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Correspondence to:
Björn Dahllöf
The PPAR (peroxisome proliferator activated receptor) transcription factors are ligand-activated nuclear receptors that regulate genes involved in lipid metabolism and homeostasis. PPAR
Supplementary key words:
BRL49653, WY14,643, peroxisome proliferation, PPAR, proteomics, ob/ob, obese mice, insulin resistance, two-dimensional gel electrophoresis
Peroxisome proliferator activated receptors (PPAR) are nuclear transcription factors that heterodimerize with RXR
In rodent livers, activation of PPAR
It is therefore adequate that both PPAR
Reporter gene assays in transfected cell lines have shown that TZD are highly selective PPAR
Materials
Animals and drug treatment
Metabolic effects
Sample preparation for two-dimensional electrophoresis
First dimension (isoelectric focusing)
Equilibration of IPG gel strips
Second dimension (SDS-PAGE)
Silver staining
Image analysis
RNA isolation
Ribonuclease protection assay (RPA)
The RPAII kit (Ambion Inc., Austin, TX) was used for mRNA quantification. Briefly, 20 µg total liver RNA or 5 µg total RNA from white adipose tissue was hybridized at 45°C overnight to 80,000 cpm probe. The samples were subsequently treated with an RNaseT1/RNaseA mix at 37°C for 30 min to digest single-stranded RNA prior to separation on a 6% denaturing polyacrylamide gel. Radioactivity on the dried gel was visualized using a STORMTM phosphorimager (Molecular Dynamics, Sunnyvale, CA).
Drug treatment and therapeutic effects
Two-dimensional gel electrophoresis
Thereafter, semiquantitative data obtained from computer-aided image analysis were analyzed and we found that in obese animals, out of these 15 spots, WY14,643 and rosiglitazone induced significant up-regulation of 14 and 9 spots, respectively ( Figure 3a). As each enzyme is represented by several spots, a common finding in two-dimensional electrophoresis most likely representing cleavage and degradation occurring in vivo, it is important to note that rosiglitazone did affect at least one spot from all of the three identified peroxisomal enzymes. To explain that several spots, originating from one protein, are not regulated in a coordinated manner by pharmacological treatments would require complete knowledge of the primary sequence of each spot, as well as an understanding of each activation/degradation pathway. Such an analysis has not been possible to perform in this study. In lean mice, rosiglitazone did not cause any significant changes whereas WY14,643 caused significant up-regulation of 15 spots (Figure 3b). It is interesting to note that all spots representing ACO, PBE, and 3KCT had a higher basal expression in obese compared to lean mice (Figure 3c), but this was not the case for aFABP. Thus, rosiglitazone caused a similar, but somewhat less pronounced, induction of peroxisomal enzymes in obese mice as compared to WY14,643. In contrast, only WY14,643 induced this metabolic pathway in lean mice.
Liver expression of PPAR
In our efforts to map the mechanisms of action of antihyperlipidemic drugs, we first characterized the response of the selective PPAR
The results are summarized as follows. i) At equally effective doses in obese mice (with regard to correction of hypertriglyceridemia and hyperglycemia), rosiglitazone and WY14,643 induce similar responses identified as up-regulation of peroxisomal fatty acid ß-oxidation. ii) In lean mice, WY14,643 exerted effects similar to those in obese mice whereas rosiglitazone had no effect on the studied proteins. iii) Livers from obese mice contain more PPAR
Lena Amrot-Fors, Ann-Christine Carlsson, Ann Kjellstedt, and Charlotte Lindgren are acknowledged for excellent technical assistance, Jan Fryklund for constructive criticism of the manuscript, and Germán Camejo, Tony Clementz, and Nick Oakes for fruitful discussions during the course of this work.
Manuscript received December 28, 1998; and in revised form March 12, 1999.
Abbreviations:
3KCT, 3-ketoacyl CoA thiolase; ACO, acyl CoA oxidase; CYP4A, cytochrome P450-4A; aFABP, adipocyte fatty acid binding protein; PBE, peroxisomal bifunctional enzyme; PPAR, peroxisome proliferator activated receptor; PPRE, peroxisome proliferator response element; TZD, thiazolidinedione
Copyright © 1999 by Lipid Research, Inc.
Original Article
Rosiglitazone (BRL49653), a PPAR
Ulrika Edvardssona,
Monica Bergströma,
Maria Alexanderssona,
Krister Bambergb,
Bengt Ljungc, and
Björn Dahllöfa
-selective agonist, causes peroxisome proliferator-like liver effects in obese mice
a Cell Biology and Biochemistry, Astra Hässle AB, S-431 83 Mölndal, Sweden
b Molecular Biology, Astra Hässle AB, S-431 83 Mölndal, Sweden
c Cardiovascular Pharmacology, Astra Hässle AB, S-431 83 Mölndal, Sweden
ABSTRACT
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ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
is preferentially expressed in liver and PPAR preferentially in adipose tissue. Activation of PPAR leads to peroxisome proliferation and increased ß-oxidation of fatty acids in rodents. PPAR-activation leads to adipocyte differentiation and improved insulin signaling of mature adipocytes. Both PPAR receptors are believed to be functional targets for treatment of hyperlipidemia in man. We have treated obese diabetic mice (ob/ob), which have highly elevated levels of plasma triglycerides, glucose and insulin, for 1 week with WY14,643 (180 µmol/kg/day), a selective PPAR agonist, or rosiglitazone (BRL49653; 2.5 µmol/kg/day), a selective PPAR agonist. The doses used produce a similar therapeutic effect in both treatment groups (lowering of triglycerides and glucose). High resolution two-dimensional gel electrophoresis of livers showed that WY14,643 and rosiglitazone both produced changes in expression pattern of many proteins involved in peroxisomal fatty acid ß-oxidation. However, similar experiments performed in lean mice showed significant up-regulation of these proteins only with WY14,643 treatment. Furthermore, the proteins up-regulated by the drugs in obese mice had a higher basal expression in obese controls compared to the lean littermates. Liver PPAR mRNA levels were determined and we observed that PPAR2 mRNA levels were elevated in obese mice compared to lean littermates. As PPAR and PPAR recognize similar DNA response elements, it is likely that the effects of rosiglitazone on PPAR responsive genes in livers of the ob/ob mice are mediated by PPAR2. — Edvardsson, U., M. Bergström, M. Alexandersson, K. Bamberg, B. Ljung, and B. Dahllöf. Rosiglitazone (BRL49653), a PPAR-selective agonist, causes peroxisome proliferator-like liver effects in obese mice. J. Lipid Res. 1999. 40: 1177;–1184.
INTRODUCTION
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MATERIALS AND METHODS
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DISCUSSION
REFERENCES
and activate a multitude of genes involved in lipid metabolism (1) (3). There are three PPAR subtypes known to date with different tissue distribution; PPAR is highly expressed in liver and kidney and PPAR
is ubiquitously expressed. The PPAR protein exists in two isoforms, 1 and 2. Profiling their relative abundance revealed that PPAR1 is expressed in several tissues, whereas PPAR2 is preferentially expressed in adipose tissue (1) (3) (6). The 1 and 2 isoforms arise from differential promoter usage, which results in 30 additional N-terminal amino acids in PPAR2. Also, a third PPAR mRNA transcript has recently been reported (7). This transcript gives rise to a protein identical to PPAR1 and is preferentially expressed in adipose tissue and large intestine. It has been shown that fatty acids and/or fatty acid metabolites are activators of PPARs (8) (12) and it is possible to view PPARs as physiological sensors of intracellular lipid/fatty acid concentrations (1) (2) (10). promotes increased fatty acid oxidation in peroxisomes, mitochondria and microsomes, and induces proliferation of peroxisomes (4) (13) (15). Several proteins involved in lipid metabolism, such as lipoprotein lipase, apolipoproteins A-I, A-II and C-III, and cytochrome P450 4A, are regulated by PPAR (1) (15) (16). Ligand activation of PPAR leads to adipocyte differentiation in cell culture as well as in whole animals (3) (17) (22). In white adipose tissue, expression of adipocyte fatty acid binding protein (aFABP) (18) and expression of insulin receptors increase upon PPAR activation (21) (23). Other proteins, such as TNF, TNF receptor (24), and leptin (25) (27), are down-regulated in adipocytes by PPAR-activation. Taken together, activation of either PPAR or PPAR may act to withdraw lipids and fatty acids from the circulation through increased oxidation or storage, respectively (1) (2). and PPAR may represent functional targets for hypolipidemic agents. Thus, fibrates, used for clinical treatment of severe hypertriglyceridemia, have been found to activate PPAR (4) (13) and in humans, a major effect is thought to be down-regulation of apolipoprotein C-III (2) (28) (29), an inhibitor of peripheral lipolysis. Peroxisome proliferation, as a result of PPAR activation, is considered a rodent-specific phenomenon and has not been convincingly detected in humans (30). Thiazolidinediones (TZD) (23) (31) (32) are a new class of insulin sensitizers and antidiabetic agents, with substantial effects on circulating lipids in diabetic rodents, and PPAR has been shown to be a molecular target of TZD action (9) (33). The first TZD in clinical use is troglitazone, which recently was registered in the US for treatment of non-insulin-dependent diabetes mellitus (34). Rosiglitazone (BRL49653), a more potent PPAR-activator, is currently near registration (35). -agonists (3) (12) (33). Thus, primary effects of TZD are expected in tissues expressing PPAR. Previously, we have used proteomics (high-resolution two-dimensional electrophoresis and mass spectrometry) to characterize the effect of the peroxisome proliferator and PPAR agonist WY14,643 on the livers of obese mice (36). These experiments showed that WY14,643 induced expression of most enzymes involved in the peroxisomal fatty acid ß-oxidation. Now, we have characterized the effects of both rosiglitazone and WY14,643 on the same set of proteins in the livers of both obese and lean mice. We found that whereas WY14,643 produced a similar response in both strains, rosiglitazone showed peroxisome proliferator-like effects only in obese mice. When compared to lean littermates, expression analysis of mRNA showed that obese mice have elevated liver PPAR2 levels. We conclude that obesity in this model leads to an up-regulation in the liver of the PPAR2 isoform and suggest that rosiglitazone causes peroxisome proliferator-like effects by activating liver PPAR2 in obese mice.
MATERIALS AND METHODS
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The IsoDalt system was from Hoefer (San Francisco, CA). Equipment for isoelectric focusing (IEF), IPGphor, Immobiline DryStrips (18 cm, pH 3 – 10 NL (non-linear)), IPG-buffer 3 – 10 NL, and Drystrip cover fluid were purchased from Amersham Pharmacia Biotech (Uppsala, Sweden). Iodoacetamide and sodium thiosulfate were from Sigma (St. Louis, MO). Silver nitrate, formaldehyde, and sodium carbonate were from Merck (Darmstadt, Germany). Nonidet P-40 (NP-40) was from United States Biochemical Corp. (Cleveland, OH). Duracryl (30%, 0.65% Bis) and all other chemicals were electrophoresis grade, obtained from ESA Inc. (Chelmsford, MA). WY14,643 was purchased from Sigma (St. Louis, MO) and rosiglitazone was obtained from Medicinal Chemistry, Astra Hässle AB.
Obese mice (ob/ob; Umeå) and their lean littermates (+/?) were from Bomholtgård Breeding and Research Centre, Denmark (genotyping of lean mice was not considered critical for this study and for practical reasons we therefore used +/? lean control mice). The 7-week-old animals were treated orally once daily for 1 week with WY14,643 (180 µmol/kg/day) or rosiglitazone (2.5 µmol/kg/day). On the last day of the experiment the mice were anesthetized in CO2 and exsanguinated via a carotid artery. The blood was collected in vials containing EDTA.
In plasma, insulin was analyzed using a rat insulin RIA kit (RI-13K; Linco, St. Louis, MO) and triglycerides (TG) and glucose were analyzed spectrophotometrically on the Cobas Mira plus (Hoffman la Roche, Basel, CH) using Calibrator Human (07 3718 6; Roche, Basel, CH) as calibrant. For TG the enzymatic kit "Triglycerides/Glycerol Blanking" (450032; Boehringer Mannheim, Indianapolis, IN) was used, and for glucose "Glucose HK" (07 3672 4; Roche, Basel, CH).
The apical ends of the left liver lobes were rapidly removed, frozen in liquid nitrogen, and stored at -150°C until subsequent electrophoretic analysis. Liver samples were weighed and homogenized with a glass/Teflon homogenizer (5 strokes at 400 rpm) in 8 volumes of solubilizing solution (8 M Urea, 0.3% (w/v) dithiothreitol (DTT), 2% (v/v) NP-40, and 2% (v/v) IPG-buffer 3 – 10 NL). To remove solid tissue, the homogenate was centrifuged at 100 000 g for 30 min at 15°C. The supernatant was carefully removed and immediately frozen at -70°C.
Electrophoresis of mouse liver proteins was performed on individual samples, four from each treatment group and from lean controls, and six from obese controls. Immobiline DryStrips (18 cm, pH 3 – 10 NL (non-linear)) were used for isoelectric focusing. Each strip was rehydrated for 12 h in 350 µl of rehydration solution containing 4 µl (~100 µg) of solubilized liver protein. The rehydration solution consisted of 8 M urea, 2% (v/v) NP-40, 0.3% (w/v) DTT, and 0.5% (v/v) IPG-buffer 3 – 10 NL. The strips were run under a layer of Drystrip cover fluid, at 20°C, in a IPGphor unit according to the manufacturer's instructions. The focusing was carried out at 500 V; 1 h, 1000 V; 1 h and 8000 V; 9 h to reach a total of 74 kVh.
After IEF the strips were equilibrated 2 x 15 min with gentle shaking (37). The first equilibration solution contained 30% glycerol (w/v), 6 M urea, 2% SDS, 50 mM Tris/HCl, pH 8.8, 65 mM DTT, and a trace of bromophenol blue as tracking dye. The second equilibration was carried out in same solution, except that DTT was replaced by 260 mM iodoacetamide.
The gels used in this study were continuous 14% T, 0.3% C gels in the format of 23 x 20 x 0.1 cm. After the equilibration, each IEF strip was drained on a filter paper and immersed in SDS running buffer (24 mM Tris base, 0.2 M glycine, and 0.1% SDS) before it was sealed at the top of the second dimension gel with 1% agarose in SDS running buffer. Electrophoresis was performed in the IsoDalt tank (Hoefer) at 100 V for ~19 h, until the tracking dye reached the anodic end of the gels.
Analytical gels were silver stained according to Shevchenko et al. (38) with some modifications. The gels were fixed in 50% ethanol, 5% acetic acid for 1 h, washed in 50% ethanol for 30 min and additionally 60 min with water to remove the remaining acid. Thereafter, the gels were sensitized by a 1-min incubation in 0.02% sodium thiosulfate and rinsed with two changes of distilled water for 1 min each. After rinsing, the gels were incubated in 0.1% silver nitrate for 30 min. After incubation, the gels were rinsed twice with distilled water for 1 min and then developed in 0.04% formaldehyde, 2% sodium carbonate. When the developer turned yellow (~30 sec) it was discarded and replaced with fresh solution. When desired intensity of staining was achieved (~3.5 min), the development was terminated by discarding the reagent, followed by washing with 5% acetic acid for 5 – 10 min. Finally, the gels were washed in water and stored in sealed plastic bags at 4°C.
Silver-stained gels were imaged using a cooled CCD camera-based instrument, Fluor-STM MultiImager (Bio-Rad). Raw scans were processed by the 2D software PDQuest (PC version 5.1) according to the following procedure: make gel image, ball background subtraction (radius 80), two times averaging smooth, spots detected and fitted to Gaussian volumes (39). After manual landmarking of approximately 140 spots in each gel image, the spot patterns of the different gels were automatically matched to each other and each spot was given a unique identification number (SSP). Individual quantifications of resolved proteins were normalized to the total intensity of detected spots in each gel. To find spots that differed quantitatively between the control and treated groups, the average intensities (n = 4 – 6) of resolved spots were compared using the statistical and quantitative functions within the PDQuest software.
Fresh liver samples were rinsed in PBS and frozen immediately in liquid N2. Total RNA was prepared using RNA-Stat 60 (Tel-Test, Inc., Friendswood, TX) according to the manufacturer's suggestions. Concentration and yield were determined by optical density measurement at 260 nm and the integrity of the RNA was verified by agarose gel electrophoresis and quantification of the 28S and 18S ribosomal bands.
Nucleotides 1 – 323 (position 1 is the A in the initial ATG) from mouse PPAR2 in a pBluescript vector (Stratagene, La Jolla, CA) served as template for PPAR probe synthesis. 32P-labeled antisense probe was generated using Promega in vitro transcription kit and the probe was purified by PAGE.
RESULTS
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ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
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Male obese and lean mice were treated for 1 week with WY14,643 (180 µmol/kg/day) or rosiglitazone (2.5 µmol/kg/day), doses that were previously determined by dose –response experiments to be equally effective in male obese mice regarding lowering of plasma triglycerides and glucose (data not shown). In Figure 1 we show that both substances again caused similar reductions in plasma triglycerides and glucose in obese insulin-resistant mice, to levels of the lean control mice. In lean insulin-sensitive mice, drug treatment did not significantly affect triglyceride or glucose levels.
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Figure 1.
Therapeutic effects of rosiglitazone and WY14,643. Plasma levels of triglycerides (A), insulin (B), and glucose (C) in obese and lean mice after 1 week treatment with rosiglitazone (2.5 µmol/kg/day) or WY14,643 (180 µmol/kg/day) in comparison to untreated obese and lean animals. Values are mean ± SE, n = 4 (obese controls, n = 6). * P < 0.05 using Student's t-test for each treated group versus obese or lean controls.
Liver samples, 4 from each treatment group and 6 from obese controls, were homogenized in rehydration buffer and analyzed by two-dimensional electrophoresis as described in Materials and Methods. The images of the 26 gels were captured and analyzed by using the PDQuest software as described in Materials and Methods. Previously, we have characterized the dominant response to WY14,643 in obese mice and found that 16 spots were clearly up-regulated by the treatment. These spots were identified by in-gel tryptic digestion and mass spectrometry (MALDI-TOF and MS/MS) as described (36). Of these spots, 14 were identified as polypeptides from acyl CoA oxidase (ACO), peroxisomal bifunctional enzyme (PBE), and 3-ketoacyl thiolase (3KCT), enzymes which are central components of the peroxisomal fatty acid ß-oxidation. Furthermore, one spot was identified as adipocyte fatty acid binding protein, aFABP, which may be viewed as a substrate carrier for this metabolic pathway, and one spot was identified as HMG-CoA synthase which is not directly involved in peroxisomal fatty acid ß-oxidation. In this study, we focused on the regulation of the 15 spots that are components of, or are related to (aFABP), peroxisomal fatty acid ß-oxidation. These spots are located in the basic region of the gels covering a pI range from 3 to 10 (see the master gel in Figure 2a). Representative gels of liver samples from untreated, rosiglitazone- and WY14,643-treated obese mice are shown as cut-outs from 2D-gels in Figure 2b. By visual inspection of the gels, we found that both rosiglitazone and WY14,643 apparently up-regulated most of these 15 spots. mRNA
PPAR and PPAR show similar binding to the peroxisomal proliferator response element (PPRE) of ACO (20). It is therefore conceivable that PPAR, if expressed in liver, will bind to the same PPREs as PPAR and hence mimic PPAR-mediated gene regulation. Therefore, we decided to compare mRNA expression levels of PPAR1 and PPAR2 in livers from the lean and obese mice. As can be seen in Figure 4, lean mice expressed only low levels of PPAR1 and barely detectable amounts of PPAR2. However, obese animals showed markedly elevated levels of the PPAR2 isoform, whereas the PPAR1 levels remained low. Thus, the peroxisome proliferator-like liver effects of rosiglitazone in obese mice may be due to activation of PPAR2.
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Figure 4.
PPAR 1 and PPAR2 expression in lean and obese mice quantified by RPA. Five µg total white adipose tissue RNA from obese mice (lane 2) or 20 µg total liver RNA from 3 obese (lanes 3 – 5) or 3 lean (lanes 6 – 8) animals was hybridized to a 32P-labeled antisense probe, digested with a RNaseT1/RNaseA mix, and separated on a 6% denaturing polyacrylamide gel. The probe contained the nucleotides 1 – 323, counting from the initiating ATG in PPAR2, plus vector sequence to account for a total of 379 nt (lane 9, undigested probe). PPAR1 mRNA protects a 233 nt fragment, PPAR2 protects a 323 nt fragment. Lane 1 contains a molecular size marker.
DISCUSSION
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MATERIALS AND METHODS
RESULTS
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REFERENCES
activator WY14,643 in livers from obese mice (36). We found the expected induction of central components of the peroxisomal fatty acid ß-oxidation pathway, a response typical for peroxisome proliferators. Now, we asked whether the TZD rosiglitazone, reported to be a selective PPAR-agonist (9) (33), may cause similar effects as WY14,643 in lean and obese mice. 2 mRNA than livers from lean mice. To conclude, our findings suggest that the elevated levels of liver PPAR2 in obese mice may render these animals susceptible to a peroxisome proliferator-like activation by rosiglitazone. In relation to this, it is interesting to note that others have found elevated PPAR expression in livers from obese mice fed a high fat-containing diet (40). Also, a recent report on PPAR knockout mice, which become obese, showed an increased expression of liver PPAR in fat-filled liver cells from males, whereas the expression of aFABP, adipoQ, and hormone-sensitive lipase remained unchanged (41). The results are in line with our data concerning the hepatic expression of PPAR and aFABP in obesity. Thus, obesity and high-fat feeding regulate PPAR levels in mice, and this may determine the response to PPAR activators in vivo. In particular, the PPAR2 isoform may be the one that is regulated in obesity. To understand the pharmacodynamic effects of PPAR activators in humans, it will be important to investigate possible regulatory effects of obesity on hepatic PPAR expression in human subjects.
ACKNOWLEDGMENTS
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, -ß, and - in the adult rat. Endocrinology. 137:354-366[Abstract]. and its receptor during drug and dietary modulation of insulin resistance. Endocrinology. 134:264-270-isoform defiency leads to progressive dyslipidemia with sexually dimorphic obesity and steatosis. J. Biol. Chem. 273:29577-29585
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M.-H. Hsu, U. Savas, K. J. Griffin, and E. F. Johnson Identification of Peroxisome Proliferator-responsive Human Genes by Elevated Expression of the Peroxisome Proliferator-activated Receptor alpha in HepG2 Cells J. Biol. Chem., July 20, 2001; 276(30): 27950 - 27958. [Abstract] [Full Text] [PDF]
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