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Journal of Lipid Research, Vol. 46, 2282-2288, October 2005
Copyright © 2005 by American Society for Biochemistry and Molecular Biology

Suppression of estrogen-related receptor and medium-chain acyl-coenzyme A dehydrogenase in the acute-phase response

Min Sun Kim, Judy K. Shigenaga, Arthur H. Moser, Kenneth R. Feingold and Carl Grunfeld¹

Department of Medicine, University of California San Francisco, and Metabolism Section, Department of Veterans Affairs Medical Center, San Francisco, CA 94121

Published, JLR Papers in Press, August 1, 2005. DOI 10.1194/jlr.M500217-JLR200

¹ To whom correspondence should be addressed. e-mail: grunfld{at}itsa.ucsf.edu

	ABSTRACT

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION REFERENCES

 
Fatty acid oxidation provides energy in tissues with high metabolic demands. During the acute-phase response (APR) induced by infection and inflammation, fatty acid oxidation is decreased associated with hypertriglyceridemia. Little is known about the mechanism by which the APR decreases fatty acid oxidation. Therefore, we investigated whether the APR affects the expression of medium-chain acyl-coenzyme A dehydrogenase (MCAD), its regulator the estrogen-related receptor (ERR), and a key coactivator of ERR, the peroxisome proliferator-activated receptor coactivator-1 (PGC-1). mRNA levels of PGC-1, ERR, and MCAD are markedly reduced in the liver, heart, and kidney of mice during the lipopolysaccharide (LPS)-induced APR. The decreases were rapid and occurred at very low doses of LPS. MCAD activity in liver was also reduced. Furthermore, binding of hepatic nuclear extracts to the ERR response element found in the promoter region of MCAD was significantly decreased during the APR, suggesting the decreased transcription of the MCAD gene. The binding activity was identified as ERR by supershift with antibody to ERR. Similar decreases in mRNA levels of these genes occur during zymosan- and turpentine-induced inflammation, indicating that suppression of the PGC-1, ERR, and MCAD pathway is a general response during infection and inflammation.

Our study provides a potential mechanism by which the APR decreases fatty acid oxidation.

Supplementary key words peroxisome proliferator-activated receptor coactivator-1 • ß-oxidation • fatty acid oxidation

	INTRODUCTION

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION REFERENCES

 
Estrogen-related receptor (ERR) is a nuclear receptor that was initially cloned based on its homology to the estrogen receptor (1). ERR is not activated by estrogen and is an orphan receptor whose ligand has not yet been defined. However, it can accentuate estrogen-dependent induction of the complex lactoferrin estrogen response element (2). It has also been shown that ERR regulates the transcription of medium-chain acyl-coenzyme A dehydrogenase (MCAD), which mediates the initial step in the mitochondrial ß-oxidation of fatty acids (3). Changes in the expression of MCAD modulate the rate of tissue fatty acid ß-oxidation (4), and its deficiency has been linked to childhood nonketotic hypoglycemia, coma, or sudden death, which occurs with prolonged fasting or during intercurrent infection (4–6).

Infection, inflammation, and trauma induce the acute-phase response (APR) via the release of proinflammatory cytokines such as tumor necrosis factor- (TNF-), interleukin-1 (IL-1), and IL-6 (7). These cytokines, in turn, trigger signaling pathways and cause characteristic changes in lipid metabolism, including decreased hepatic fatty acid oxidation (7, 8). Our previous studies showed that the APR suppresses the nuclear hormone receptors retinoid X receptor (RXR) and its heterodimeric partners retinoic acid receptor (RAR), liver X receptor, farnesoid X receptor, thyroid receptor, and peroxisome proliferator-activated receptor (PPAR), which is associated with decreased expression of their target genes (9–11). Because PPAR target genes such as L-Carnitine palmitoyl transferase-I, acyl-CoA oxidase, and acyl-CoA synthase are involved in fatty acid metabolism, the APR-induced suppression of PPAR provides at least a partial explanation for the decreased fatty acid oxidation observed during the APR.

However, cooperative induction of PPAR target genes by peroxisome proliferator-activated receptor coactivator-1 (PGC-1) raises the possibility that PGC-1 may also play a role in the APR-induced suppression of fatty acid oxidation (12). PGC-1 is abundantly expressed in tissues reliant on oxidative metabolism, such as heart and brown adipose tissue, but it is also present in liver and kidney. During the APR, the mRNA level of PGC-1 is dramatically decreased in mouse heart (13). Overexpression of PGC-1 in hearts of transgenic mice leads to the transcriptional activation of genes encoding mitochondrial fatty acid oxidation enzymes, such as MCAD (14). A recent study by Huss, Kopp, and Kelly (15) demonstrated that PGC-1 interacts with and coactivates ERR and enhances the transcriptional activation of MCAD by ERR, suggesting the possibility that ERR and the MCAD pathway are also suppressed during the APR.

In the present study, we hypothesized that decreased expression of PGC-1 downregulates the ERR and MCAD pathway, which would provide an additional mechanism for the decreased fatty acid oxidation during infection and inflammation. We found that inflammation induced by lipopolysaccharide (LPS) decreases the expression of PGC-1, ERR, and MCAD in liver, heart, and kidney. In addition, zymosan and turpentine, which also induce inflammation, decrease PGC-1, ERR, and MCAD, indicating that this suppression is a general response to infection and inflammation. Results from the present study provide a potential mechanism for the APR-induced decrease in fatty acid oxidation, which could contribute to the hypertriglyceridemia characteristically observed during infection and inflammation.

	METHODS

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Animals
All animal experimentation described in the present study was conducted in accordance with accepted standards of humane animal care approved by an Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC) approved animal subcommittee. Eight week old female C57BL/6 mice were purchased from the Jackson Laboratory. Only female mice were used in the present study because they do not fight as much as males and fighting leads to an inflammatory response. The animals were maintained in a normal light cycle room and were provided with rodent chow and water ad libitum. Their weight was 20 g at the time of experiment. Anesthesia was induced with halothane. To determine the effect of the APR on PGC-1, ERR, and MCAD mRNA levels, mice were studied using three different protocols: intraperitoneal injection with 0.1–100 µg of LPS in saline or with saline alone; intraperitoneal injection with 80 mg/kg body weight zymosan A in saline or with saline alone; or subcutaneous injection of 100 µl of turpentine per mouse, or a similar volume of saline. Food was withdrawn at the time of injection, because LPS, zymosan, and turpentine induce anorexia in rodents (16). Organs were removed at the times indicated below after treatment. The doses of LPS used in this study have significant effects on triglyceride and cholesterol metabolism (17, 18) but are not lethal, as the LD₅₀ for LPS in rodents is 5 mg/100 g body weight.

Materials
LPS (Escherichia coli 55:B5) was obtained from Difco Laboratories and freshly diluted to the desired concentration in pyrogen-free 0.9% saline. Turpentine was purchased from BDH. Zymosan A and Tri-Reagents were purchased from Sigma. Minimal essential medium was purchased from Fisher Scientific. [-³²P]dCTP (3,000 Ci/mmol) and [-³²P]dATP (3,000 Ci/mmol) were purchased from NEN Life Science Products. Oligo(dT)-cellulose type 77F was from Amersham Pharmacia Biotech. Antibody to ERR was from Affinity Bioreagents.

RNA isolation and Northern blot analysis
Total RNA from mouse was isolated from 300–400 mg of snap-frozen liver, heart, and kidney tissues using Tri-Reagent (Sigma). Poly(A)⁺ RNA was subsequently purified using oligo(dT) cellulose. RNA was quantified by measuring absorption at 260 nm. Ten micrograms of poly(A)⁺ was denatured and electrophoresed on a 1% agarose-formaldehyde gel. The uniformity of RNA loading was checked by ultraviolet visualization of 18S and 28S bands on the ethidium bromide-stained gel before electrotransfer to Nytran membrane (Schleicher and Schuell). Prehybridization, hybridization, and washing procedures were performed as described previously (19). Membranes were probed with [-³²P] dCTP-labeled cDNAs using the random priming technique (Amersham Biosciences). mRNA levels were detected by exposure of the membrane to X-ray film and quantified by densitometry. Housekeeping genes such as GAPDH were used to confirm the equal amount of RNA loading. PGC-1, ERR, and MCAD probes were prepared by PCR using the following primers; PGC-1, 5'-GACCACAAACGATGACCCTCC -3' (upper), 5'-GCCTCCAAAGTCTCTCTCAGG-3' (lower); ERR, 5'-GGGCATCGAGCCTCTCTAC-3' (upper), 5'-GCACTCCCTCCTTGAGCAT-3' (lower); MCAD, 5'-GAACAGCAGAAAGAGTTTCAAGC-3' (upper), 5'-GCTTCCACAATGAATCCAGTAA-3' (lower).

Preparation of nuclear extracts
Nuclear extracts were prepared according to Neish et al. (20). Briefly, cells were disrupted in sucrose-HEPES buffer containing 0.5% Nonidet-P40 as a detergent, protease inhibitors, and DTT. After a 5 min incubation on ice, cells were centrifuged, then nuclear proteins were separated in NaCl-HEPES buffer and resuspended in glycerol-containing buffer. All of the procedures were carried out on ice. Protein quantification was determined by the Bradford assay (Bio-Rad), and yields were similar in control and LPS-treated groups.

Electrophoretic gel mobility shift assays
Double-stranded oligonucleotides were end-labeled with T₄-polynucleotide kinase in the presence of 50 µCi of [-³²P]dATP and purified on a Sephadex G-25 column (Amersham Pharmacia Biotech). Ten micrograms of crude nuclear extract was incubated on ice for 30 min with 6 x 10⁴ cpm of ³²P-labeled oligonucleotides in 15 µl of binding buffer [20% glycerol, 25 mM Tris-HCl (pH 7.5), 40 mM KCl, 0.5 mM MgCl₂, 0.1 mM EDTA, and 1 mM dithiothreitol], 2 µg of poly(dI-dC), and 1 µg of salmon sperm DNA. DNA-protein complexes were separated by electrophoresis (constant voltage of 300 V) on a 5% nondenaturing polyacrylamide gel in 1x TBE at 4°C. The gel was dried, exposed to X-ray film, and quantified by densitometry. In the competition assay, a 100-fold molar excess of the specific or mutated unlabeled oligonucleotide was preincubated on ice for 1 h with 10 µg of nuclear extract from control mice in the binding buffer before adding the oligonucleotide probe. The following oligonucleotides were used: nuclear receptor response element 1 (NRRE1), 5'-GGGTTTGACCTTTCTCTCCGGGTAAAGGTCAA-3'; estrogen response element consensus, 5'-GAGTTTTTCAAGGTCATGCTCATTT-3' (21). In supershift studies, control nuclear extract was preincubated with 2 µl of ERR- antibody (Affinity BioReagents) for 1 h at room temperature before the addition of the labeled probe.

Measurement of MCAD activity
Briefly, frozen liver samples (50 mg) were homogenized (20%, w/v) in ice-cold buffer containing 100 mM HEPES and 0.1 mM EDTA, pH 7.6, and then centrifuged at 700 g. MCAD activity was determined as described (22) by adding 20 µl of supernatant to 500 µl of reaction mixture containing 100 mM HEPES, pH 7.6, 0.1 mM EDTA, 200 µM ferricenium hexafluorophosphate, 0.5 mM sodium tetrathionate, and 50 µM octanoyl-CoA and incubated at 37°C. The decrease in ferricenium hexafluorophosphate absorption at 300 nm in the presence of supernatant was stable for at least 3 min; the results were calculated from the decrease observed over this period with correction by subtracting the absorbance of a tissue blank measured without the addition of octanoyl-CoA.

Statistical analysis
Data are expressed as means ± SEM of experiments from three to five animals or plates for each group or time point. The difference between two experimental groups was analyzed using Student's t-test. Differences among multiple groups were analyzed using one-way ANOVA with the Bonferroni post hoc test. P < 0.05 was considered significant.

	RESULTS

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION REFERENCES

 
mRNA levels of PGC-1 are decreased during the APR
To determine the effect of LPS on the mRNA levels of PGC-1, mice were administered LPS intraperitoneally and tissues were collected after 16 h. Results from Northern analysis are shown in Fig. 1 and demonstrate that LPS dramatically decreased mRNA levels of PGC-1 in liver, heart, and kidney. These results suggested that during the APR, oxidative metabolism that is dependent on the coactivator function of PGC-1 may be suppressed in these tissues.

View larger version (73K): [in this window] [in a new window]   Fig. 1. mRNA levels of peroxisome proliferator-activated receptor coactivator-1 (PGC-1) are decreased during the acute-phase response (APR). C57BL/6 mice were injected intraperitoneally with either saline or lipopolysaccharide (LPS; 100 µg per mouse), and the animals were euthanized 16 h later. Poly(A)+ RNA was prepared from liver, heart, and kidney, and Northern blot analysis was carried out as described in Methods. GAPDH, 18S, and 36B4 were used as loading controls for the liver, heart, and kidney, respectively. For the liver, there were five control and five LPS animals; for the heart, there were four control and five LPS animals; for the kidney, there were five control and four LPS animals.

mRNA levels of ERR are decreased during the APR

View larger version (23K): [in this window] [in a new window]   Fig. 2. mRNA levels of estrogen-related receptor (ERR) are decreased during the APR. A: mRNA levels of ERR in the liver, heart, and kidney. Poly(A)+ RNA was prepared from liver, heart, and kidney, and Northern blot analysis was carried out as described in Methods. B: Dose response in the liver. C57BL/6 mice were injected intraperitoneally with LPS at various concentrations as indicated, and animals were euthanized 16 h later. C: Time course in the liver. C57BL/6 mice were injected intraperitoneally with either saline or LPS (100 µg of LPS per mouse), and the animals were euthanized at the times indicated after injection. Data (means ± SEM, n = 45) are expressed as a percentage of controls. * P < 0.05 versus control.

View larger version (24K): [in this window] [in a new window]   Fig. 3. mRNA levels of medium-chain acyl-coenzyme A dehydrogenase (MCAD) are decreased during the APR. A: mRNA levels of MCAD in the liver, heart, and kidney. Poly(A)+ RNA was prepared from liver, heart, and kidney, and Northern blot analysis was carried out as described in Methods. B: Dose response in the liver. C57BL/6 mice were injected intraperitoneally with LPS at various concentrations as indicated, and animals were euthanized 16 h later. C: Time course in the liver. C57BL/6 mice were injected intraperitoneally with either saline or LPS (100 µg of LPS per mouse), and the animals were euthanized at the times indicated after injection. Data (means ± SEM, n = 45) are expressed as a percentage of controls. * P < 0.05 versus control.

View larger version (48K): [in this window] [in a new window]   Fig. 4. MCAD activity is decreased during the APR. C57BL/6 mice were injected intraperitoneally with either saline (Control) or LPS (100 µg of LPS per mouse). Four and 16 h later, the animals were euthanized, and hepatic extracts were prepared as described in Methods. Data are means ± SEM of four to five animals for each condition.

Binding activity of hepatic nuclear extracts to ERR response elements is significantly decreased during the APR

View larger version (165K): [in this window] [in a new window]   Fig. 5. Binding activity of hepatic nuclear extract to ERR response elements is significantly decreased during the APR. C57BL/6 mice were injected intraperitoneally with either saline (Control) or LPS (100 µg of LPS per mouse). Sixteen hours later, the animals were euthanized, and hepatic nuclear extracts were prepared as described in Methods. Ten micrograms of nuclear extracts was incubated with radiolabeled oligonucleotides and run on gels. In some experiments, oligonucleotide (oligo) competition was performed. In others, antibody was used to induce shifts. A: Radiolabeled nuclear receptor response element 1 (NRRE1) was used as a binding site for ERR. Arrows indicate the complex between nuclear protein and radiolabeled NRRE1. NS, competition with 100x unlabeled nonspecific DNA; S, competition with 100x unlabeled NRRE1. B: In a similar experiment, the consensus sequence for ERR was used, and specific shifting was similarly shown. The data represent means ± SEM of four to five animals for each condition. C: The consensus sequence for ERR was used as the probe. Antibody specific to ERR was used to induce a supershift, which was not seen with control antibody. RE, response element.

We then identified the binding activity in these extracts as ERR by a supershift experiment (Fig. 5C). Nearly all of the binding was shifted by an antibody to ERR (lane 3 vs. lane 2). In contrast, control antibody produced no significant shift. Hence, the majority of binding in the nuclear extracts is mediated by a complex that includes ERR.

Zymosan and turpentine suppress mRNA levels of PGC-1, ERR, and MCAD
Having found that LPS strongly suppresses the mRNA levels of PGC-1, ERR, and MCAD, we next determined the effect of weak inducers of inflammatory responses, such as zymosan and turpentine, on the hepatic expression of these genes. Whereas zymosan is a fungal product and signals through Toll-like receptor 2, causing systemic inflammation through the induction of TNF and IL-1, turpentine causes localized inflammation mediated by IL-1. As shown in Fig. 6A , zymosan decreased the mRNA levels of PGC-1, ERR, and MCAD by 44–58%. Also, turpentine caused a decrease in the mRNA levels of these genes to a similar extent (Fig. 6B). These data clearly demonstrate that expression of PGC-1, ERR, and MCAD is suppressed during the inflammatory response regardless of the types of inflammation.

View larger version (95K): [in this window] [in a new window]   Fig. 6. mRNA levels of PGC-1, ERR, and MCAD are decreased during zymosan- and turpentine-induced inflammation. A: C57BL/6 mice were injected intraperitoneally with either saline or zymosan (80 mg/kg body weight), and the animals were euthanized 16 h later. B: C57BL/6 mice were injected subcutaneously with either saline or turpentine (100 µl), and the animals were euthanized 16 h later. Poly(A)+ RNA was prepared from liver, heart, and kidney, and Northern blot analysis was carried out as described in Methods.

	DISCUSSION

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION REFERENCES

Because MCAD mediates the initial step in mitochondrial fatty acid oxidation, these findings suggest that suppression of the PGC-1, ERR, and MCAD pathway could contribute to the decreased fatty acid oxidation observed during the APR. The hypertriglyceridemia of the APR is substrate-driven (7), and decreased fatty acid oxidation is one of several mechanisms that could provide increased fatty acid as substrate for VLDL production. Furthermore, the similar suppressive effects shown by zymosan and turpentine strongly indicate that suppression of this pathway is a universal inflammatory response.

The regulation of MCAD expression in vivo may involve not only ERR but also other nuclear hormone receptors. DNase I footprinting assays demonstrate that the NRRE1 site in the MCAD promoter interacts with COUP (23), PPAR (24), RXR/RAR (25), and Hepatocyte Nuclear Factor-4 (HNF-4) (26). Whereas COUP functions as a trans-repressing regulatory element (23), RXR/RAR (25) or PPAR (23) can activate MCAD transcription via an NRRE1 site. Our previous studies found that the expression and activity of RXR/RAR and RXR/PPAR are downregulated during the APR (9). Therefore, it is possible that PPAR, RXR, and other nuclear receptors, in addition to ERR, also play a role in regulating MCAD transcription. Results from the present study provide clear evidence for the downregulation of MCAD and its regulators, providing additional explanation for the altered fatty acid oxidation during the APR. The decrease in fatty acid oxidation, in turn, may contribute to the increase in triglycerides that accompanies the APR and potentially contributes to atherosclerosis.

We also found that the expression of PGC-1 is dramatically decreased in the liver, heart, and kidney. Considering the versatile role that PGC-1 plays (27), a significant decrease in PGC-1 expression could downregulate many biological functions that are important in the normal maintenance of metabolism. Microarray analysis revealed that PGC-1-responsive genes are involved in oxidative phosphorylation and that their expression is downregulated in human diabetes. PGC-1 expression in human diabetes was reported to be decreased by 20% (28). However, in the present study, we report that the mRNA level of PGC-1 was decreased more dramatically, with levels that were barely detectable during the APR. This finding may imply that the disturbances in oxidative metabolism during the APR could be more detrimental. The decrease in fatty acid oxidation in various tissues likely provides fatty acids that contribute to the increase in triglycerides during infection and inflammation (7, 8), which in turn could contribute to the higher incidence of atherosclerosis among patients with infections and inflammatory diseases (7).

Hypertriglyceridemia is one of the components that constitute the metabolic syndrome, which is also associated with an increased risk of developing atherosclerosis (29, 30). Numerous studies have demonstrated that increased levels of the acute-phase protein C-reactive protein and the adipocyte-derived cytokines IL-6 and TNF are found in the metabolic syndrome (31–33). Thus, the metabolic syndrome is also a low-grade inflammatory state, but the underlying mechanisms by which inflammation may be linked to the features of the metabolic syndrome and ultimately the development of atherosclerosis have not been elucidated. The data from our group and others show that the changes in lipid profiles during the APR are similar to those in the metabolic syndrome, including hypertriglyceridemia and decreases in serum HDL cholesterol levels. Likewise, both states have increased mobilization of adipose tissue fatty acids and increased hepatic fatty acid synthesis, coupled with decreased hepatic fatty acid oxidation and ketogenesis (7). Whether the low-grade inflammation seen in the metabolic syndrome contributes to the changes in fatty acid metabolism, hypertriglyceridemia, and insulin resistance remains to be determined.

In summary, decreased fatty acid oxidation that results from the suppression of MCAD, possibly via decreases in PGC-1, PPAR, and ERR, reported herein could explain some of the changes in lipid metabolism that are observed during infection and inflammation.

	ACKNOWLEDGMENTS

 
This work was supported by grants from the Research Service of the Department of Veterans Affairs and by National Institutes of Health Grant AR-39639.

Manuscript received October 19, 2004 and in revised form May 27, 2005.

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