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The Division of Nutritional Sciences and the Institute for Cellular and Molecular Biology, The University of Texas, Austin, TX 78712 and * Division of Life Sciences, Hallym University, Chunchon, 200–702, Korea
2To whom correspondence should be addressed. E-mail: ClarkeSD{at}pbrc.edu.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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KEY WORDS: • sterol regulatory element binding protein • polyunsaturated fatty acids • transcription • liver • rats
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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–5
). PUFA influence these metabolic changes in two ways. First, they induce the transcription of genes encoding proteins involved in lipid oxidation (e.g., carnitine palmitoyltransferase and acyl-CoA oxidase); second, PUFA suppress the expression of genes encoding proteins involved with lipid synthesis [e.g., fatty acid synthase (FAS) and acetyl-CoA carboxylase] (6
–8
). Genes encoding the oxidative enzymes appear to be regulated by a common PUFA-activated transcription factor, peroxisome proliferator-activated receptor 
(9
,10
). On the other hand, the PUFA-induced inhibition of lipogenic gene expression is highly correlated with a reduction in the nuclear content of sterol regulatory element binding protein-1 (SREBP-1) and with a decrease in the transactivation activity of nuclear factor-Y (7
,11
–13
).
The SREBP family of transcription factors consists of three members: 1a, 1c and 2 (14
,15
). SREBP-1c appears to be involved with the regulation of lipogenic gene transcription (e.g., FAS), whereas SREBP-2 appears to be more specific for the activation of genes responsible for cholesterol synthesis [e.g., cytosolic 3-hydroxy-3-methylglutaryl (HMG)-CoA synthase] (14
,15
). In vivo, SREBP-1a constitutes <10% of the hepatic SREBP-1 pool, but in cell lines, SREBP-1a makes up >90% of the SREBP-1 pool (16
–20
). Moreover, SREBP-1a appears to be able to activate both lipogenic and cholesterolgenic genes (15
–17
). SREBP are synthesized as 125-kDa precursor proteins that contain two transmembrane domains for insertion into the endoplasmic reticulum membrane. The N-terminal and carboxy-terminal domains extend into the cytosol (14
,15
). The N-terminal domain, a 68-kDa helix-loop-helix leucine zipper transcription factor (i.e., mature SREBP), is released for nuclear translocation by a two-step proteolytic cascade that takes place in the Golgi (14
). Movement of the SREBP-precursor to the Golgi requires a chaperone protein (SREBP cleavage-activating protein) that is common to all three forms of SREBP (14
,19
). After the proteolytic release of the N-terminal domain, the mature SREBP translocates to the nucleus where it functions as a transactivating factor for select target genes. Dietary (n-6) and (n-3) PUFA, but not saturated or (n-9) unsaturated fatty acids, uniquely reduce the hepatic abundance of SREBP-1c mRNA (7
,18
). However, unlike insulin and carbohydrate, which regulate SREBP-1 mRNA abundance by inducing gene transcription (20
), PUFA decrease the hepatic abundance of SREBP-1c and -1a by accelerating the rate of mRNA decay (7
,18
). Recently, Hannah et al. (19
) reported that fatty acids also reduced the nuclear concentration of SREBP-1 in human embryonic kidney cells by inhibiting the proteolytic release of mature SREBP-1. However, unlike the in vivo situation in which only PUFA reduce the nuclear content of mature SREBP-1 (7
,18
), Hannah and colleagues (19
) found that 16:1(n-9) and 18:1(n-9) were as effective as (n-6) and (n-3) PUFA at inhibiting the events governing the proteolytic release of mature SREBP-1. Thus, the in vivo regulation of SREBP-1 metabolism by fatty acids appears to differ from that of the cell line models. Moreover, it is not known how dietary PUFA lower the nuclear concentration of SREBP-1. For example, do dietary PUFA reduce the size of the SREBP-1 precursor pool; inhibit proteolytic release of mature SREBP-1; or regulate both processes?
Meal-trained rats provide a unique nutritional model in which to explore the mechanisms by which dietary PUFA regulate SREBP-1 and -2 metabolism and expression (21
–24
). Training rats to consume their daily food during a single 3-h meal yields metabolically homogeneous animals, but does not interfere with normal growth and development (21
–24
). Meal-trained rats reach metabolic equilibrium within 90–120 min after the meal has been initiated and this steady-state metabolism and gene expression are maintained for at least an additional 3 h (21
–24
). For example, hepatic malonyl-CoA concentrations increase 10-fold during the first 60 min of meal consumption, and this high level of production is maintained for an additional 3 h (21
,23
). Similarly, hepatic FAS gene expression increases 20-fold within 2 h after the meal begins and this higher rate of gene transcription is maintained for at least 2 h after completion of the 3-h meal (24
). In contrast, rats consuming food ad libitum eat small discrete meals during the customary 12-h dark cycle. Thus, the nutrient intake and absorption pattern for rats consuming food ad libitum vary throughout the feeding cycle, depending upon the eating behavior of individual rats. The outcome of this variation in feeding pattern is that the amplitude of the change in a metabolic variable (e.g., the ratio of precursor to nuclear SREBP-1) may be small, highly variable among animals and reflective of a mixture of signals influenced by eating and food deprivation. In contrast, the metabolically homogeneous state of postmeal rats provides a unique in vivo model in which to evaluate the effect of acute changes in nutrient composition of the meal on metabolic and genomic events governing lipogenesis.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Animal studies were conducted in accordance with the Animal Welfare Act and followed a protocol approved by the Animal Research Center of The University of Texas. The fat-free, high carbohydrate diet was purchased from Dyets (Bethlehem, PA), and formulated according to AIN-93-G diet (25
). Sterol-free fish oil [35% 20:5 and 22:6(n-3)] and safflower oil [65% 18:2(n-6)], and the fat-free diet were purchased from Dyets. Triolein [99% 18:1(n-9)] and chemicals were purchased from Sigma Chemical (St. Louis, MO). Male Sprague-Dawley (130–150 g) rats were purchased from Harlan Sprague Dawley (Indianapolis, IN). Nitrocellulose and the Zeta Probe were purchased from Bio-Rad Laboratories (Hercules, CA). Chemiluminescence detection kits were purchased from Amersham Pharmacia (Piscataway, NJ). Anti-SREBP-1 (immunoglobulin G-2A4) was prepared from hybridoma cells purchased from ATTCC (Rockville, MD). Anti-SREBP-2 and a cDNA specific for SREBP-2 were generously provided by M. Brown and J. Goldstein (UT-Southwestern Medical School, Dallas, TX). The [-32P]-dCTP and [-32P]-UTP were purchased from NEN Life Science (Boston, MA). The RPA III RNA protection assay kits were purchased from Ambion (Austin, TX). Random priming kits for labeling cDNA probes were purchased from Life Technologies (Rockville, MD).
Dietary protocol.
Male Sprague-Dawley rats were trained to eat the high carbohydrate fat-free diet in a single daily 3-h period (0900–1200 h) (21
–24
). After a 7-d adaptation period, rats (n = 4) were blocked according to body weight. The "premeal" rats described in Figure 1
were killed before the beginning of meal 8, and "postmeal" rats were killed exactly 3 h after starting meal 8. At this point in the meal, maximal levels of malonyl-CoA, and rates of fatty acid biosynthesis and FAS gene transcription have been achieved; these rates are preserved for at least 2 h after ending the meal (21
,23
,24
). Fats were supplemented (10 g/100 g fat-free diet) for 1 (meal 8), 2 (meal 9) and 5 (meal 13) d.
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Nuclear and microsomal membrane proteins were isolated from freshly removed liver (7
,26
). To prevent proteolysis of precursor and mature SREBP-1 and -2, all buffers contained 50 mg/L N-acetylleucylleucylnorleucinal, 24 mg/L pefabloc, 5 mg/L pepstatin A, 10 mg/L leupeptin and 2 mg/L aprotinin. Briefly, liver was homogenized in a 30 mL buffer containing 10 mmol/L Hepes (pH 7.6), 25 mmol/L KCl, 1 mmol/L sodium EDTA, 2 mol/L sucrose, 1 mol/L glycerol, 0.15 mmol/L spermine, 2 mmol/L spermidine and protease inhibitors. The homogenate was layered over a 10-mL cushion of the described buffer and was centrifuged in SW-27 rotor (Beckman, Palo Alto, CA) at 75,000 x g for 1 h (4°C). The resulting pellet was suspended in 1 mL buffer comprised of 10 mmol/L Hepes, pH 7.6, 100 mmol/L KCl, 2 mmol/L MgCl2, 1 mmol/L EDTA, 1 mmol/L dithiothreitol, 1 mol/L glycerol and protease inhibitors. After addition of ammonium sulfate (4 mol/L, pH 7.9), the suspension was centrifuged at 257,000 x g for 45 min (4°C). The resulting supernatant was collected as nuclear protein extract. For membrane protein extraction, liver was homogenized in 20 mmol/L Tris/HCl, pH 8, 150 mmol/L NaCl, 1 mmol/L CaCl2 plus protease inhibitors. The homogenate was centrifuged at 800 x g, 10 min at 4°C. Microsomal membranes were collected by centrifuging the 800 x g supernatant for 1 h at 100,000 x g, 4°C (SW55 rotor, Beckman). The pellet was briefly rinsed with homogenization buffer, and subsequently suspended in 1.5 mL of 250 mmol/L Tris/HCl (pH 6), 2 mmol/L CaCl2 plus protease inhibitors. Membrane proteins were extracted from the 100,000 x g pellet by adding an equal volume of 2 mmol/L CaCl2, 320 mmol/L NaCl, Triton X-100 (2 g/100 g) and protease inhibitors to the membrane pellet, mixing and subsequently centrifuging 45 min, 100,000 x g (4°C). The abundance of SREBP-1 and -2 proteins was determined by Western blotting (40 µg protein/lane). It should be noted that the availability of anti-SREBP-2 was extremely limited and prevented us from quantifying SREBP-2 protein abundance on individual rats within the 0, 1 and 2 meal groups. Consequently, we measured the abundance of SREBP-2 protein after 0, 1 and 2 meals of fish oil using a pooled protein sample that included equal amounts of protein extracted from each of the four rats within the 0, 1 and 2 meal groups, respectively. Values for SREBP-2 protein abundance after meal 5 are based upon individual measures of n = 4/dietary treatment. The abundance of each protein was quantified by integrating each protein band using visual imaging and data are expressed as relative integrated units.
Total RNA was extracted from frozen liver using the phenol-guanidinium isothiocyanate procedure (27
). The abundance of hepatic transcripts for SREBP-1, SREBP-2, FAS, HMG-CoA synthase and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) was determined by Northern analysis. Total RNA (30 µg) was size-fractionated on a 1% agarose/formaldehyde denaturing gel, and subsequently transferred to a Zeta Probe nylon membrane (7
). Transcript abundance was measured by hybridization with [-32P]dCTP-labeled random prime cDNA probes specific for each transcript. The abundance of the respective transcripts was quantified using radioimaging, and expressing data as dpm x 103/transcript. The effect of 5 meals of PUFA on the abundance of SREBP-1c and -1a was determined using the ribonuclease protection assay (18
). Antisense probes were transcribed using bacteriophage T3 RNA polymerase. The probes were radiolabeled with [-32P]UTP and possessed specific activities of 5–8 x 108 dpm/µg for SREBP-1 and 4–10 x 103 dpm/µg for 18S RNA. Hybridization was conducted by incubating 10 µg total RNA with at least a fourfold molar excess of probe at 56°C overnight. After RNase A/T1 digestion, the protected fragments were separated on a 8 mol/L urea/5% polyacrylamide gel. The abundance of each transcript was quantified using radioimaging. The relative level of SREBP-1a and -1c mRNA was compared upon correcting for the number of 32P-labeled UTP atoms in each protected fragment.
Statistics.
The effect of meal ingestion (Fig. 1)
and the effect of fish oil supplementation for 1 and 2 meals (Figs. 2
, 4)
were evaluated using pooled t tests and one-tail tests of significance. The means in the fish oil groups were compared to those in rats fed the high carbohydrate, fat-free diet for an equivalent number of meals. Gene expression in the rats fed the fat-free diet was not different after 7, 8 or 9 meals. The effect of type of fat (Figs. 3
, 5)
was evaluated using one-way ANOVA; means were ranked using least-square differences. Means were considered significantly different at P < 0.05.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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The hepatic abundance of membrane-anchored (precursor) and nuclear (mature) SREBP-1 increased several fold 3 h after the rats began ingesting a high glucose meal, but by the start of the next meal, the hepatic concentration of precursor and mature SREBP-1 had fallen to barely detectable levels (Fig. 1
A). Before consumption of the high glucose meal, nearly all of the hepatic SREBP-1 was associated with the membrane-anchored precursor pool, but immediately after consumption of the high glucose meal, 70% of the SREBP-1 protein was located in the nuclear compartment (Fig. 1
A). The rise and fall in total hepatic SREBP-1 protein (i.e., precursor plus nuclear) that occurs with meal-feeding was paralleled by comparable changes in SREBP-1 mRNA (Fig. 1
B). In addition, the large increase in nuclear concentration of SREBP-1 resulting from the consumption of the fat-free, high glucose meal was accompanied by an enhanced expression of the SREBP-1 target gene, FAS, and by an increase in the expression of the insulin target gene, GAPDH (Fig. 1
B). On the other hand, consumption of the high glucose meal suppressed (P < 0.05) the expression of hepatic carnitine palmitoyltransferase-1, an enzyme that catalyzes a rate-limiting step in fatty acid oxidation (Fig. 1
B). Meal consumption also increased (P < 0.05) the total amount of hepatic SREBP-2 (precursor plus nuclear). Moreover, the amount of SREBP-2 located in the nucleus rose ninefold (P < 0.05), and the distribution of hepatic SREBP-2 between the nuclear compartment and the membrane-anchored pool shifted from a the ratio of 1:3 before consumption of the high glucose meal to 5:1 after ingestion of the high glucose meal (Fig. 1
A).
The time course for dietary PUFA suppression of hepatic SREBP-1 expression.
Having established the influence of meal ingestion on the pattern of change for precursor and nuclear pools of SREBP-1 and -2 (Fig. 1)
, our second objective was to employ the meal-feeding model in a study that determined whether PUFA supplementation to the high glucose, fat-free meal modified the increase in precursor and mature SREBP-1 and -2 proteins, and/or the abundance of SREBP-1 and -2 mRNA that resulted from consumption of the fat-free meal. Supplementing the high glucose, fat-free diet with 10 g/100 g fish oil for a single meal (i.e., 3 h) decreased (P < 0.05) the nuclear content of SREBP-1 protein, but the amount of membrane-anchored precursor SREBP-1 and the abundance of SREBP-1 mRNA were not reduced (Fig. 2
). Consumption of a second meal of fish oil reduced the nuclear content of SREBP-1 protein even further, but again the size of the SREBP-1 precursor pool was not different from that in the rats fed the high glucose diet (Fig. 2
A). The 50 and 84% reductions in nuclear content of SREBP-1 protein observed after 1 and 2 meals of fish oil supplementation were accompanied by 63 and 87% decreases in the expression of the SREBP-1 target gene, FAS (Fig. 2
B). On the other hand, fish oil ingestion had no effect on the expression of the insulin-dependent gene, GAPDH, which is consistent with our earlier observations indicating that PUFA do not interfere with the insulin-signaling cascade (8
,28
). Even though supplementing the high glucose diet with fish oil for 1 or 2 meals did not interfere with the meal-induced accumulation of SREBP-1 precursor protein, the abundance of hepatic SREBP-1 mRNA in rats fed 2 meals of fish oil was only 27% (P < 0.05) of that in the livers of rats fed the fat-free diet (Fig. 2)
. Apparently, this reduced amount of SREBP-1 mRNA was sufficient to sustain the synthesis of precursor SREBP-1 and consequently maintain the SREBP-1 precursor pool size. We have previously reported that the abundance of hepatic SREBP-1 mRNA, as well as the level of precursor and nuclear SREBP-1 protein, are all suppressed after the consumption of 10 meals of PUFA (7
). The data of Figures 2
and 3
indicate that the time for consumption of 2 meals of PUFA was not sufficient to achieve a lower steady state for all variables, but the lower steady-state condition for SREBP-1 mRNA as well as precursor and mature SREBP-1 was complete after the consumption of 5 meals of (n-6) or (n-3) PUFA (Fig. 3)
. It should be noted that dietary 18:1(n-9) had no effect on the hepatic abundance of SREBP-1c or -1a mRNA. Moreover, dietary 18:1(n-9) did not reduce the size of the precursor and nuclear pools of SREBP-1 (Fig. 3)
.
The influence of dietary PUFA on hepatic SREBP-2 expression.
The response of hepatic SREBP-2 to dietary PUFA was very different from that of SREBP-1 (Figs. 4
, 5
). Specifically, the abundance of SREBP-2 precursor protein and the level of SREBP-2 mRNA were unaffected by the ingestion of 1, 2 or 5 meals of PUFA (Figs. 4
, 5)
. However, the ingestion of a single meal of fish oil was associated with a 42% reduction in the nuclear content of mature SERBP-2 protein, and this was accompanied by a decrease (P < 0.05) in the mRNA abundance of the SREBP-2 target gene, HMG-CoA synthase (Fig. 4)
. Interestingly, the nuclear level of SREBP-2 and the abundance of HMG-CoA synthase mRNA were not reduced by the ingestion of 2 meals of fish oil. Moreover, the consumption of 5 meals of PUFA as either safflower oil [75% 18:2(n-6)] or fish oil [40% 20:5 and 22:6(n-3)] actually increased the size of the nuclear SREBP-2 protein pool two- to threefold (P < 0.05) (Fig. 5)
. The PUFA-dependent enrichment of the nucleus with SREBP-2 was paralleled by a rise in the HMG-CoA synthase mRNA (Fig. 5)
; but as with SREBP-1, the expression of SREBP-2 and particularly the amount of SREBP-2 in the nucleus was not affected by the consumption of 18:1(n-9) (Fig. 5)
.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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,14
,15
,29
). Recently, we found that the inhibition of lipogenic gene transcription resulting from PUFA ingestion was associated with a 65–85% reduction in the nuclear content of mature SREBP-1 (7
). This effect was specific for (n-6) and (n-3) fatty acids and could not be mimicked by oleic acid [18:1 (n-9)] or saturated fatty acids (7
). In this report, we demonstrate that PUFA lower the steady-state levels of mature and precursor SREBP-1 protein, and the abundance of SREBP-1 mRNA in three temporal stages. Moreover, we show that the PUFA regulation of SREBP-2 is distinctly different from that of SREBP-1 (Fig. 6
). The first stage of PUFA control involves an immediate (<3 h) decrease in the nuclear abundance of mature SREBP-1 and -2 which is paralleled by a reduction in the transcription of the SREBP-1 and -2 target genes, FAS and HMG-CoA synthase, respectively. Accelerated nuclear decay of mature SREBP-1 or -2 does not appear to explain the depletion of these two transcription factors from the nuclear compartment (19
,29
). Moreover, the decrease in mature SREBP-1 and -2 was not associated with a reduction in the amount of precursor SREBP-1 or -2 (Fig. 6)
. This latter observation strongly suggests that PUFA suppress the proteolytic processes governing the release of mature SREBP-1 and -2 from their respective membrane-anchored precursors. How PUFA regulate the proteolytic release of mature SREBP from their precursors remains unclear. In Drosophila, phosphatidylethanolamine synthesis is required for the fatty acid-induced inhibition of the proteolytic release of SREBP (30
). Recently, Worgall et al. (31
) reported that ceramide release from sphingomyelin was an essential step in oleic acid’s inhibition of the proteolytic release of SREBP-1 and -2 in Chinese hamster ovary cells. However, unlike the intact animal, neither of these models displayed a selective response to (n-6) and (n-3) PUFA. In fact, suppression of SREBP release in Drosophila was specific for saturated fatty acids, whereas PUFA were not inhibitory. Nevertheless, these observations suggest that the regulation of the proteolytic events governing the nuclear concentration of SREBP-1 and -2 may involve some type of phospholipid signaling mechanism, but the nature of this signal may be unique to the intact animal and distinctly different from those operating in cell lines.
|
. The PUFA-dependent reduction in hepatic SREBP-1 mRNA was not due to an inhibition of gene transcription; rather, it reflected an accelerated rate of SREBP-1a and -1c mRNA decay (7
,18
). In contrast to our in vivo studies (7
,18
), work with rat hepatoma cells suggests that fatty acids suppress SREBP-1 gene transcription by functioning as competitive ligand antagonists for the liver X receptor (32
,33
). However, like the effect of fatty acids on the proteolytic release of mature SREBP-1, the fatty acid-induced inhibition of SREBP-1 gene transcription in hepatoma cells was not unique to PUFA. In fact, 18:0 and 18:1(n-9), which have no in vivo inhibitory activity, both suppressed SREBP-1 gene transcription in the hepatoma cells. The failure of immortalized cells to fully replicate the regulatory mechanisms of the intact animals is a common feature in the study of nutrient-gene interactions, and suggests that dietary PUFA modulate a signaling pathway that is unique to the in vivo situation.
The third stage of PUFA regulation, which required >48 h of PUFA consumption, included two notable features, i.e., a 50% decrease in the size of the precursor pool for SREBP-1 and a 250% increase in the nuclear content of mature SREBP-2 that was paralleled by a 2.5-fold increase in the expression of the SREBP-2 target gene, HMG-CoA synthase (Fig. 6)
. As might be expected, the reduction in the amount of precursor SREBP-1 was preceded by a decrease in the abundance of SREBP-1 mRNA. However, the reciprocal changes in nuclear content of SREBP-1 and -2 that resulted from PUFA ingestion present an interesting mechanistic dilemma because the processes releasing mature SREBP-1 and -2 are reportedly the same for both precursor proteins. Precursor SREBP-1 and -2 are both associated with the endoplasmic reticulum, and they both require the same SREBP cleavage-activating protein for movement to the Golgi, and they utilize the same two Golgi proteases for the release of mature SREBP-1 and -2 (14
,15
,19
,34
). One possible explanation for these divergent responses is that the interaction of SREBP-1 with SREBP cleavage-activating protein and its subsequent movement to the Golgi may be more sensitive to (n-6) and (n-3) fatty acid enrichment of the phospholipids of the endoplasmic reticulum, whereas the shuttling of SREBP-2 from the endoplasmic reticulum to the Golgi for protease attack may be more sensitive to depletion of cholesterol from the endoplasmic reticulum membrane resulting from a PUFA enhancement of bile acid production (35
). In support of this hypothesis, Shimomura et al. (29
) found that feeding hamsters an inhibitor of cholesterol synthesis combined with a bile acid sequestrant depleted the liver of cholesterol, and that this was associated with concomitant increase in nuclear SREBP-2, and a reciprocal decrease in SREBP-1c.
In summary, in vivo data have been presented that reveal the complexity and multifaceted nature of the dietary PUFA regulation of SREBP-1 and SREBP-2, and hence the control of lipogenic and cholesterolgenic gene expression. In particular, our data demonstrate that the mechanisms governing SREBP metabolism in the intact animal differ from those of cell line models, and are unique to (n-6) and (n-3) PUFA. In addition, the observations that PUFA increase the nuclear content of SREBP-2 and the expression of the cholesterolgenic gene, HMG-CoA synthase, whereas they concomitantly suppress the hepatic abundance of SREBP-1 and consequently the expression of lipogenic genes, challenge the contention that sterols and fatty acids up- and down-regulate the expression of cholesterolgenic and lipogenic genes by the same mechanisms (36
).
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FOOTNOTES |
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3 Abbreviations used: FAS, fatty acid synthase; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; HMG, 3-hydroxy-3-methylglutaryl; PUFA, polyunsaturated fatty acids; SREBP, sterol regulatory element binding protein.
Manuscript received 20 May 2002. Initial review completed 20 June 2002. Revision accepted 19 August 2002.
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LITERATURE CITED |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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