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PPAR Research
Volume 2010 (2010), Article ID 542359, 11 pages
http://dx.doi.org/10.1155/2010/542359
Review Article

The Role of PPAR Activation in Liver and Muscle

1Institute of Medicine, Haukeland University Hospital, University of Bergen, 5021 Bergen, Norway
2Department of Pharmaceutical Biosciences, School of Pharmacy, University of Oslo, 0316 Oslo, Norway

Received 1 May 2010; Accepted 12 July 2010

Academic Editor: J. Corton

Copyright © 2010 Lena Burri et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

PPAR is one of three members of the soluble nuclear receptor family called peroxisome proliferator-activated receptor (PPAR). It is a sensor for changes in levels of fatty acids and their derivatives that responds to ligand binding with PPAR target gene transcription, inasmuch as it can influence physiological homeostasis, including lipid and carbohydrate metabolism in various tissues. In this paper we summarize the involvement of PPAR in the metabolically active tissues liver and skeletal muscle and provide an overview of the risks and benefits of ligand activation of PPAR , with particular consideration to interspecies differences.

1. Introduction

Dietary fatty acids (FAs) are not only important for membrane structures and in signalling processes, but also have the ability to influence gene expression by binding to specific transcription factors [1]. One receptor family that acts as mediators to influence transcription according to nutritional state is the peroxisome proliferator-activated receptor (PPAR) family. There are three isoforms of PPAR receptors that have specific, but also overlapping target genes: , /δ, and [24]. Early on PPAR activity was thought to mainly influence lipid metabolism, inflammation, and glucose homeostasis. Later it became clear that PPARs also play a role in modulating the processes of cell proliferation and differentiation, apoptosis, and aging [58]. The receptors show a nuclear localization in the form of a heterodimer with the retinoid X receptor (RXR). A ligand activated PPAR -RXR heterodimer regulates the transcription of genes by binding to their peroxisome proliferator response elements (PPREs), a process called “transactivation” [911]. Besides, a mechanism based on “transrepression” has been described and is reviewed in [12]. The anti-inflammatory actions of PPAR ligands are mostly thought to be based on “transrepression” by the negative interference of PPAR with other transcription factor pathways [13, 14].

Here we focus on the first identified PPAR receptor, PPAR [15], and its activation in different tissues and physiological states in humans and mice. It is expressed at elevated levels in tissues with high metabolic rates, such as the liver, heart, skeletal muscle, kidney, and also in the intestine [12, 16]. Additionally, it is present in cells of the immune system (e.g., macrophages, monocytes, and lymphocytes) [1719]. The receptor has a central role in fatty acid oxidation, lipid and lipoprotein metabolism, inflammatory responses, and oxidative stress. Its position in the centre of energy balance, lipid metabolism, and inflammation makes it an important factor in the development of obesity-related diseases, and therefore, presents a possible target to influence metabolic disorders. Ligands include saturated and unsaturated FA and their derivatives, hypolipidemic fibrates (ciprofibrate, clofibrate, fenofibrate, and gemfibrozil), and modified fatty acids (e.g., tetradecylthioacetic acid, TTA), as well as xenobiotics [2022]. In particular during fasting, when free FAs are released into the blood, endogenous lipid-activation is of importance. The importance of PPAR in the cellular metabolic response to fasting was clearly shown in PPAR -null mice [23]. Whereas under normal conditions, these mice do not display a strong phenotype, the absence of PPAR causes lipid accumulation in liver and heart, hypoglycemia, hypothermia, ketonuria, and elevated free fatty acids during fasting ultimately leading to premature death [23]. In contrast, wildtype mice adapt to fasting by induction of hepatic and cardiac PPAR target genes that results in increased FA uptake and oxidation [24].

A great number of animal studies have demonstrated beneficial effects of specific PPAR activation in counteracting metabolic disorders. An increasing number of human studies supports the findings obtained in animal studies. When it comes to PPAR activation, however, it has become clear that not all results obtained in mice can be extrapolated to humans and caution is warranted in predicting tissue-specific effects.

This paper will focus on the tissues liver and skeletal muscle exploring tissue-specific effects of PPAR activation and stress the differences of human- and mouse-based studies.

2. PPAR in Liver

There are substantial differences between human and mouse target gene expression in terms of the effect of PPAR activation in the liver (Figure 1). Overall, the effect of activation by the PPAR agonist WY14643 is more prominent in mice than in humans [25]. In primary hepatocytes from mice and humans treated with WY14643, only a few target genes were affected similarly in the two species. However, both species share multiple changed gene ontology classes, including lipid metabolism. Individual PPAR regulation was observed for enzymes involved in biotransformation (chemical alterations of compounds in the body), as well as apolipoprotein and bile acid synthesis in human hepatocytes, and glucose homeostasis in mouse hepatocytes [25]. It was proposed earlier that the response might be dampened by quantitative differences of PPARα expression or different splice forms of PPARα. Indeed, there exist two splice variants of PPARα giving rise to an active and inactive receptor in humans [26]. To compare PPARα expression levels between human and mouse liver is, however, difficult due to daily variations [27] and differing reports have been published. Some reports show lower PPARα expression levels in human than in rodent liver [2830], while another shows comparable expression levels between the two species [25].

542359.fig.001
Figure 1: Examples of the multiple metabolic effects of PPAR activation in mouse or human liver. FA, fatty acid; TAG, triacylglycerol.

One of the main pathways involving PPAR regulation in mice and humans includes FA metabolism. In mice, PPAR activation is important for FA metabolism through the induction of genes coding for the fatty acid transporter CD36 [31] and the FA binding protein 1 (FABP1) that brings the FAs from the plasma membrane to the nucleus [32]. Another PPAR target gene is carnitine palmitoyl transferase 1 (Cpt1), that codes for a protein important for FA transport into mitochondria [25].Whereas CPT1 is localized to the outer membrane, CPT2, that is also regulated by PPAR , is found in the inner mitochondrial membrane. It converts acyl-carnitine to acyl-CoA and is strongly upregulated by PPAR agonists [33]. Most of the genes of FA metabolism are regulated by PPAR in both humans and mice, however Cd36 is an example of species-specific induction in mice [25].

Genes encoding for mitochondrial proteins of the -oxidation pathway are induced by PPAR activation, such as acyl-CoA synthetase (Acs) coding for an enzyme responsible for activation of FA to their fatty acyl-CoA derivatives. Also genes of the short-, medium-, long- and very-long-chain acyl-CoA dehydrogenases (Acad -s, -m, -l, -vl) coding for proteins that catalyze the first step in FA oxidation in a chain length-specific manner, are under the control of PPAR . In addition, the expression of the gene encoding the enzyme acetyl-CoA acyltransferase 2 (ACAA2) involved in the final step of -oxidation, is PPAR dependent. Furthermore, hepatic carnitine synthesis is enhanced by PPAR activation in mice [34, 35]. Carnitine is a conditionally essential nutrient that plays an important role in mitochondrial long-chain FA import for -oxidation [36]. In PPAR -null mice, free carnitine levels were drastically suppressed in plasma and several tissues including liver, the primary site of carnitine biosynthesis. This was consistent with reduced hepatic expression of the genes involved in carnitine biosynthesis (Bbox1) and transport (Octn2) [37]. In an earlier study, Van Vlies and colleagues established a fasting-induced elevation of these genes that is PPAR -dependent [38]. Both studies point to an essential position for PPAR in carnitine metabolism in mice [37, 38]. No similar indications of PPAR -induced carnitine synthesis have been described in humans. However, pigs that also are a nonproliferative species and are considered similar to humans due to their metabolic features, show an increased carnitine production upon fasting [39]. It is therefore likely that also humans will prove to have a similar response.

Peroxisomal fatty acid oxidation is important for the partial oxidation of long, very long, and branched FAs. The first characterized PPAR target gene, acyl-CoA oxidase 1 (Acox1) encodes the rate-limiting enzyme of this process [40]. After ACOX1 has introduced a double bond to generate enoyl-CoA and H2O2, the bifunctional protein/enoyl-CoA hydratase (BIEN), that carries two enzymatic activities, performs the second step of -oxidation resulting in 3-ketoacyl-CoA. 3-ketoacyl-CoA is then cleaved by acetyl-CoA acyltransferase 1 (ACAA1) to produce acetyl-CoA [41]. All the above-mentioned genes are under the regulation of PPAR in mice.

In addition to mitochondrial and peroxisomal -oxidation, -hydroxylation occurs in smooth endoplasmic reticulum. In both mice and humans, this process is upregulated by the effect of PPAR on expression of cytochrome P450 4A11 (CYP4A11) [25, 4244]. The hepatic cytochrome P450 4A11 catalyzes -hydroxylation of medium and long-chain FAs. Subsequently cytosolic dehydrogenases convert them to dicarboxylic acids, which can be further processed by peroxisomal -oxidation. Human PPAR also is a transcriptional regulator of FA oxidation in the different organelles, but shows overlap with mice rather on the pathway than on the gene level [25]. To conclude, PPAR regulates enzymes important for uptake, traffic to final destination, activation, and oxidation of FAs in the three organelles mitochondria, peroxisomes, and microsomes in both mice and humans.

Paradoxically, at the same time as PPAR activation leads to an increase in FA oxidation, it also augments FA synthesis by affecting gene expression levels of several enzymes involved in lipogenesis. In mice, PPAR stimulates the conversion of malate into pyruvate to generate NADPH for lipogenesis by upregulating the expression of malic enzyme (ME1) [45]. Besides, the ∆5, ∆6, and ∆9 desaturases, rate-limiting enzymes in the synthesis of polyunsaturated FAs (PUFAs) from saturated FAs, are found in increased amounts after PPAR activation [4648]. The induction of desaturases could help to ensure that there are always enough PUFAs for their diverse functions, including being effective PPAR agonists as proposed by others [46]. Likewise, PPAR activation in human hepatocytes induces the expression of several target genes involved in FA synthesis [25].

Other crucial processes requiring PPAR activation are lipoprotein synthesis and assembly. The impact of PPAR agonist on lipoprotein gene expression in humans or mice is distinct. The use of fibrates in humans leads to reduced plasma triacylglycerol (TAG) levels and increased high-density lipoprotein (HDL) cholesterol levels. In mice, plasma TAG as well as HDL levels are lowered. The liver, besides the intestine, determines the amount of HDL in plasma by regulating HDL synthesis and catabolism. The reason for the species-specific opposite effect of PPAR activation on HDL levels is probably increased production levels of apolipoprotein A-I (APOA1) and APOA2 in humans [49, 50] and suppressed (APOA1) or unchanged (APOA2) expression in mice [51]. These apolipoproteins are part of HDL cholesterol and are crucial for reverse cholesterol transport from peripheral cells to the liver, where excess cholesterol can be eliminated into the bile [52]. The liver is also the place where very low-density lipoprotein (VLDL) particles are assembled and then secreted into the plasma. The VLDL amount in peripheral cells is influenced by lipoprotein lipase (LPL). The hepatic expression of this hydrolase, which mediates VLDL triglyceride lipolysis, is upregulated by PPAR [53]. Moreover, its activity is stimulated by APOA5 and inhibited by APOC3. Activation of PPAR increases APOA5 [5456] and decreases APOC3 [57] transcription, resulting in a plasma TAG lowering effect, thereby, together with increased HDL concentrations, reducing the risk for atherosclerosis in humans [58].

The removal of excess cholesterol from the body is via the bile, a fluid produced in the liver, stored in the gall bladder, and secreted into the small intestine. Cholesterol is eliminated either intact or as bile acids that are steroid acids made from cholesterol. In humans, the two main bile acids synthesized in the liver, are chenodeoxycholic acid (CDCA) and cholic acid (CA) [59, 60]. Due to their amphipathic character they aid in the small intestine for the digestion and absorption of dietary lipids. There is controversy in the literature regarding the regulation of the rate-limiting enzyme in hepatic bile acid synthesis, called cholesterol 7 -hydroxylase (CYP7A1). Some reports suggest a transcriptional upregulation of Cyp7a1 upon PPAR activation in mice [61, 62]. In particular, the upregulation of Cyp7a1 under fasting conditions and the downregulation of this enzyme in PPAR -null mice corroborate a PPAR regulatory involvement and suggest increased expression upon fasting-induced PPAR activation [62]. Other studies support a downregulation of this endoplasmic reticulum enzyme upon induction with PPAR agonists in both humans and rodents [6367]. This could be a potential risk for gallstone formation, if in humans receiving treatment with fibrates, bile acid synthesis is decreased over a longer period of time by a hepatic decrease of CYP7A1 activity. On the other hand, gene expression of sterol 12 -hydroxylase (Cyp8b1), an enzyme involved in CA synthesis, is increased under fasting and also with ligand-induced PPAR -activation in both rodents and humans [62, 67, 68]. This protein of the cytochrome P450 family controls the balance between CA and CDCA levels. Upon Cyp8b1 induction, higher CA concentrations positively influence the bile acid composition by increasing cholesterol solubility.

Important under conditions of extended fasting is the process called ketogenesis. In mice and humans, the production of ketone bodies is under the control of PPAR that upregulates the gene expression of mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase (Hmgcs2), coding for the rate-limiting enzyme of ketogenesis [25, 69, 70]. Of particular importance in regulating ketogenesis, in addition to FA oxidation, TAG clearance, and de novo lipogenesis is the ‘hormone-like’ fibroblast growth factor 21 (FGF21) [7173]. Its hepatic expression is PPAR -dependent and is induced by fasting, a ketogenic diet, and WY14643 [25, 71, 74, 75]. FGF21 positively influences lipid and glucose metabolism, in addition to insulin sensitivity in animals [76].

Hepatic gluconeogenesis is also regulated during fasting, when the liver changes from glucose uptake and glycogen synthesis to glucose production. The chain of reactions converting glycerol, lactate, or glucogenic amino acids to glucose involves the two rate-limiting enzymes, phosphoenol-pyruvate carboxykinase (PEPCK) and pyruvate carboxylase (PYC). Of these two genes, only the promoter for Pepck was found to have a functional PPRE in mice [77]. The induction of other enzymes in this pathway is PPAR -dependent, such as glycerol-3-phosphate dehydrogenase (GPDH) and glycerol kinase (GK), as well as the aquaporins (AQP) 3 and 9 that act as liver glycerol import channels [78]. The observation that PPAR -null mice manifest lower fed and fasted glucose levels supports an involvement of PPAR in hepatic glucose production [77]. However, another report proposes as a reason for fasting hypoglycemia, the preferential channelling of glucose-6-phosphate to hepatic glycogen stores and shows unchanged glucose 6-phosphate synthesis in PPAR -null mice [79]. The pathway glycolysis/gluconeogenesis is specifically affected by PPAR activation in mice and shows no response in human primary hepatocytes [25].

The enzyme glyoxylate reductase/hydroxypyruvate reductase (GRHPR) is important in the channelling of carbons from the glyoxylate cycle into gluconeogenesis or into the urea cycle depending on the body energy demands. In mice, PPAR activation (e.g., in the fasted state) is crucial in inducing transcriptional activation of Grhpr, thereby favouring a conversion of hydroxypyruvate to D-glycerate, a substrate needed in glucose synthesis [80]. In humans however, GRHPR expression was shown to be PPAR -independent due to promoter reorganisation during primate evolution. Moreover, alanine:glyoxylate aminotransferase (AGT), an enzyme of the glyoxylate cycle with two enzymatic activities is positively regulated by PPAR [80]. Its transaminase activity leads to the production of glycine and hydroxypyruvate.

Beyond the transcriptional activation of genes involved in lipid and glucose metabolism, the PPAR agonist WY14643 affects amino acid metabolism in rodents [81, 82]. The metabolic consequences include alterations in plasma amino acid levels. Whereas branched-chain amino acid amounts showed no change upon PPAR activation with WY14643, a significant increase in various glucogenic and some ketogenic amino acids was detected in rats [82]. Only one amino acid was lowered, namely arginine, a conditionally nonessential amino acid made in the urea cycle. mRNA levels of enzymes involved in the conversion of citrulline to arginine in the kidney are unknown, but hepatic levels of argininosuccinate synthetase (Ass) and argininosuccinate lyase (Asl) show a decrease [81, 82]. The exact mechanism of PPAR regulation of amino acid metabolism is unknown but certain genes involved in the regulation of amino acid degradation have also been shown to be negatively regulated, with the exclusion of Grhpr and arginase (Arg1) [81, 82]. The decreased amino acid degradation upon WY14643 treatment is accompanied by an increase in protein degradation. Some possible explanations for the observed amino acid mobilization upon PPAR induction are give in [82] and might be due to increased hepatic growth. The current findings are restricted to rodents and it is unclear at present if the situation is similar in humans that show no liver enlargement. One study points to a different situation in humans and describes increased plasma arginine levels after fenofibrate treatment of hypertriglyceridemic men [83]. The findings in rodents are limited to WY14643 treatment and it remains to be shown if they are of general character for PPAR ligands. The clofibrate-induced increased oxidation of branched-chain amino acids seems to be due to its direct inhibitory actions on branched-chain -keto acid dehydrogenase kinase (BCKDK) that regulates the key enzyme of this process, and not due to effects mediated through PPAR activation [84].

Additionally, in mice, PPAR activation inhibits inflammatory gene expression by downregulation of acute phase proteins such as C-reactive protein (CRP), fibrinogen, and serum amyloid A (SAA) resulting in reduced hepatic inflammation and risk for cardiovascular disease and cancer [85]. Likewise in humans, there is a similar downregulation of plasma acute phase proteins after fenofibrate treatment [86]. Recently, it was demonstrated that the expression of the transcription factor CREBH that is exclusively found in the liver, is regulated by PPAR in both mice and humans [25]. It plays an important role in the activation of the acute inflammatory response and is also a regulator of hepatic gluconeogenesis [87, 88].

Described in mice is the reduced risk of liver damage by chemical-induced stress. Exposure to hepatotoxic agents like the environmental pollutant carbon tetrachloride (CCl4) induces reversible liver damage [89]. The underlying reason is a decreased resistance to oxidative stress that leads to lipid peroxidation, altered calcium homeostasis, and membrane damage. Stimulated mRNA expression of uncoupling protein 2 (Ucp2) by PPAR in rodents results in uncoupling of the proton gradient across the inner mitochondrial membrane and a downregulation of reactive oxygen species (ROS) induced by CCl4 metabolites [90, 91]. In addition, PPAR helps to protect from chemical-induced oxidative stress by upregulating genes of the chaperone family and of the proteasome, thereby influencing protein folding and degradation of harmed proteins in mice [92]. Furthermore, the observation that PPAR -null mice demonstrate decreased longevity, where stress response genes are of importance, and that PPAR expression decreases with age, suggests an involvement of PPAR in this process [7].

In rodents, long-term administration of PPAR leads to increased peroxisome proliferation, in addition to hepatic hypertrophy and hyperplasia that will ultimately result in liver tumors [9398]. The carcinogenic response is based on enhanced cell replication that might increase the risk for DNA damage and altered oncogene and tumor suppressor gene expressions. Moreover, there is evidence for suppressed apoptosis in liver cells, a process important for the removal of damaged cells [99102]. There is also a close relationship of PPAR -induced cancer formation with increased production of ROS due to peroxisome proliferation that might contribute to DNA damage [103].

Shah and colleagues have proposed changed hepatic microRNA (miR) expression via PPAR -regulation as the reason for liver cancer formation [104]. miRs are 21–23 nucleotide long sequences that are suggested to regulate the expression of up to 30% of all genes [105, 106]. Experimental evidence pointed to PPAR -involvement in several changed miR levels, in particular in the downregulation of miR let-7c by an as yet unidentified mechanism [104]. Let-7c controls c-Myc protein levels, a transcription factor regulating target genes involved in cell proliferation. Downregulation of let-7c stabilizes c-Myc mRNA leading to the expression of c-Myc target genes. This could be a reason for enhanced hepatocyte proliferation, that together with the induction of oxidative stress might lead to hepatocarcinogenesis in rodents. Induction of hepatocarcinogenesis seems to be restricted to rodents and is not documented in humans (extensively reviewed in [107]). Cancer formation after PPAR activation in tissues other than the liver has been described in rats and includes testicular (Ledig cell) and pancreatic acinar cell tumors [108]. However, if these findings are of significance for humans requires further in-depth risk assessments.

In summary, the hepatic response to PPAR activation is essential under fasting conditions. PPAR activation by FAs released from the adipose tissue leads to induction of several metabolic processes in mice: -oxidation, ketogenesis, glycolysis/gluconeogenesis, with concomitant reduction of amino acid catabolism and an anti-inflammatory response. The changes result in an increased plasma concentration of glucose and ketone bodies and decreased urea and acute phase proteins. PPAR is important in both mice and humans for the regulation of lipid metabolism. In contrast to mice, humans show no effect on the glycolysis/gluconeogenesis pathway. One pathway specifically affected in humans and not in mice is apolipoprotein production. In humans treated with a PPAR activator, hepatic transcription activation leads to decreased VLDL production and plasma TAG levels, but increased HDL cholesterol, important parameters in the treatment for dyslipidemia, type 2 diabetes, or cardiometabolic disorders.

3. PPAR in Skeletal Muscle

In human skeletal muscles, three main muscle fiber types, type I (oxidative, slow twitch), IIA (intermediate) and IIX (glycolytic, fast twitch), can be delineated based on histochemical, functional and biochemical properties (reviewed in [109]). In human skeletal muscle cells in vitro, PPARα was shown to be induced early during myocyte differentiation [110, 111]. A correlation between the expression of PPARα, proportion of type I fibers and endurance exercise has been found in human skeletal muscle in vivo [112, 113]. The expression of PPARα (as well as of PPARδ and the PPAR coactivator (PGC)- and -1ß) in skeletal muscle was increased in athletes and reduced in spinal cord-injured subjects [113]. The observed increase of PPARα expression after endurance training [112, 114] was greater in type I fibers than in type IIA and IIX fibers [112]. Also in rat skeletal muscle, fiber-type specific PPAR activation was found. When treated with the PPAR agonist fenofibrate, 26 genes were identified that were significantly regulated in soleus (type I) but not in quadriceps femoris (type II) rat muscle [115]. The correlation of PPARα expression and exercise has not been found in animal studies. In rats, four weeks of exercise did not change the PPARα mRNA expression in skeletal muscle in control chow-fed animals, and in fat-fed rats exercise counteracted the diet-induced increase of PPARαexpression [116].

Both in human and rodent skeletal muscle, activation of PPAR affects lipid metabolism. Activation of PPAR by a potent agonist (GW7647) in differentiated human myotubes in vitro stimulated lipid oxidation [110, 117] and decreased accumulation of TAG [110]. Other, less potent PPAR agonists did not increase lipid oxidation in human myotubes [118]. In the same cell model, GW7647 upregulated the expression of pyruvate dehydrogenase kinase (PDK)4 [119]. PDK4 is an important isoenzyme regulating the activity of pyruvate dehydrogenase complex. The enzyme phosphorylates and inhibits the pyruvate dehydrogenase complex and thereby blocks the entry of carbohydrates into the mitochondria for oxidation (for reviews see [120, 121]. Pdk4 was also induced in rat gastrocnemius muscle after treatment of the animals with the PPAR agonist WY14643, by streptozotocin-induced diabetes, or by starvation, i.e. conditions where increased levels of long-chain fatty acids may activate PPAR [122]. Pathway analysis of the genes significantly regulated in soleus (type I), but not in quadriceps femoris (type II) muscle by fenofibrate in rats, revealed that the most significant function represented in the gene set was lipid metabolism [115]. Treatment with a potent PPAR agonist increased the expression of Cpt-1 in hamster soleus muscle [123].

Influence of PPAR on both lipid and glucose metabolism was highlighted in transgenic mice overexpressing PPAR in skeletal muscle [124]. In these animals many known PPAR target genes involved in cellular fatty acid import and binding, TAG synthesis, and mitochondrial and peroxisomal β-oxidation were activated, and genes involved in cellular glucose utilization were downregulated in skeletal muscle. Basal and insulin-stimulated glucose uptake was reduced in isolated skeletal muscle, and the transgenic animals developed glucose intolerance despite being protected from diet-induced obesity [124]. In contrast, in PPAR -null mice, glucose tolerance, insulin-stimulated glucose disposal and glucose uptake were increased in spite of high fat-induced weight gain and increased levels of TAGs in muscle [124]. In another study, fatty acid oxidation in skeletal muscle was found to be reduced by 28% in starved PPAR -null mice compared to wild type (WT) mice, however in fed animals fatty acid oxidation in PPAR -null and WT mice was similar [125]. TCA cycle intermediates, amino acids and short-chain acylcarnitine species were reduced in skeletal muscle of PPAR -null mice compared to WT mice, indicating impaired TCA cycle flux and increased protein catabolism combined with defects in fatty acid catabolism in PPAR -null mice [37].

In humans and mice, a negative side effect of PPAR activation in muscle is in rare cases (<1%) muscle weakness and pain (myopathy) or very seldom breakdown of muscle (rhabdomyolysis) [126129]. In particular, type I fibers are affected by skeletal muscle toxicity in rats [115]. The exact mechanisms are unclear at present, but might include oxidative stress and tissue damage from elevated peroxisomal and mitochondrial -oxidation [130].

PPAR also seems to exert a role in protecting against ischemic injury in skeletal muscle as well as in heart and liver [131]. Thus, in mouse skeletal muscle, loss of the oxygen sensor prolyl oxidase (PHD)1 was found to lower oxygen consumption by shifting to a more anaerobic glucose utilization through activation of PPAR -dependent genes [131].

Another PPAR, PPARδ, is the most abundant PPAR isoform in skeletal muscle. Similar to PPARα, the expression of PPARδ has been described to be higher in type I fibers compared to type II fibers (reviewed in [132]). Also alike to PPAR , activation of PPARδ induces a number of genes involved in fatty acid import and oxidation, and increases lipid oxidation in skeletal muscle [125, 133136], indicating redundancy in the functions of PPAR and δ as regulators of fatty acid metabolism [125]. However, in contrast to PPAR , activation of PPARδ has been shown to increase glucose uptake [136, 137] and prevent insulin resistance in skeletal muscle (Figure 2) [138].

542359.fig.002
Figure 2: Examples of metabolic effects of PPAR or PPARδ activation in skeletal muscle. FA, fatty acid; TAG, triacylglycerol. For references, see the text.

In summary, PPAR has been shown to be involved in lipid and glucose metabolism in skeletal muscle. PPAR activation increases lipid oxidation and decreases TAG accumulation. Overexpression of PPARα in skeletal muscle causes reduced glucose uptake in muscle and glucose intolerance in the animals, while PPAR -null mice show increased glucose tolerance, increased insulin-stimulated glucose disposal and enhanced glucose uptake in skeletal muscle, in spite of high fat-induced weight gain and increased levels of TAGs in muscle. Thus, PPAR activation may potentially exert both beneficial and undesirable effects on skeletal muscle fuel metabolism. Activation of PPAR and PPARδ seems to have overlapping effects on fatty acid metabolism, but possibly different effects on glucose metabolism in skeletal muscle.

4. Concluding Remarks

The transcription factor PPAR influences metabolism through activation of many target genes in a variety of metabolically active tissues, in particular under fasting conditions. Cross-species prognostics are not always possible due to differences in metabolism, expression levels, or diet. While observations in rodents could have pointed to risks for human treatment with PPAR agonists (e.g., hepatocarcinogenesis, skeletal muscle insulin resistance, and myopathy) it has been shown that in humans, PPAR activation is a useful therapeutic target in treating metabolic disorders. Clinical studies on drug-induced PPAR activation include fibrates, statins, and more recently the combination of statins with fibrates. In humans, fibrates have the characteristic of reducing TAG levels and increasing HDL cholesterol, however not all trials show a vascular benefit. In some trials, clinical end-points like the rate of coronary heart disease in type 2 diabetes patients (VAHIT: Veterans affairs HDL intervention Trial, [139]) or the progression of atherosclerosis in young men after a first myocardial infarction (BECAIT: Bezafibrate Coronary Atherosclerosis Intervention Trial, [140]) could be reduced by treatment. Statin therapy shows more consistent benefits with decreased plasma LDL cholesterol levels and reduced vascular disorders and death [141]. The Action to Control Cardiovascular Risk in Diabetes (ACCORD) lipid study, addressed whether a fibrate (fenofibrate) and statin (simvastatin) combination would reduce the rate of cardiovascular events more than individual treatments in type 2 diabetes patients [142]. The combination treatment however did not influence the primary outcome significantly more than simvastatin alone, but instead showed a sex-dependent difference, with more benefits for men than women.

Rodent studies are mostly done in male animals, but the response of PPAR activation in male versus females was investigated in some studies and seems to be influenced by estrogen [143, 144]. This female hormone inhibits PPAR action and represses lipid regulatory pathways in the liver. Thus, in the treatment with PPAR agonists, gender-differences have to be taken into consideration and while therapy might be advantageous against lipid disorders in men and postmenopausal women with no interfering estrogen, premenopausal women might not benefit from the same treatment [145].

Acknowledgments

The authors thank Bodil Bjørndal, Jon Skorve, and Thomas Lundåsen for critical reading of the paper. This work was supported by a grant from NordForsk, Grant no. 070010, MitoHealth (to L. Burri and R. K. Berge).

References

  1. B. Desvergne, L. Michalik, and W. Wahli, “Transcriptional regulation of metabolism,” Physiological Reviews, vol. 86, no. 2, pp. 465–514, 2006. View at Publisher · View at Google Scholar · View at Scopus
  2. S. A. Kliewer, B. M. Forman, B. Blumberg et al., “Differential expression and activation of a family of murine peroxisome proliferator-activated receptors,” Proceedings of the National Academy of Sciences of the United States of America, vol. 91, no. 15, pp. 7355–7359, 1994. View at Publisher · View at Google Scholar · View at Scopus
  3. A. Schmidt, N. Endo, S. J. Rutledge, R. Vogel, D. Shinar, and G. A. Rodan, “Identification of a new member of the steroid hormone receptor superfamily that is activated by a peroxisome proliferator and fatty acids,” Molecular Endocrinology, vol. 6, no. 10, pp. 1634–1641, 1992. View at Publisher · View at Google Scholar · View at Scopus
  4. C. Dreyer, G. Krey, H. Keller, F. Givel, G. Helftenbein, and W. Wahli, “Control of the peroxisomal β-oxidation pathway by a novel family of nuclear hormone receptors,” Cell, vol. 68, no. 5, pp. 879–887, 1992. View at Publisher · View at Google Scholar · View at Scopus
  5. K. L. Houseknecht, B. M. Cole, and P. J. Steele, “Peroxisome proliferator-activated receptor gamma (PPARγ) and its ligands: a review,” Domestic Animal Endocrinology, vol. 22, no. 1, pp. 1–23, 2002. View at Publisher · View at Google Scholar · View at Scopus
  6. D. Bishop-Bailey, “Peroxisome proliferator-activated receptors in the cardiovascular system,” British Journal of Pharmacology, vol. 129, no. 5, pp. 823–834, 2000. View at Google Scholar · View at Scopus
  7. P. Howroyd, C. Swanson, C. Dunn, R. C. Cattley, and J. C. Corton, “Decreased longevity and enhancement of age-dependent lesions in mice lacking the nuclear receptor peroxisome proliferator-activated receptor α (PPARα),” Toxicologic Pathology, vol. 32, no. 5, pp. 591–599, 2004. View at Publisher · View at Google Scholar · View at Scopus
  8. G. Chinetti, J.-C. Fruchart, and B. Staels, “Peroxisome proliferator-activated receptors and inflammation: from basic science to clinical applications,” International Journal of Obesity, vol. 27, supplement 3, pp. S41–S45, 2003. View at Publisher · View at Google Scholar · View at Scopus
  9. C. Qi, Y. Zhu, and J. K. Reddy, “Peroxisome proliferator-activated receptors, coactivators, and downstream targets,” Cell Biochemistry and Biophysics, vol. 32, pp. 187–204, 2000. View at Google Scholar · View at Scopus
  10. K. Schoonjans, G. Martin, B. Staels, and J. Auwerx, “Peroxisome proliferator-activated receptors, orphans with ligands and functions,” Current Opinion in Lipidology, vol. 8, no. 3, pp. 159–166, 1997. View at Publisher · View at Google Scholar · View at Scopus
  11. N. S. Tan, L. Michalik, B. Desvergne, and W. Wahli, “Multiple expression control mechanisms of peroxisome proliferator-activated receptors and their target genes,” Journal of Steroid Biochemistry and Molecular Biology, vol. 93, no. 2–5, pp. 99–105, 2005. View at Publisher · View at Google Scholar · View at Scopus
  12. S. Mandard, M. Müller, and S. Kersten, “Peroxisome proliferator-activated receptor α target genes,” Cellular and Molecular Life Sciences, vol. 61, no. 4, pp. 393–416, 2004. View at Publisher · View at Google Scholar · View at Scopus
  13. P. Delerive, P. Gervois, J.-C. Fruchart, and B. Staels, “Induction of IκBα expression as a mechanism contributing to the anti-inflammatory activities of peroxisome proliferator-activated receptor-α activators,” Journal of Biological Chemistry, vol. 275, no. 47, pp. 36703–36707, 2000. View at Publisher · View at Google Scholar · View at Scopus
  14. P. Delerive, K. De Bosscher, W. V. Berghe, J.-C. Fruchart, G. Haegeman, and B. Staels, “DNA binding-independent induction of IκBα gene transcription by PPARα,” Molecular Endocrinology, vol. 16, no. 5, pp. 1029–1039, 2002. View at Publisher · View at Google Scholar · View at Scopus
  15. I. Issemann and S. Green, “Activation of a member of the steroid hormone receptor superfamily by peroxisome proliferators,” Nature, vol. 347, no. 6294, pp. 645–650, 1990. View at Publisher · View at Google Scholar · View at Scopus
  16. M. Bünger, H. M. van den Bosch, J. van der Meijde, S. Kersten, G. J. E. J. Hooiveld, and M. Müller, “Genome-wide analysis of PPARα activation in murine small intestine,” Physiological Genomics, vol. 30, no. 2, pp. 192–204, 2007. View at Publisher · View at Google Scholar · View at Scopus
  17. N. Marx, N. Mackman, U. Schönbeck et al., “PPARα activators inhibit tissue factor expression and activity in human monocytes,” Circulation, vol. 103, no. 2, pp. 213–219, 2001. View at Google Scholar · View at Scopus
  18. B. P. Neve, D. Corseaux, G. Chinetti et al., “PPARα agonists inhibit tissue factor expression in human monocytes and macrophages,” Circulation, vol. 103, no. 2, pp. 207–212, 2001. View at Google Scholar · View at Scopus
  19. D. C. Jones, X. Ding, and R. A. Daynes, “Nuclear receptor peroxisome proliferator-activated receptor α (PPARα) is expressed in resting murine lymphocytes,” Journal of Biological Chemistry, vol. 277, no. 9, pp. 6838–6845, 2002. View at Publisher · View at Google Scholar · View at Scopus
  20. R. K. Berge, K. J. Tronstad, K. Berge et al., “The metabolic syndrome and the hepatic fatty acid drainage hypothesis,” Biochimie, vol. 87, no. 1, pp. 15–20, 2005. View at Publisher · View at Google Scholar · View at Scopus
  21. S. A. Kliewer, S. S. Sundseth, S. A. Jones et al., “Fatty acids and eicosanoids regulate gene expression through direct interactions with peroxisome proliferator-activated receptors α and γ,” Proceedings of the National Academy of Sciences of the United States of America, vol. 94, no. 9, pp. 4318–4323, 1997. View at Publisher · View at Google Scholar · View at Scopus
  22. B. M. Forman, J. Chen, and R. M. Evans, “Hypolipidemic drugs, polyunsaturated fatty acids, and eicosanoids are ligands for peroxisome proliferator-activated receptors α and δ,” Proceedings of the National Academy of Sciences of the United States of America, vol. 94, no. 9, pp. 4312–4317, 1997. View at Publisher · View at Google Scholar · View at Scopus
  23. T. C. Leone, C. J. Weinheimer, and D. P. Kelly, “A critical role for the peroxisome proliferator-activated receptor α (PPARα) in the cellular fasting response: the PPARα-null mouse as a model of fatty acid oxidation disorders,” Proceedings of the National Academy of Sciences of the United States of America, vol. 96, no. 13, pp. 7473–7478, 1999. View at Publisher · View at Google Scholar · View at Scopus
  24. S. Kersten, J. Seydoux, J. M. Peters, F. J. Gonzalez, B. Desvergne, and W. Wahli, “Peroxisome proliferator-activated receptor α mediates the adaptive response to fasting,” Journal of Clinical Investigation, vol. 103, no. 11, pp. 1489–1498, 1999. View at Google Scholar · View at Scopus
  25. M. Rakhshandehroo, G. Hooiveld, M. Müller, and S. Kersten, “Comparative analysis of gene regulation by the transcription factor PPARα between mouse and human,” PLoS ONE, vol. 4, no. 8, Article ID e6796, 2009. View at Publisher · View at Google Scholar · View at Scopus
  26. P. Gervois, I. P. Torra, G. Chinetti et al., “A truncated human peroxisome proliferator-activated receptor α splice variant with dominant negative activity,” Molecular Endocrinology, vol. 13, no. 9, pp. 1535–1549, 1999. View at Google Scholar · View at Scopus
  27. D. D. Patel, B. L. Knight, D. Wiggins, S. M. Humphreys, and G. F. Gibbons, “Disturbances in the normal regulation of SREBP-sensitive genes in PPARα-deficient mice,” Journal of Lipid Research, vol. 42, no. 3, pp. 328–337, 2001. View at Google Scholar · View at Scopus
  28. S. Luci, B. Giemsa, H. Kluge, and K. Eder, “Clofibrate causes an upregulation of PPAR-α target genes but does not alter expression of SREBP target genes in liver and adipose tissue of pigs,” American Journal of Physiology, vol. 293, no. 1, pp. R70–R77, 2007. View at Publisher · View at Google Scholar · View at Scopus
  29. C. N. A. Palmer, M.-H. Hsu, K. J. Griffin, J. L. Raucy, and E. F. Johnson, “Peroxisome proliferator activated receptor-α expression in human liver,” Molecular Pharmacology, vol. 53, no. 1, pp. 14–22, 1998. View at Google Scholar · View at Scopus
  30. J. D. Tugwood, P. R. Holden, N. H. James, R. A. Prince, and R. A. Roberts, “A peroxisome proliferator-activated receptor-alpha (PPARα) cDNA cloned from guinea-pig liver encodes a protein with similar properties to the mouse PPARα: Implications for species differences in responses to peroxisome proliferators,” Archives of Toxicology, vol. 72, no. 3, pp. 169–177, 1998. View at Publisher · View at Google Scholar · View at Scopus
  31. K. Motojima, P. Passilly, J. M. Peters, F. J. Gonzalez, and N. Latruffe, “Expression of putative fatty acid transporter genes are regulated by peroxisome proliferator-activated receptor α and γ activators in a tissue- and inducer-specific manner,” Journal of Biological Chemistry, vol. 273, no. 27, pp. 16710–16714, 1998. View at Publisher · View at Google Scholar · View at Scopus
  32. H. Poirier, I. Niot, M.-C. Monnot et al., “Differential involvement of peroxisome-proliferator-activated receptors α and δ in fibrate and fatty-acid-mediated inductions of the gene encoding liver fatty-acid-binding protein in the liver and the small intestine,” Biochemical Journal, vol. 355, no. 2, pp. 481–488, 2001. View at Publisher · View at Google Scholar · View at Scopus
  33. T. Aoyama, J. M. Peters, N. Iritani et al., “Altered constitutive expression of fatty acid-metabolizing enzymes in mice lacking the peroxisome proliferator-activated receptor α (PPARα),” Journal of Biological Chemistry, vol. 273, no. 10, pp. 5678–5684, 1998. View at Publisher · View at Google Scholar · View at Scopus
  34. J. Gloerich, N. Van Vlies, G. A. Jansen et al., “A phytol-enriched diet induces changes in fatty acid metabolism in mice both via PPARα-dependent and -independent pathways,” Journal of Lipid Research, vol. 46, no. 4, pp. 716–726, 2005. View at Publisher · View at Google Scholar · View at Scopus
  35. H. S. Paul, C. E. Gleditsch, and S. A. Adibi, “Mechanism of increased hepatic concentration of carnitine by clofibrate,” American Journal of Physiology, vol. 251, no. 3, part 1, pp. E311–E315, 1986. View at Google Scholar · View at Scopus
  36. J. D. McGarry and N. F. Brown, “The mitochondrial carnitine palmitoyltransferase system. From concept to molecular analysis,” European Journal of Biochemistry, vol. 244, no. 1, pp. 1–14, 1997. View at Google Scholar · View at Scopus
  37. L. Makowski, R. C. Noland, T. R. Koves et al., “Metabolic profiling of PPARα-/- mice reveals defects in carnitine and amino acid homeostasis that are partially reversed by oral carnitine supplementation,” FASEB Journal, vol. 23, no. 2, pp. 586–604, 2009. View at Publisher · View at Google Scholar · View at Scopus
  38. N. van Vlies, S. Ferdinandusse, M. Turkenburg, R. J. A. Wanders, and F. M. Vaz, “PPARα-activation results in enhanced carnitine biosynthesis and OCTN2-mediated hepatic carnitine accumulation,” Biochimica et Biophysica Acta, vol. 1767, no. 9, pp. 1134–1142, 2007. View at Publisher · View at Google Scholar · View at Scopus
  39. R. Ringseis, N. Wege, G. Wen et al., “Carnitine synthesis and uptake into cells are stimulated by fasting in pigs as a model of nonproliferating species,” Journal of Nutritional Biochemistry, vol. 20, no. 11, pp. 840–847, 2009. View at Publisher · View at Google Scholar · View at Scopus
  40. J. D. Tugwood, I. Issemann, R. G. Anderson, K. R. Bundell, W. L. McPheat, and S. Green, “The mouse peroxisome proliferator activated receptor recognizes a response element in the 5' flanking sequence of the rat acyl CoA oxidase gene,” EMBO Journal, vol. 11, no. 2, pp. 433–439, 1992. View at Google Scholar · View at Scopus
  41. V. Nicolas-Frances, V. K. Dasari, E. Abruzzi, T. Osumi, and N. Latruffe, “The peroxisome proliferator response element (PPRE) present at positions -681/-669 in the rat liver 3-ketoacyl-CoA thiolase B gene functionally interacts differently with PPARα and HNF-4,” Biochemical and Biophysical Research Communications, vol. 269, no. 2, pp. 347–351, 2000. View at Publisher · View at Google Scholar · View at Scopus
  42. Ü. Savas, D. E. W. Machemer, M.-H. Hsu et al., “Opposing roles of peroxisome proliferator-activated receptor α and growth hormone in the regulation of CYP4A11 expression in a transgenic mouse model,” Journal of Biological Chemistry, vol. 284, no. 24, pp. 16541–16552, 2009. View at Publisher · View at Google Scholar · View at Scopus
  43. E. Sérée, P.-H. Villard, J.-M. Pascussi et al., “Evidence for a new human CYP1A1 regulation pathway involving PPAR-α and 2 PPRE sites,” Gastroenterology, vol. 127, no. 5, pp. 1436–1445, 2004. View at Publisher · View at Google Scholar · View at Scopus
  44. S. Yu, S. Rao, and J. K. Reddy, “Peroxisome proliferator-activated receptors, fatty acid oxidation, steatohepatitis and hepatocarcinogenesis,” Current Molecular Medicine, vol. 3, no. 6, pp. 561–572, 2003. View at Publisher · View at Google Scholar · View at Scopus
  45. H. Castelein, T. Gulick, P. E. Declercq, G. P. Mannaerts, D. D. Moore, and M. I. Baes, “The peroxisome proliferator activated receptor regulates malic enzyme gene expression,” Journal of Biological Chemistry, vol. 269, no. 43, pp. 26754–26758, 1994. View at Google Scholar · View at Scopus
  46. H. Guillou, P. Martin, S. Jan et al., “Comparative effect of fenofibrate on hepatic desaturases in wild-type and peroxisome proliferator-activated receptor α-deficient mice,” Lipids, vol. 37, no. 10, pp. 981–989, 2002. View at Publisher · View at Google Scholar · View at Scopus
  47. C. W. Miller and J. M. Ntambi, “Peroxisome proliferators induce mouse liver stearoyl-CoA desaturase 1 gene expression,” Proceedings of the National Academy of Sciences of the United States of America, vol. 93, no. 18, pp. 9443–9448, 1996. View at Publisher · View at Google Scholar · View at Scopus
  48. C. Tang, H. P. Cho, M. T. Nakamura, and S. D. Clarke, “Regulation of human Δ-6 desaturase gene transcription: identification of a functional direct repeat-1 element,” Journal of Lipid Research, vol. 44, no. 4, pp. 686–695, 2003. View at Publisher · View at Google Scholar · View at Scopus
  49. G. F. Watts, P. H. R. Barrett, J. Ji et al., “Differential regulation of lipoprotein kinetics by atorvastatin and fenofibrate in subjects with the metabolic syndrome,” Diabetes, vol. 52, no. 3, pp. 803–811, 2003. View at Publisher · View at Google Scholar · View at Scopus
  50. N. Vu-Dac, K. Schoonjans, V. Kosykh et al., “Fibrates increase human apolipoprotein A-II expression through activation of the peroxisome proliferator-activated receptor,” Journal of Clinical Investigation, vol. 96, no. 2, pp. 741–750, 1995. View at Google Scholar · View at Scopus
  51. N. Vu-Dac, S. Chopin-Delannoy, P. Gervois et al., “The nuclear receptors peroxisome proliferator-activated receptor α and rev-erbα mediate the species-specific regulation of apolipoprotein A-I expression by fibrates,” Journal of Biological Chemistry, vol. 273, no. 40, pp. 25713–25720, 1998. View at Publisher · View at Google Scholar · View at Scopus
  52. M. Eriksson, L. A. Carlson, T. A. Miettinen, and B. Angelin, “Stimulation of fecal steroid excretion after infusion of recombinant proapolipoprotein A-I: potential reverse cholesterol transport in humans,” Circulation, vol. 100, no. 6, pp. 594–598, 1999. View at Google Scholar · View at Scopus
  53. K. Schoonjans, J. Peinado-Onsurbe, A.-M. Lefebvre et al., “PPARα and PPARγ activators direct a distinct tissue-specific transcriptional response via a PPRE in the lipoprotein lipase gene,” EMBO Journal, vol. 15, no. 19, pp. 5336–5348, 1996. View at Google Scholar · View at Scopus
  54. X. Prieur, P. Lesnik, M. Moreau et al., “Differential regulation of the human versus the mouse apolipoprotein AV gene by PPARalpha. Implications for the study of pharmaceutical modifiers of hypertriglyceridemia in mice,” Biochimica et Biophysica Acta, vol. 1791, no. 8, pp. 764–771, 2009. View at Publisher · View at Google Scholar · View at Scopus
  55. N. Vu-Dac, P. Gervois, H. Jakel et al., “Apolipoprotein A5, a crucial determinant of plasma triglyceride levels, is highly responsive to peroxisome proliferator-activated receptor α activators,” Journal of Biological Chemistry, vol. 278, no. 20, pp. 17982–17985, 2003. View at Publisher · View at Google Scholar · View at Scopus
  56. A. E. Schultze, W. E. Alborn, R. K. Newton, and R. J. Konrad, “Administration of a PPARα agonist increases serum apolipoprotein A-V levels and the apolipoprotein A-V/apolipoprotein C-III ratio,” Journal of Lipid Research, vol. 46, no. 8, pp. 1591–1595, 2005. View at Publisher · View at Google Scholar · View at Scopus
  57. B. Staels, N. Vu-Dac, V. A. Kosykh et al., “Fibrates downregulate apolipoprotein C-III expression independent of induction of peroxisomal acyl coenzyme A oxidase. A potential mechanism for the hypolipidemic action of fibrates,” Journal of Clinical Investigation, vol. 95, no. 2, pp. 705–712, 1995. View at Google Scholar · View at Scopus
  58. R. S. Birjmohun, B. A. Hutten, J. J. P. Kastelein, and E. S. G. Stroes, “Efficacy and safety of high-density lipoprotein cholesterol-increasing compounds: a meta-analysis of randomized controlled trials,” Journal of the American College of Cardiology, vol. 45, no. 2, pp. 185–197, 2005. View at Publisher · View at Google Scholar · View at Scopus
  59. D. W. Russell and K. D. R. Setchell, “Bile acid biosynthesis,” Biochemistry, vol. 31, no. 20, pp. 4737–4749, 1992. View at Google Scholar · View at Scopus
  60. Z. R. Vlahcevic, D. M. Heuman, and P. B. Hylemon, “Regulation of bile acid synthesis,” Hepatology, vol. 13, no. 3, pp. 590–600, 1991. View at Publisher · View at Google Scholar · View at Scopus
  61. S. K. Cheema and L. B. Agellon, “The murine and human cholesterol 7α-hydroxylase gene promoters are differentially responsive to regulation by fatty acids mediated via peroxisome proliferator-activated receptor α,” Journal of Biological Chemistry, vol. 275, no. 17, pp. 12530–12536, 2000. View at Publisher · View at Google Scholar · View at Scopus
  62. M. C. Hunt, Y.-Z. Yang, G. Eggertsen et al., “The peroxisome proliferator-activated receptor α (PPARα) regulates bile acid biosynthesis,” Journal of Biological Chemistry, vol. 275, no. 37, pp. 28947–28953, 2000. View at Google Scholar · View at Scopus
  63. J. Y. L. Chiang, “Bile acid regulation of gene expression: roles of nuclear hormone receptors,” Endocrine Reviews, vol. 23, no. 4, pp. 443–463, 2002. View at Publisher · View at Google Scholar · View at Scopus
  64. M. Marrapodi and J. Y.L. Chiang, “Peroxisome proliferator-activated receptor α (PPARα) and agonist inhibit cholesterol 7α-hydroxylase gene (CYP7A1) transcription,” Journal of Lipid Research, vol. 41, no. 4, pp. 514–520, 2000. View at Google Scholar · View at Scopus
  65. D. D. Patel, B. L. Knight, A. K. Soutar, G. F. Gibbons, and D. P. Wade, “The effect of peroxisome-proliferator-activated receptor-α on the activity of the cholesterol 7α-hydroxylase gene,” Biochemical Journal, vol. 351, no. 3, pp. 747–753, 2000. View at Publisher · View at Google Scholar · View at Scopus
  66. S. M. Post, H. Duez, P. P. Gervois, B. Staels, F. Kuipers, and H. M. G. Princen, “Fibrates suppress bile acid synthesis via peroxisome proliferator-activated receptor-α-mediated downregulation of cholesterol 7α-hydroxylase and sterol 27-hydroxylase expression,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 21, no. 11, pp. 1840–1845, 2001. View at Google Scholar · View at Scopus
  67. D. Ståhlberg, E. Reihnér, M. Rudling, L. Berglund, K. Einarsson, and B. O. Angelin, “Influence of bezafibrate on hepatic cholesterol metabolism in gallstone patients: reduced activity of cholesterol 7α-hydroxylase,” Hepatology, vol. 21, no. 4, pp. 1025–1030, 1995. View at Publisher · View at Google Scholar · View at Scopus
  68. H. Ishida, Y. Kuruta, O. Gotoh, C. Yamashita, Y. Yoshida, and M. Noshiro, “Structure, evolution, and liver-specific expression of sterol 12α-hydroxylase P450 (CYP8B),” Journal of Biochemistry, vol. 126, no. 1, pp. 19–25, 1999. View at Google Scholar · View at Scopus
  69. M.-H. Hsu, Ü. Savas, K. J. Griffin, and E. F. Johnson, “Identification of peroxisome proliferator-responsive human genes by elevated expression of the peroxisome proliferator-activated receptor α in HepG2 cells,” Journal of Biological Chemistry, vol. 276, no. 30, pp. 27950–27958, 2001. View at Publisher · View at Google Scholar · View at Scopus
  70. J. C. Rodríguez, G. Gil-Gómez, F. G. Hegardt, and D. Haro, “Peroxisome proliferator-activated receptor mediates induction of the mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase gene by fatty acids,” Journal of Biological Chemistry, vol. 269, no. 29, pp. 18767–18772, 1994. View at Google Scholar · View at Scopus
  71. M. K. Badman, P. Pissios, A. R. Kennedy, G. Koukos, J. S. Flier, and E. Maratos-Flier, “Hepatic fibroblast growth factor 21 is regulated by PPARα and is a key mediator of hepatic lipid metabolism in ketotic states,” Cell Metabolism, vol. 5, no. 6, pp. 426–437, 2007. View at Publisher · View at Google Scholar · View at Scopus
  72. T. Coskun, H. A. Bina, M. A. Schneider et al., “Fibroblast growth factor 21 corrects obesity in mice,” Endocrinology, vol. 149, no. 12, pp. 6018–6027, 2008. View at Publisher · View at Google Scholar · View at Scopus
  73. J. Xu, D. J. Lloyd, C. Hale et al., “Fibroblast growth factor 21 reverses hepatic steatosis, increases energy expenditure, and improves insulin sensitivity in diet-induced obese mice,” Diabetes, vol. 58, no. 1, pp. 250–259, 2009. View at Publisher · View at Google Scholar · View at Scopus
  74. T. Inagaki, P. Dutchak, G. Zhao et al., “Endocrine regulation of the fasting response by PPARα-mediated induction of fibroblast growth factor 21,” Cell Metabolism, vol. 5, no. 6, pp. 415–425, 2007. View at Publisher · View at Google Scholar · View at Scopus
  75. T. Lundåsen, M. C. Hunt, L.-M. Nilsson et al., “PPARα is a key regulator of hepatic FGF21,” Biochemical and Biophysical Research Communications, vol. 360, no. 2, pp. 437–440, 2007. View at Publisher · View at Google Scholar · View at Scopus
  76. A. Kharitonenkov, T. L. Shiyanova, A. Koester et al., “FGF-21 as a novel metabolic regulator,” Journal of Clinical Investigation, vol. 115, no. 6, pp. 1627–1635, 2005. View at Publisher · View at Google Scholar · View at Scopus
  77. J. Xu, G. Xiao, C. Tirujillo et al., “Peroxisome proliferator-activated receptor α (PPARα) influences: substrate utilization for hepatic glucose production,” Journal of Biological Chemistry, vol. 277, no. 52, pp. 50237–50244, 2002. View at Publisher · View at Google Scholar · View at Scopus
  78. D. Patsouris, S. Mandard, P. J. Voshol et al., “PPARα governs glycerol metabolism,” Journal of Clinical Investigation, vol. 114, no. 1, pp. 94–103, 2004. View at Publisher · View at Google Scholar · View at Scopus
  79. R. H. J. Bandsma, T. H. van Dijk, A. ter Harmsel et al., “Hepatic de novo synthesis of glucose 6-phosphate is not affected in peroxisome proliferator-activated receptor α-deficient mice but is preferentially directed toward hepatic glycogen stores after a short term fast,” Journal of Biological Chemistry, vol. 279, no. 10, pp. 8930–8937, 2004. View at Publisher · View at Google Scholar · View at Scopus
  80. R. Genolet, S. Kersten, O. Braissant et al., “Promoter rearrangements cause species-specific hepatic regulation of the glyoxylate reductase/hydroxypyruvate reductase gene by the peroxisome proliferator-activated receptor α,” Journal of Biological Chemistry, vol. 280, no. 25, pp. 24143–24152, 2005. View at Publisher · View at Google Scholar · View at Scopus
  81. S. Kersten, S. Mandard, P. Escher et al., “The peroxisome proliferator-activated receptor α regulates amino acid metabolism,” FASEB Journal, vol. 15, no. 11, pp. 1971–1978, 2001. View at Publisher · View at Google Scholar · View at Scopus
  82. K. Sheikh, G. Camejo, B. Lanne, T. Halvarsson, M. R. Landergren, and N. D. Oakes, “Beyond lipids, pharmacological PPARα activation has important effects on amino acid metabolism as studied in the rat,” American Journal of Physiology, vol. 292, no. 4, pp. E1157–E1165, 2007. View at Publisher · View at Google Scholar · View at Scopus
  83. J. Dierkes, S. Westphal, J. Martens-Lobenhoffer, C. Luley, and S. M. Bode-Böger, “Fenofibrate increases the L-arginine: ADMA ratio by increase of L-arginine concentration but has no effect on ADMA concentration,” Atherosclerosis, vol. 173, no. 2, pp. 239–244, 2004. View at Publisher · View at Google Scholar · View at Scopus
  84. R. Kobayashi, T. Murakami, M. Obayashi et al., “Clofibric acid stimulates branched-chain amino acid catabolism by three mechanisms,” Archives of Biochemistry and Biophysics, vol. 407, no. 2, pp. 231–240, 2002. View at Publisher · View at Google Scholar · View at Scopus
  85. P. Gervois, R. Kleemann, A. Pilon et al., “Global suppression of IL-6-induced acute phase response gene expression after chronic in vivo treatment with the peroxisome proliferator-activated receptor-α activator fenofibrate,” Journal of Biological Chemistry, vol. 279, no. 16, pp. 16154–16160, 2004. View at Publisher · View at Google Scholar · View at Scopus
  86. R. Belfort, R. Berria, J. Cornell, and K. Cusi, “Fenofibrate reduces systemic inflammation markers independent of its effects on lipid and glucose metabolism in patients with the metabolic syndrome,” Journal of Clinical Endocrinology and Metabolism, vol. 95, no. 2, pp. 829–836, 2010. View at Publisher · View at Google Scholar · View at Scopus
  87. M.-W. Lee, D. Chanda, J. Yang et al., “Regulation of hepatic gluconeogenesis by an ER-bound transcription factor, CREBH,” Cell Metabolism, vol. 11, no. 4, pp. 331–339, 2010. View at Publisher · View at Google Scholar · View at Scopus
  88. K. Zhang, X. Shen, J. Wu et al., “Endoplasmic reticulum stress activates cleavage of CREBH to induce a systemic inflammatory response,” Cell, vol. 124, no. 3, pp. 587–599, 2006. View at Publisher · View at Google Scholar · View at Scopus
  89. C. Yu, F. Wang, C. Jin, X. Wu, W.-K. Chan, and W. L. McKeehan, “Increased carbon tetrachloride-induced liver injury and fibrosis in FGFR4-deficient mice,” American Journal of Pathology, vol. 161, no. 6, pp. 2003–2010, 2002. View at Google Scholar · View at Scopus
  90. K. S. Echtay, D. Roussel, J. St-Plerre et al., “Superoxide activates mitochondrial uncoupling proteins,” Nature, vol. 415, no. 6867, pp. 96–99, 2002. View at Publisher · View at Google Scholar · View at Scopus
  91. Q. Wu, D. Gong, N. Tian et al., “Protection of regenerating liver after partial hepatectomy from carbon tetrachloride hepatotoxicity in rats: roles of mitochondrial uncoupling protein 2 and ATP stores,” Digestive Diseases and Sciences, vol. 54, no. 9, pp. 1918–1925, 2009. View at Publisher · View at Google Scholar · View at Scopus
  92. S. P. Anderson, P. Howroyd, J. Liu et al., “The transcriptional response to a peroxisome proliferator-activated receptor α agonist includes increased expression of proteome maintenance genes,” Journal of Biological Chemistry, vol. 279, no. 50, pp. 52390–52398, 2004. View at Publisher · View at Google Scholar · View at Scopus
  93. J. Ashby, A. Brady, C. R. Elcombe et al., “Mechanistically-based human hazard assessment of peroxisome proliferator-induced hepatocarcinogenesis,” Human and Experimental Toxicology, vol. 13, supplement 2, pp. S1–S117, 1994. View at Google Scholar · View at Scopus
  94. P. Bentley, I. Calder, C. Elcombe, P. Grasso, D. Stringer, and H.-J. Wiegand, “Hepatic peroxisome proliferation in rodents and its significance for humans,” Food and Chemical Toxicology, vol. 31, no. 11, pp. 857–907, 1993. View at Publisher · View at Google Scholar · View at Scopus
  95. T. Hays, I. Rusyn, A. M. Burns et al., “Role of peroxisome proliferator-activated receptor-α (PPARα) in bezafibrate-induced hepatocarcinogenesis and cholestasis,” Carcinogenesis, vol. 26, no. 1, pp. 219–227, 2005. View at Publisher · View at Google Scholar · View at Scopus
  96. J. M. Peters, C. Cheung, and F. J. Gonzalez, “Peroxisome proliferator-activated receptor-α and liver cancer: where do we stand?” Journal of Molecular Medicine, vol. 83, no. 10, pp. 774–785, 2005. View at Publisher · View at Google Scholar · View at Scopus
  97. M. S. Rao and J. K. Reddy, “An overview of peroxisome proliferator-induced hepatocarcinogenesis,” Environmental Health Perspectives, vol. 93, pp. 205–209, 1991. View at Google Scholar · View at Scopus
  98. J. K. Reddy and M. S. Rao, “Malignant tumors in rats fed nafenopin, a hepatic peroxisome proliferator,” Journal of the National Cancer Institute, vol. 59, no. 6, pp. 1645–1650, 1977. View at Google Scholar · View at Scopus
  99. A. C. Bayly, R. A. Roberts, and C. Dive, “Suppression of liver cell apoptosis in vitro by the non-genotoxic hepatocarcinogen and peroxisome proliferator nafenopin,” Journal of Cell Biology, vol. 125, no. 1, pp. 197–203, 1994. View at Google Scholar · View at Scopus
  100. M. L. Cunningham, M. S. Soliman, M. Z. Badr, and H. B. Matthews, “Rotenone, an anticarcinogen, inhibits cellular proliferation but not peroxisome proliferation in mouse liver,” Cancer Letters, vol. 95, no. 1-2, pp. 93–97, 1995. View at Publisher · View at Google Scholar · View at Scopus
  101. N. H. James, A. R. Soames, and R. A. Roberts, “Suppression of hepatocyte apoptosis and induction of DNA synthesis by the rat and mouse hepatocarcinogen diethylhexylphlathate (DEHP) and the mouse hepatocarcinogen 1,4-dichlorobenzene (DCB),” Archives of Toxicology, vol. 72, no. 12, pp. 784–790, 1998. View at Publisher · View at Google Scholar · View at Scopus
  102. F. A. Oberhammer and H.-M. Qin, “Effect of three tumour promoters on the stability of hepatocyte cultures and apoptosis after transforming growth factor-β1,” Carcinogenesis, vol. 16, no. 6, pp. 1363–1371, 1995. View at Google Scholar
  103. J. K. Reddy and M. S. Rao, “Oxidative DNA damage caused by persistent peroxisome proliferation: its role in hepatocarcinogenesis,” Mutation Research, vol. 214, no. 1, pp. 63–68, 1989. View at Google Scholar · View at Scopus
  104. Y. M. Shah, K. Morimura, Q. Yang, T. Tanabe, M. Takagi, and F. J. Gonzalez, “Peroxisome proliferator-activated receptor α regulates a microRNA-mediated signaling cascade responsible for hepatocellular proliferation,” Molecular and Cellular Biology, vol. 27, no. 12, pp. 4238–4247, 2007. View at Publisher · View at Google Scholar · View at Scopus
  105. J. Brennecke, A. Stark, R. B. Russell, and S. M. Cohen, “Principles of microRNA-target recognition,” PLoS Biology, vol. 3, no. 3, article e85, 2005. View at Google Scholar · View at Scopus
  106. B. P. Lewis, C. B. Burge, and D. P. Bartel, “Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets,” Cell, vol. 120, no. 1, pp. 15–20, 2005. View at Publisher · View at Google Scholar · View at Scopus
  107. J. A. Balfour, D. McTavish, and R. C. Heel, “Fenofibrate. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic use in dyslipidaemia,” Drugs, vol. 40, no. 2, pp. 260–290, 1990. View at Google Scholar · View at Scopus
  108. J. E. Klaunig, M. A. Babich, K. P. Baetcke et al., “PPARα agonist-induced rodent tumors: modes of action and human relevance,” Critical Reviews in Toxicology, vol. 33, no. 6, pp. 655–780, 2003. View at Google Scholar · View at Scopus
  109. R. Bottinelli and C. Reggiani, “Human skeletal muscle fibres: molecular and functional diversity,” Progress in Biophysics and Molecular Biology, vol. 73, no. 2–4, pp. 195–262, 2000. View at Publisher · View at Google Scholar · View at Scopus
  110. D. M. Muoio, J. M. Way, C. J. Tanner et al., “Peroxisome proliferator-activated receptor-α regulates fatty acid utilization in primary human skeletal muscle cells,” Diabetes, vol. 51, no. 4, pp. 901–909, 2002. View at Google Scholar · View at Scopus
  111. E. T. Kase, B. Andersen, H. I. Nebb, A. C. Rustan, and G. Hege Thoresen, “22-Hydroxycholesterols regulate lipid metabolism differently than T0901317 in human myotubes,” Biochimica et Biophysica Acta, vol. 1761, no. 12, pp. 1515–1522, 2006. View at Publisher · View at Google Scholar · View at Scopus
  112. A. P. Russell, J. Feilchenfeldt, S. Schreiber et al., “Endurance training in humans leads to fiber type-specific increases in levels of peroxisome proliferator-activated receptor-gamma coactivator-1 and peroxisome proliferator-activated receptor-alpha in skeletal muscle,” Diabetes, vol. 52, no. 12, pp. 2874–2881, 2003. View at Publisher · View at Google Scholar · View at Scopus
  113. D. K. Krämer, M. Ahlsén, J. Norrbom et al., “Human skeletal muscle fibre type variations correlate with PPARα, PPARδ and PGC-1α mRNA,” Acta Physiologica, vol. 188, no. 3-4, pp. 207–216, 2006. View at Publisher · View at Google Scholar · View at Scopus
  114. J. F. Horowitz, T. C. Leone, W. Feng, D. P. Kelly, and S. Klein, “Effect of endurance training on lipid metabolism in women: a potential role for PPARα in the metabolic response to training,” American Journal of Physiology, vol. 279, no. 2, pp. E348–E355, 2000. View at Google Scholar · View at Scopus
  115. A. T. De Souza, P. D. Cornwell, X. Dai, M. J. Caguyong, and R. G. Ulrich, “Agonists of the peroxisome proliferator-activated receptor alpha induce a fiber-type-selective transcriptional response in rat skeletal muscle,” Toxicological Sciences, vol. 92, no. 2, pp. 578–586, 2006. View at Publisher · View at Google Scholar · View at Scopus
  116. K. Kannisto, A. Chibalin, B. Glinghammar, J. R. Zierath, A. Hamsten, and E. Ehrenborg, “Differential expression of peroxisomal proliferator activated receptors alpha and delta in skeletal muscle in response to changes in diet and exercise,” International Journal of Molecular Medicine, vol. 17, no. 1, pp. 45–52, 2006. View at Google Scholar · View at Scopus
  117. F. Djouadi, F. Aubey, D. Schlemmer, and J. Bastin, “Peroxisome proliferator activated receptor δ (PPARδ) agonist but not PPARα corrects carnitine palmitoyl transferase 2 deficiency in human muscle cells,” Journal of Clinical Endocrinology and Metabolism, vol. 90, no. 3, pp. 1791–1797, 2005. View at Publisher · View at Google Scholar · View at Scopus
  118. K. Løvås, T. H. Røst, J. Skorve et al., “Tetradecylthioacetic acid attenuates dyslipidaemia in male patients with type 2 diabetes mellitus, possibly by dual PPAR-α/δ activation and increased mitochondrial fatty acid oxidation,” Diabetes, Obesity and Metabolism, vol. 11, no. 4, pp. 304–314, 2009. View at Publisher · View at Google Scholar · View at Scopus
  119. E. L. Abbot, J. G. McCormack, C. Reynet, D. G. Hassall, K. W. Buchan, and S. J. Yeaman, “Diverging regulation of pyruvate dehydrogenase kinase isoform gene expression in cultured human muscle cells,” FEBS Journal, vol. 272, no. 12, pp. 3004–3014, 2005. View at Publisher · View at Google Scholar · View at Scopus
  120. H. Pilegaard and P. D. Neufer, “Transcriptional regulation of pyruvate dehydrogenase kinase 4 in skeletal muscle during and after exercise,” Proceedings of the Nutrition Society, vol. 63, no. 2, pp. 221–226, 2004. View at Publisher · View at Google Scholar · View at Scopus
  121. M. C. Sugden and M. J. Holness, “Mechanisms underlying regulation of the expression and activities of the mammalian pyruvate dehydrogenase kinases,” Archives of Physiology and Biochemistry, vol. 112, no. 3, pp. 139–149, 2006. View at Publisher · View at Google Scholar · View at Scopus
  122. P. Wu, K. Inskeep, M. M. Bowker-Kinley, K. M. Popov, and R. A. Harris, “Mechanism responsible for inactivation of skeletal muscle pyruvate dehydrogenase complex in starvation and diabetes,” Diabetes, vol. 48, no. 8, pp. 1593–1599, 1999. View at Publisher · View at Google Scholar · View at Scopus
  123. A. Minnich, N. Tian, L. Byan, and G. Bilder, “A potent PPARα agonist stimulates mitochondrial fatty acid β-oxidation in liver and skeletal muscle,” American Journal of Physiology, vol. 280, no. 2, pp. E270–E279, 2001. View at Google Scholar · View at Scopus
  124. B. N. Finck, C. Bernal-Mizrachi, D. H. Han et al., “A potential link between muscle peroxisome proliferator-activated receptor-α signaling and obesity-related diabetes,” Cell Metabolism, vol. 1, no. 2, pp. 133–144, 2005. View at Publisher · View at Google Scholar · View at Scopus
  125. D. M. Muoio, P. S. MacLean, D. B. Lang et al., “Fatty acid homeostasis and induction of lipid regulatory genes in skeletal muscles of peroxisome proliferator-activated receptor (PPAR) α knock-out mice. Evidence for compensatory regulation by PPARδ,” Journal of Biological Chemistry, vol. 277, no. 29, pp. 26089–26097, 2002. View at Publisher · View at Google Scholar · View at Scopus
  126. C. Hodel, “Myopathy and rhabdomyolysis with lipid-lowering drugs,” Toxicology Letters, vol. 128, no. 1–3, pp. 159–168, 2002. View at Publisher · View at Google Scholar · View at Scopus
  127. G. J. Magarian, L. M. Lucas, and C. Colley, “Gemfibrozil-induced myopathy,” Archives of Internal Medicine, vol. 151, no. 9, pp. 1873–1874, 1991. View at Publisher · View at Google Scholar · View at Scopus
  128. T. Langer and R. I. Levy, “Acute muscular syndrome associated with administration of clofibrate,” The New England Journal of Medicine, vol. 279, no. 16, pp. 856–858, 1968. View at Google Scholar · View at Scopus
  129. P. Rush, M. Baron, and M. Kapusta, “Clofibrate myopathy: a case report and a review of the literature,” Seminars in Arthritis and Rheumatism, vol. 15, no. 3, pp. 226–229, 1986. View at Google Scholar · View at Scopus
  130. B. Faiola, J. G. Falls, R. A. Peterson et al., “PPAR alpha, more than PPAR delta, mediates the hepatic and skeletal muscle alterations induced by the PPAR agonist GW0742,” Toxicological Sciences, vol. 105, no. 2, pp. 384–394, 2008. View at Publisher · View at Google Scholar · View at Scopus
  131. J. Aragonés, M. Schneider, K. Van Geyte et al., “Deficiency or inhibition of oxygen sensor Phd1 induces hypoxia tolerance by reprogramming basal metabolism,” Nature Genetics, vol. 40, no. 2, pp. 170–180, 2008. View at Publisher · View at Google Scholar · View at Scopus
  132. E. Ehrenborg and A. Krook, “Regulation of skeletal muscle physiology and metabolism by peroxisome proliferator-activated receptor δ,” Pharmacological Reviews, vol. 61, no. 3, pp. 373–393, 2009. View at Publisher · View at Google Scholar · View at Scopus
  133. U. Dressel, T. L. Allen, J. B. Pippal, P. R. Rohde, P. Lau, and G. E. O. Muscat, “The peroxisome proliferator-activated receptor beta/delta agonist, GW501516, regulates the expression of genes involved in lipid catabolism and energy uncoupling in skeletal muscle cells,” Molecular Endocrinology, vol. 17, no. 12, pp. 2477–2493, 2003. View at Publisher · View at Google Scholar · View at Scopus
  134. D. Holst, S. Luquet, V. Nogueira, K. Kristiansen, X. Leverve, and P. A. Grimaldi, “Nutritional regulation and role of peroxisome proliferator-activated receptor δ in fatty acid catabolism in skeletal muscle,” Biochimica et Biophysica Acta, vol. 1633, no. 1, pp. 43–50, 2003. View at Publisher · View at Google Scholar · View at Scopus
  135. T. Tanaka, J. Yamamoto, S. Iwasaki et al., “Activation of peroxisome proliferator-activated receptor δ induces fatty acid β-oxidation in skeletal muscle and attenuates metabolic syndrome,” Proceedings of the National Academy of Sciences of the United States of America, vol. 100, no. 26, pp. 15924–15929, 2003. View at Publisher · View at Google Scholar · View at Scopus
  136. D. K. Krämer, L. Al-Khalili, B. Guigas, Y. Leng, P. M. Garcia-Roves, and A. Krook, “Role of AMP kinase and PPARδ in the regulation of lipid and glucose metabolism in human skeletal muscle,” Journal of Biological Chemistry, vol. 282, no. 27, pp. 19313–19320, 2007. View at Publisher · View at Google Scholar · View at Scopus
  137. D. K. Krämer, L. Al-Khalili, S. Perrini et al., “Direct activation of glucose transport in primary human myotubes after activation of peroxisome proliferator-activated receptor δ,” Diabetes, vol. 54, no. 4, pp. 1157–1163, 2005. View at Publisher · View at Google Scholar · View at Scopus
  138. T. Coll, D. Álvarez-Guardia, E. Barroso et al., “Activation of peroxisome proliferator-activated receptor-δ by GW501516 prevents fatty acid-induced nuclear factor-κB activation and insulin resistance in skeletal muscle cells,” Endocrinology, vol. 151, no. 4, pp. 1560–1569, 2010. View at Publisher · View at Google Scholar · View at Scopus
  139. H. B. Rubins, S. J. Robins, D. Collins et al., “Diabetes, plasma insulin, and cardiovascular disease: subgroup analysis from the Department of Veterans Affairs High-density Lipoprotein Intervention Trial (VA-HIT),” Archives of Internal Medicine, vol. 162, no. 22, pp. 2597–2604, 2002. View at Publisher · View at Google Scholar · View at Scopus
  140. G. Ruotolo, C.-G. Ericsson, C. Tettamanti et al., “Treatment effects on serum lipoprotein lipids, apolipoproteins and low density lipoprotein particle size and relationships of lipoprotein variables to progression of coronary artery disease in the Bezafibrate Coronary Atherosclerosis Intervention Trial (BECAIT),” Journal of the American College of Cardiology, vol. 32, no. 6, pp. 1648–1656, 1998. View at Publisher · View at Google Scholar · View at Scopus
  141. C. Baigent, A. Keech, P. M. Kearney, et al., “Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins,” The Lancet, vol. 366, no. 9493, pp. 1267–1278, 2005. View at Google Scholar
  142. H. N. Ginsberg, M. B. Elam, L. C. Lovato et al., “Effects of combination lipid therapy in type 2 diabetes mellitus,” The New England Journal of Medicine, vol. 362, no. 17, pp. 1563–1574, 2010. View at Publisher · View at Google Scholar · View at Scopus
  143. N. Leuenberger, S. Pradervand, and W. Wahli, “Sumoylated PPARα mediates sex-specific gene repression and protects the liver from estrogen-induced toxicity in mice,” Journal of Clinical Investigation, vol. 119, no. 10, pp. 3138–3148, 2009. View at Publisher · View at Google Scholar · View at Scopus
  144. X. Wang and M. W. Kilgore, “Signal cross-talk between estrogen receptor alpha and beta and the peroxisome proliferator-activated receptor gamma1 in MDA-MB-231 and MCF-7 breast cancer cells,” Molecular and Cellular Endocrinology, vol. 194, no. 1-2, pp. 123–133, 2002. View at Publisher · View at Google Scholar · View at Scopus
  145. M. Yoon, “The role of PPARα in lipid metabolism and obesity: focusing on the effects of estrogen on PPARα actions,” Pharmacological Research, vol. 60, no. 3, pp. 151–159, 2009. View at Publisher · View at Google Scholar · View at Scopus