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PHYSIOLOGY, ENDOCRINOLOGY, AND REPRODUCTION |
Institute of Agricultural and Nutritional Sciences, Martin-Luther-University Halle-Wittenberg, D-06108 Halle (Saale), Germany
1 Corresponding author: klaus.eder{at}landw.uni-halle.de
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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(PPAR) has been shown in liver of chicks, but effects of its activation have not yet been investigated. In this study, laying hens were treated with clofibrate, a synthetic PPAR agonist, to investigate the effects of PPAR activation on liver lipid metabolism. Hens receiving a diet containing 5 g of clofibrate/kg had a lower food intake and higher liver mRNA concentrations of typical PPAR target genes (carnitine palmitoyltransferase 1A, acyl-coenzyme A oxidase, bifunctional enzyme, lipoprotein lipase) involved in hepatic mitochondrial and peroxisomal ß-oxidation and plasma triglyceride clearance than control hens that received the same diet without clofibrate (P < 0.05). Hens treated with clofibrate also had lower mRNA concentrations of fatty acid synthase, 3-hydroxy-3-methylglutaryl-coenzyme A reductase, and low-density lipoprotein receptor, proteins involved in fatty acid biosynthesis and cholesterol biosynthesis and uptake, than hens fed the control diet (P < 0.05). These changes in clofibrate-treated hens were accompanied by reduced liver triglyceride concentrations, strongly diminished very low density triglyceride and cholesterol concentrations (P < 0.05), a disturbed maturation of egg follicles, a complete stop of egg production, and a markedly reduced plasma 17-ß-estradiol concentration (P < 0.05). In conclusion, it is shown that clofibrate has complex effects on hepatic lipid metabolism in laying hens that mimic PPAR activation in mammals, affect maturation of egg follicles, and lead to a stop of egg production. Because clofibrate treatment strongly reduced food intake in the hens, some of these effects (i.e., egg production) may have been due to a low energy and nutrient intake.
Key Words: peroxisome proliferator-activated receptor- • clofibrate • laying hen • triglyceride • cholesterol
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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is a member of the nuclear receptor superfamily. In mammals, it is highly expressed in tissues with high fatty acid oxidation such as liver or muscle (Desvergne and Wahli, 1999). Peroxisome proliferator-activated receptor- regulates the expression of target genes by binding to DNA sequence elements as heterodimers with the 9-cis retinoic acid receptor after activation. Peroxisome proliferator-activated receptor- target genes are mainly involved in cellular fatty acid uptake and intracellular fatty acid transport, mitochondrial and peroxisomal fatty acid oxidation, ketogenesis, and gluconeogenesis (Mandard et al., 2004). Peroxisome proliferator-activated receptor- is activated by lipid soluble compounds such as eicosanoids, fatty acids, or fibrates (Desvergne and Wahli, 1999). Recently, it has been shown that activation of PPAR does not only stimulate catabolism of fatty acids but also affects synthesis of triglycerides and cholesterol by interacting with gene expression and proteolytic activation of sterol regulatory element-binding proteins (SREBP), transcription factors that have been identified and recognized as key regulators of lipid synthesis and homeostasis (Patel et al., 2001; Guo et al., 2005; Knight et al., 2005; König et al., 2007). It has been found that SREBP-1c preferentially activates genes required for fatty acid synthesis, whereas SREBP-2 preferentially activates the low-density lipoprotein (LDL) receptor gene and various genes required for cholesterol synthesis such as 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase (Horton et al., 2002). Sterol regulatory element-binding proteins are synthesized as inactive integral endoplasmic reticulum membrane proteins and are activated by proteolytic cleavages in the Golgi, releasing the mature N-terminal domain of SREBP that then translocates to the nucleus and activates transcription of sterol regulatory element-containing genes (Horton et al., 2002). Compared with mammals, laying hens have a very high rate of hepatic synthesis of triglycerides, phospholipids, and cholesterol, which plays a crucial role in lipid deposition in egg yolk (Walzem et al., 1999). Hepatic triglyceride and phospholipid synthesis in birds is strongly stimulated in bird liver by estrogens that are formed in theca cells of small white follicles (Kudzma et al., 1975; Dashti et al., 1983). Lipids synthesized in the liver are incorporated into triglyceride-rich lipoproteins that are secreted into the blood. Plasma of laying hens therefore contains extremely high concentrations of triglycerides, most of which are localized in very LDL (VLDL; Hermier et al., 1989). Very LDL with a particle diameter of 25 to 44 nm are bound to specific oocyte receptors and are deposited in developing egg yolk follicles (Walzem et al., 1999).
It has been recently shown that chick liver also expresses PPAR which has a high homology with mouse, rat, and human PPAR (Diot and Douaire, 1999; Meng et al., 2005). However, the function of PPAR in laying hens has not yet been elucidated. If activation of PPAR has similar effects on hepatic gene expression as observed in mammals, we expect that it stimulates ß-oxidation of fatty acids in the liver and lowers hepatic and plasma triglyceride concentrations, which in turn may affect lipid deposition into egg follicles. Because estrogens are produced in theca cells of small white follicles (Robinson and Etches, 1986), an inhibition of follicle maturation could also affect formation of estrogens.
The aim of this study was therefore to investigate the effect of a synthetic PPAR agonist on the lipid metabolism of laying hens. We focused our analyses mainly on lipid concentrations of liver and plasma and on hepatic expression of genes that were shown in rat studies to be upregulated by PPAR activation. These included carnitine palmitoyltransferase-1A (CPT-1A), acyl-coenzyme A oxidase (ACO), bifunctional enzyme, all genes involved in mitochondrial or peroxisomal ß-oxidation, and lipoprotein lipase (LPL), the key enzyme of plasma triglyceride clearance (Mandard et al., 2004). Recently, it has been shown that chick liver also expresses SREBP-1 and -2 (Gondret et al., 2001; Assaf et al., 2003). To find out whether there is also a functional link between PPAR and SREBP, we also determined gene expression of insulin-induced genes (Insig), SREBPs, and the important SREBP target genes involved in fatty acid synthesis [fatty acid synthase (FAS)] and cholesterol synthesis and uptake (HMG-CoA reductase, LDL receptor). Due to the close relationship between hepatic lipid metabolism and deposition of lipids in egg yolk via VLDL, we also determined amounts of triglycerides and cholesterol in egg yolks.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The hens were kept 1 bird per cage in an environmentally controlled room at 18°C. The room was lit for 14 h daily at an intensity of 20 to 30 lx. Feed and water (via nipple drinkers) were available ad libitum. The experiment was conducted over a 5-wk period. All procedures followed established guidelines for the care and handling of animals and were approved by the veterinary council of Saxony-Anhalt. The following data were recorded: BW at the start and end of the experiment, weekly food intake, and number of eggs daily.
Sample Collection
At the end of each week, a blood sample was drawn from the jugular vein of each hen (after fasting for 7 h). To determine egg yolk weight and concentrations of yolk lipids and fatty acid composition, 2 eggs from each hen were sampled at the end of wk 2. Eggs were cooked in water for 10 min. After the end of wk 5, overnight-fasted hens were anesthetized and then decapitated. Blood was collected in heparinized tubes; plasma was separated by centrifugation at 1,500 x g for 10 min at 4°C. Liver was excised, weighed, and immediately snap-frozen in liquid N. Aliquots of liver for RNA isolation were stored at –80°C; other samples were stored at –20°C. From few hens of each group, 1 ovary was excised and photographed. To separate VLDL from the remaining lipoproteins, plasma density was adjusted by NaCl and KBr to 
= 1.022 kg/L as a density cut proposed by Rodriguez-Vico et al. (1992) for chick VLDL. After ultracentrifugation at 900,000 x g at 4°C for 1.5 h, VLDL were removed by suction.
Determination of Lipids in Plasma, Lipoproteins, and Egg Yolk
Lipids from liver and cooked egg yolks were extracted with a mixture of n-hexane and isopropanol (3:2, vol/vol; Hara and Radin, 1978). For determination of the concentrations of lipids in liver and egg yolks, aliquots of the lipid extracts were dried, and the lipids were dissolved using Triton X-100 (De Hoff et al., 1978). Concentrations of triglycerides and cholesterol in plasma and lipoproteins and those of liver and egg yolk were determined using enzymatic reagent kits (1.14830, 1.14856, VWR International, Darmstadt, Germany). The fatty acid composition of egg yolk total lipids was determined by gas chromatography of fatty acid methyl esters that were prepared by methylation with trimethylsulfonium hydroxide (Brandsch et al., 2002).
Determination of Plasma 17-ß-Estradiol Concentration
Concentration of 17-ß-estradiol in plasma was determined with an ELISA (RE 52041, IBL GmbH, Hamburg, Germany).
Reverse Transcription-PCR Analysis
Total RNA was isolated from livers by Trizol reagent (Sigma-Aldrich, Steinheim, Germany) according to the protocol of the manufacturer. Complementary DNA synthesis was carried out as described (König and Eder, 2006). The mRNA concentration of genes was measured by real-time detection PCR using SYBR Green I and the RotorGene 2000 system (Corbett Research, Mortlake, Australia). Real-time detection PCR was performed with 1.25 U of Taq DNA polymerase (Promega, Mannheim, Germany), 500 µM deoxyribonucleotide triphosphate, and 26.7 pmol of the specific primers (Operon Biotechnologies, Cologne, Germany; Table 1
). For determination of mRNA concentration, a threshold cycle and amplification efficiency were obtained from each amplification curve using the software RotorGene 4.6 (Corbett Research). Calculation of the relative mRNA concentration was made using the 
threshold cycle method as previously described (Pfaffl, 2001). The housekeeping gene ß-actin was used for normalization.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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). Hens fed the diet supplemented with clofibrate consumed less feed during the whole feeding period than hens of the control group (P < 0.05, Table 2). Moreover, food intake in the group treated with clofibrate showed a large variation among the individual hens. It ranged from 945 g during the experiment in the hen with the lowest food intake to 2,975 g in that with the highest intake. Due to the low food intake, hens treated with clofibrate lost BW markedly during the 5-wk feeding period (Table 2). Within the group of hens treated with clofibrate, there was a positive linear correlation between final BW and food intake during the experimental period (R2 = 0.58, P < 0.05). Therefore, final BW was lower in hens treated with clofibrate than in control hens (P < 0.05, Table 2). Egg production in the control group was at a normal level during the whole experimental period. In contrast, egg production in the group treated with clofibrate was even reduced in the first week of treatment (Table 2). At wk 2, most hens completely stopped production of eggs. Within the group of hens treated with clofibrate, there was a positive linear correlation between egg production and food intake during the experimental period (R2 = 0.71, P < 0.05, Figure 1).
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). Already after 1 wk of treatment, hens treated with clofibrate had much lower concentrations of triglycerides in plasma than hens of the control group (P < 0.05, Figure 3). During the second week of treatment, plasma triglycerides in hens treated with clofibrate declined further and stayed at values below 1 mmol/L for the remaining feeding period (Figure 3). At wk 5, hens treated with clofibrate also had a strongly reduced concentration of triglycerides in VLDL compared with control hens (0.13 ± 0.14 vs. 8.52 ± 2.45 mmol/L, P < 0.05). Liver weight and hepatic triglyceride concentrations were also significantly lower in hens treated with clofibrate than in control hens (P < 0.05), whereas relative liver weight did not differ between both groups (Table 3). Within the group of hens treated with clofibrate, there was a positive linear correlation between liver weight and food intake during the experimental period (R2 = 0.63, P < 0.05). Liver triglyceride concentration, plasma triglyceride concentrations from wk 1 to 5, and VLDL triglyceride concentration did not show any significant correlation with food intake in the group of hens treated with clofibrate (P > 0.05).
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Weights of Egg Yolks, Concentrations of Triglycerides and Cholesterol in Egg Yolk, and Fatty Acid Composition of Egg Yolk Total Lipids
Eggs sampled from hens treated with clofibrate at wk 2 did not differ in yolk weights and concentrations of triglycerides and cholesterol in yolk from eggs of control hens (Table 3). Eggs of control hens and those of hens treated with clofibrate did not show significant differences in their yolk fatty acid composition. Amounts of fatty acids in yolk total lipids in average of both groups were as follows (g/100 g of total fatty acids): 14:0, 0.25 ± 0.03; 16:0, 24.0 ± 1.2; 16:1 (n-9), 0.76 ± 0.13; 16:1 (n-9), 1.88 ± 0.17; 18:0, 9.53 ± 0.61; 18:1 (n-9), 40.2 ± 0.9; 18:2 (n-6), 16.8 ± 0.9; 18:3 (n-3), 0.18 ± 0.02; 20:4 (n-6), 2.24 ± 0.16; 22:4 (n-6), 0.22 ± 0.04; 22:5 (n-6), 0.53 ± 0.05; and 22:6 (n-3), 0.45 ± 0.05.
mRNA Concentrations of Genes Involved in Hepatic Fatty Acid and Cholesterol Metabolism
Peroxisome proliferator-activated receptor- mRNA was detected in the liver of laying hens by reverse transcription-PCR, and its concentration did not differ between both groups of hens (Figure 4). Also, all other genes to be analyzed were well expressed in the liver according to reverse transcription-PCR data, with the only exception of LPL, which was weakly expressed in the liver of control hens. Hens treated with clofibrate had higher relative mRNA concentrations of ACO, CPT-1A, bifunctional enzyme, LPL, and hepatic lipase in the liver (Figure 4) and lower mRNA concentrations of Insig-1, SREBP-2, FAS, LDL receptor, and HMG-CoA reductase (Figure 5) than hens fed control diet (P < 0.05). Hepatic mRNA concentrations of Insig-2 and SREBP-1 did not differ between both groups of hens (Figure 5). In the groups of hens treated with clofibrate, there was a positive correlation between mRNA concentration of bifunctional enzyme in the liver and food intake during the experimental period (R2 = 0.75, P < 0.05). The mRNA concentrations of all the other genes determined did not show significant correlations with food intake within the group of hens treated with clofibrate.
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). In the plasma of hens treated with clofibrate, 17-ß-estradiol concentration further declined until the end of the experiment, whereas it remained on a constant level during the whole experiment in control hens (Figure 6). At the end of the experiment (wk 5), plasma 17-ß-estradiol concentration was about 70% lower in hens treated with clofibrate than in control hens (P < 0.05, Figure 6). In the group of hens treated with clofibrate, concentration of 17-ß-estradiol at wks 1, 2, or 5, respectively, did not show any significant correlation with food intake (P > 0.05).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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agonist. It is shown that clofibrate treatment of hens caused a strong depression of food intake, BW loss, a decline in plasma estrogen concentration, a strong reduction of plasma triglycerides, and a complete stop of egg production. Detection of PPAR mRNA in the liver of hens confirmed recent findings that showed the expression of this transcription factor in chick liver (Diot and Douaire, 1999; Meng et al., 2005). Gene expression analyses in the liver demonstrated that clofibrate treatment upregulated ACO, CPT-1A, bifunctional enzyme, and LPL. In mammals, all of these enzymes have a PPAR response element in their promoter regions. Their transcription is stimulated by the binding of the PPAR-retinoid X receptor heterodimer, formed by activation of PPAR, to the PPAR response element (reviewed in Mandard et al., 2004). The finding that the same enzymes are upregulated by clofibrate treatment in hens suggests that the avian form of these enzymes also contains PPAR response elements in their promoter regions. In mammals, LPL is expressed predominantly in adipose tissue and skeletal muscle and in the liver of newborn animals (reviewed in Merkel et al., 2006). In adult animals, LPL expression in the liver can be induced by activation of PPAR (Schoonjans et al., 1996). This is consistent with our data showing that LPL, which was weakly expressed in the liver of control hens, was strongly upregulated upon clofibrate treatment. In our study, PPAR mRNA concentration in the liver was not increased by clofibrate treatment. A functional PPAR response element has been identified in the human PPAR promoter (Pineda Torra et al., 2002). Nevertheless, in agreement with our study, several other studies have shown that PPAR activation does not necessarily upregulate expression of PPAR (Ribas et al., 2005; Morimura et al., 2006; König et al., 2007).
One finding of this study was that clofibrate treatment caused a strong reduction of food intake already in the first week of treatment. This finding agrees with a recent study by Fu et al. (2003) that showed that treatment of mice with various PPAR agonists reduces food intake and lowers BW compared with control mice. The finding that this effect does not occur in PPAR-null mice strongly suggests that this effect is due to PPAR activation. The molecular mechanisms underlying the appetite-suppressing effect of PPAR agonists have not been completely elucidated (Lo Verme et al., 2005). Nevertheless, these studies in mice suggest that the reduction of food intake by clofibrate in hens, leading to a strong reduction of BW during the experimental period, may have also been induced by PPAR activation.
Another impressing effect observed in this study was that clofibrate strongly reduced triglyceride concentration in liver, plasma, and VLDL. Hepatic gene expression analysis strongly suggests that these effects are at least in part due to increased hepatic mitochondrial and peroxisomal ß-oxidation (as shown by increased mRNA concentrations of CPT-1A, bifunctional enzyme, and ACO). Markedly reduced plasma triglyceride concentrations may also be due to an increased expression of LPL, the key enzyme of clearance of plasma triglycerides, and hepatic lipase, which hydrolyzes triglycerides and phospholipids in chylomicron remnants, intermediate and high density lipoproteins (Santamarina-Fojo et al., 2004). Because enzymes involved in ß-oxidation as well as LPL are target genes of PPAR, upregulation of these enzymes might be mediated by PPAR activation. It is well known that nonesterified fatty acids released from adipose tissue are also able to bind to and activate PPAR (Kersten et al., 1999). Because hens treated with clofibrate had a strongly negative energy balance, it is likely that they had increased concentrations of nonesterified fatty acids in plasma that were released from adipose tissue. Therefore, the possibility existed that plasma nonesterified fatty acids contributed to PPAR activation in hens treated with clofibrate. The finding that mRNA concentrations of PPAR target genes were not inversely correlated with food intake, however, suggests that nonesterified fatty acids released from adipose tissue due to negative energy balance did not play a significant role for PPAR activation in the liver. Interestingly, mRNA concentration of bifunctional enzyme, one of the PPAR target genes, was even positively correlated with food intake. We assume that hens with a low food intake had a lower upregulation of that enzyme than hens with a higher food intake, because they took in less clofibrate. Because there were no correlations between food intake and mRNA concentrations of all the other PPAR target genes, we assume that the amount of clofibrate consumed by the hens with the lowest food intake was already sufficient to induce maximum upregulation of these genes.
As indicated by reduced mRNA concentration of FAS, one of the key enzymes of fatty acid synthesis, reduced triglyceride concentrations, in hens treated with clofibrate is also caused by reduced rate of fatty acid synthesis. In avians, like in mammals, hepatic gene expression of FAS is controlled by SREBP-1 (Gondret et al., 2001). However, in contrast to mammals, chicken seem to express a single form of SREBP-1 (Zhang and Hillgartner, 2004). It is known that SREBP-1-dependent gene expression of FAS is downregulated by fasting or a low food intake (Horton et al., 1998). The lack of a correlation between FAS mRNA in the liver and food intake, however, suggests that the reduced food intake in hens treated with clofibrate was not the major reason for the strong downregulation of FAS expression. Because hepatic triglyceride biosynthesis in birds is strongly stimulated by estrogens (Kudzma et al., 1975; Chan et al., 1976), the strongly reduced plasma concentrations of 17-ß-estradiol may be mainly responsible for the downregulation of FAS expression. Because mRNA concentration of SREBP-1 was not reduced in the liver of hens treated with clofibrate compared with control hens, we assume that concentration of mature SREBP-1 in the nucleus was reduced, which led in turn to reduced mRNA concentration of FAS.
The observation that follicles remained small and immature in hens treated with clofibrate and that these hens stopped egg production shortly after the beginning of clofibrate treatment may be the consequence of the strongly reduced plasma triglyceride concentration. Plasma VLDL bound to oocyte receptors are required for lipid filling of follicles and egg yolk formation (Walzem et al., 1999). Stop of egg production in hens treated with clofibrate, however, was probably also due to their very low food intake, because we found a positive correlation between food intake and number of eggs in these hens. Interestingly, eggs produced in the first and the second week of hens treated with clofibrate did not differ in size, lipid concentrations, and fatty acid composition from those of control hens. This confirms that egg yolk composition is highly conserved (Kuksis, 1992). Inhibition of the maturation of follicles by clofibrate could also contribute to the low plasma concentrations of estrogens, which are predominantly produced in theca cells of small white follicles (Robinson and Etches, 1986). Estrogen production in follicle theca cells is stimulated by luteinizing hormone (Robinson and Etches, 1986). It has been shown that luteinizing hormone production is reduced in hens with restricted diet intake (Bruggeman et al., 1998). However, because there was no correlation between food intake and plasma 17-ß-estradiol concentration in hens treated with clofibrate, it is likely that the reduced food intake was not the major reason for reduced plasma estradiol concentration.
The present study moreover shows that clofibrate treatment caused a strong downregulation of SREBP-2 and its target genes, HMG-CoA reductase, the key enzyme of hepatic cholesterol synthesis, and LDL receptor. This indicates that clofibrate lowers hepatic cholesterol synthesis and uptake of cholesterol into the liver. We assume that hepatic SREBP-2-dependent cholesterol synthesis and uptake of LDL into the liver were downregulated, because less cholesterol was required for VLDL synthesis and VLDL assembly and secretion was strongly reduced by clofibrate. It has been shown that expression and proteolytic activation of SREBP-2 depends on cellular requirement for cholesterol in mammals. When cholesterol requirement is high and cells are depleted of cholesterol, proteolytic processing of SREBP-2 is activated, whereas it is inhibited when cellular cholesterol concentration is high (Horton et al., 2002). Similarly, downregulation of nuclear SREBP-2 has been demonstrated in chicken fed a high cholesterol diet, indicating that chicken nuclear form of SREBP-2 is controlled by cholesterol levels in a similar manner as in mammals (Matsuyama et al., 2005). Furthermore, it has been shown that levels of nuclear SREBP-2 controlled the expression of HMG-CoA reductase and LDL receptor also in chicken liver (Matsuyama et al., 2005). Thus, we assume that the reduced mRNA concentrations of HMG-CoA reductase and LDL receptor in hens fed clofibrate are due to reduced amounts of nuclear SREBP-2. Whether this reduction in nuclear SREBP-2 is made up by reduced transcription of the gene, as indicated by reduced SREBP-2 mRNA concentration, or by posttranslational processes remains unclear. In mammals, proteolytic activation of SREBP-2 is controlled by Insig-1 and Insig-2 (Yabe et al., 2002; Yang et al., 2002). Although Insig-2 mRNA concentration was not changed upon clofibrate treatment, Insig-1 mRNA concentration was reduced in hens fed clofibrate compared with control hens. In mammals, Insig-1 but not Insig-2 is also a target gene of SREBP-2. Its upregulation by SREBP-2 provides a feedback mechanism for cholesterol homeostasis (Yabe et al., 2002). Thus, the reduced mRNA concentration of Insig-1 in chicken upon clofibrate treatment is possibly mediated by decreased nuclear SREBP-2 levels. Reduction of nuclear SREBP-2 levels by inhibition of its proteolytic activation and a subsequent decrease of the transcription of its target genes has also been found upon PPAR activation in rat liver (König et al., 2007).
In conclusion, this study shows for the first time that PPAR activation by clofibrate causes a strong reduction of food intake and complex alterations of the lipid metabolism, namely an increase of hepatic fatty acid oxidation and a reduction of fatty acid and cholesterol synthesis. These changes in turn lead to a dramatic reduction of VLDL triglyceride and cholesterol concentrations, which, in conclusion, affect lipid deposition in yolk and lead to a stop of egg production.
Received for publication December 15, 2006. Accepted for publication January 29, 2007.
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