR and is constituted of: 1) increased hydrolysis of plasma triglycerides due to induction of LPL and reduction of apoC-III expression; 2) stimulation of cellular fatty acid uptake and conversion to acyl-CoA derivatives due to increased expression of genes for fatty acid transport protein and acyl-CoA synthetase; 3) increased peroxisomal and mitochondrial beta-oxidation; and 4) decreased synthesis of fatty acids and triglycerides and decreased production of very low density lipoprotein (VLDL). Hence, both enhanced catabolism of triglyceride-rich particles and reduced secretion of VLDL particles contribute to the hypolipidemic effect of fibrates and fatty acids. Finally, PPARs appear to be involved in differentiation processes because activation of PPAR gamma 2 triggers adipocyte differentiation and stimulates expression of several genes critical to adipogenesis. It is suggested that PPARs are key messengers responsible for the translation of nutritional and pharmacological stimuli into changes in gene expression and differentiation pathways.

The peroxisome proliferator activated receptors (PPARS) and their effects on lipid metabolism and adipocyte differentiation

Johan Auwerx, Kristina Schoonjans

The three types of peroxisome proliferator activated receptor (PPAR), alpha, beta (or delta), and gamma, each with a specific tissue distribution, compose a subfamily of the nuclear hormone receptor gene family. Although peroxisome proliferators, including fibrates and fatty acids, activate the transcriptional activity of these receptors, only prostaglandin J2 derivatives have been identified as natural ligands of the PPAR gamma subtype, which also binds thiazolidinedione antidiabetic agents with high affinity. Activated PPARs heterodimerize with RXR and alter the transcription of target genes after binding to specific response elements or PPREs, consisting of a direct repeat of the nuclear receptor hexameric DNA core recognition motif spaced by one nucleotide. The different PPARs can be considered key messengers responsible for the translation of nutritional, pharmacological and metabolic stimuli into changes in the expression of genes, more specifically those genes involved in lipid metabolism. PPAR alpha is involved in stimulating beta-oxidation of fatty acids. In rodents, a PPAR alpha-mediated change in the expression of genes involved in fatty acid metabolism lies at the basis of the phenomenon of peroxisome proliferation, a pleiotropic cellular response, mainly limited to liver and kidney and which can lead to hepatocarcinogenesis. In addition to their role in peroxisome proliferation in rodents, PPAR is also involved in the control of HDL cholesterol levels by fibrates and fatty acids in rodents and humans. This effect is, at least partially, based on a PPAR-mediated transcriptional regulation of the major HDL apolipoproteins, apo A-I and apo A-II. The hypotriglyceridemic action of fibrates and fatty acids also involves PPARs and can be summarized as follows: (1) an increased lipolysis and clearance of remnant particles, due to changes in LPL and apo C-III levels, (2) a stimulation of cellular fatty acid uptake and their conversion to acyl-CoA derivatives by the induction of FAT, FATP and ACS activity, (3) an induction of fatty acid beta-oxidation pathways, (4) a reduction in fatty acid and triglyceride synthesis, and finally (5) a decrease in VLDL production. Hence, both enhanced catabolism of triglyceride-rich particles as well as reduced secretion of VLDL particles are mechanisms that contribute to the hypolipidemic effect of fibrates and FFAs. Whereas for PPAR beta no function so far has been identified, PPAR gamma triggers adipocyte differentiation by inducing the expression of several genes critical for adipogenesis.

1996

Opposite regulation of human versus mouse apolipoprotein A-I by fibrates in human apolipoprotein A-I transgenic mice

Johan Auwerx

The regulation of liver apolipoprotein (apo) A-I gene expression by fibrates was studied in human apo A-I transgenic mice containing a human genomic DNA fragment driving apo A-I expression in liver. Treatment with fenofibrate (0.5% wt/wt) for 7 d increased plasma human apo A-I levels up to 750% and HDL-cholesterol levels up to 200% with a shift to larger particles. The increase in human apo A-I plasma levels was time and dose dependent and was already evident after 3 d at the highest dose (0.5% wt/wt) of fenofibrate. In contrast, plasma mouse apo A-I concentration was decreased after fenofibrate in nontransgenic mice. The increase in plasma human apo A-I levels after fenofibrate treatment was associated with a 97% increase in hepatic human apo A-I mRNA, whereas mouse apo A-I mRNA levels decreased to 51%. In nontransgenic mice, a similar down-regulation of hepatic apo A-I mRNA levels was observed. Nuclear run-on experiments demonstrated that the increase in human apo A-I and the decrease in mouse apo A-I gene expression after fenofibrate occurred at the transcriptional level. Since part of the effects of fibrates are mediated through the nuclear receptor PPAR (peroxisome proliferator-activated receptor), the expression of the acyl CoA oxidase (ACO) gene was measured as a control of PPAR activation. Both in transgenic and nontransgenic mice, fenofibrate induced ACO mRNA levels up to sixfold. When transgenic mice were treated with gemfibrozil (0.5% wt/wt) plasma human apo A-I and HDL-cholesterol levels increased 32 and 73%, respectively, above control levels. The weaker effect of this compound on human apo A-I and HDL-cholesterol levels correlated with a less pronounced impact on ACO mRNA levels (a threefold increase) suggesting that the level of induction of human apo A-I gene is related to the PPAR activating potency of the fibrate used. Treatment of human primary hepatocytes with fenofibric acid (500 microM) provoked an 83 and 50% increase in apo A-I secretion and mRNA levels, respectively, supporting that a direct action of fibrates on liver human apo A-I production leads to the observed increase in plasma apo A4 and HDL-cholesterol.

American Society for Clinical Investigation1996

Activation of PPARdelta alters lipid metabolism in db/db mice

Johan Auwerx

Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors, which heterodimerize with the retinoid X receptor and bind to peroxisome proliferator response elements in the promoters of regulated genes. Despite the wealth of information available on the function of PPARalpha and PPARgamma, relatively little is known about the most widely expressed PPAR subtype, PPARdelta. Here we show that treatment of insulin resistant db/db mice with the PPARdelta agonist L-165041, at doses that had no effect on either glucose or triglycerides, raised total plasma cholesterol concentrations. The increased cholesterol was primarily associated with high density lipoprotein (HDL) particles, as shown by fast protein liquid chromatography analysis. These data were corroborated by the chemical analysis of the lipoproteins isolated by ultracentrifugation, demonstrating that treatment with L-165041 produced an increase in circulating HDL without major changes in very low or low density lipoproteins. White adipose tissue lipoprotein lipase activity was reduced following treatment with the PPARdelta ligand, but was increased by a PPARgamma agonist. These data suggest both that PPARdelta is involved in the regulation of cholesterol metabolism in db/db mice and that PPARdelta ligands could potentially have therapeutic value.

2000

Opposite regulation of human versus mouse apolipoprotein A-I by fibrates in human apolipoprotein A-I transgenic mice

Johan Auwerx

American Society for Clinical Investigation1996

The peroxisome proliferator activated receptors (PPARS) and their effects on lipid metabolism and adipocyte differentiation

Johan Auwerx, Kristina Schoonjans

1996