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Department of Biochemistry and Molecular Pharmacology, School of Medicine, West Virginia University, Morgantown, WV 265061
2To whom correspondence should be addressed. E-mail: fbhillgartner{at}hsc.wvu.edu.
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ABSTRACT |
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 TOP ABSTRACT MATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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(ACC) sterol regulatory element (SRE) in chick liver and that the binding activity of 2 of these complexes was increased by consumption of a high-carbohydrate, low-fat diet. Additional analyses showed that feeding a high-carbohydrate, low-fat diet had no effect on the concentration of mature SREBP-2 and the binding of SREBP-2 to the ACC SRE in chick liver. These results indicate that alterations in the concentration of mature SREBP-1 play a role in mediating the effects of starvation and feeding a high-carbohydrate, low-fat diet on ACC transcription in chick liver and that diet-induced changes in mature SREBP-1 concentration in chick liver are mediated primarily by a posttranslational mechanism.
KEY WORDS: • transcription • fatty acid synthesis • acetyl-CoA carboxylase • insulin • thyroid hormone
Sterol regulatory element binding proteins (SREBP)3 are basic helix-loop-helix-leucine zipper (bHLH-Zip) transcription factors that play an important role in controlling genes involved in the synthesis of cholesterol and fatty acids (1). SREBPs are synthesized as inactive precursor proteins that are embedded in endoplasmic reticulum membranes (2,3). To become transcriptionally active, precursor SREBP is escorted to the Golgi apparatus, where it undergoes a sequential 2-step proteolytic cleavage catalyzed by site-1 protease and site-2 protease. This process releases an amino-terminal SREBP fragment that is referred to as the mature form. Mature SREBP is transported into the nucleus, where it binds sterol regulatory elements (SRE) of genes involved in lipid biosynthesis. Three isoforms of SREBP have been identified in mammals. Two of these isoforms, designated SREBP-1a and SREBP-1c, are expressed from the same gene. They vary in sequence at their amino termini due to the use of alternative promoters and leading exons. The third isoform, designated SREBP-2, is expressed from a separate gene. SREBP-1c and SREBP-2 are the major isoforms of SREBP expressed in mammalian liver (4). Results from studies using transgenic mice indicate that SREBP-1c is more effective than SREBP-2 in modulating expression of genes involved in fatty acid synthesis, whereas SREBP-2 is more effective than SREBP-1c in modulating genes involved in cholesterol synthesis (5–7).
In mammals, alterations in nutritional status regulate the concentration of SREBP-1c in liver. For example, feeding previously starved mice a high-carbohydrate, low-fat diet increases the hepatic concentration of mature SREBP-1c (5,6,8). This effect is mediated primarily by changes in the abundance of SREBP-1c messenger RNA (mRNA). Currently, there is no information on whether alterations in nutritional status modulate the concentration of SREBPs in nonmammalian species.
One gene whose transcription is controlled by SREBP is acetyl-CoA carboxylase- (ACC). ACC catalyzes the ATP-dependent carboxylation of acetyl-CoA to malonyl CoA and is considered a key control point in the de novo fatty acid synthesis pathway (9). In livers of avians and mammals, transcription of ACC is low during starvation and is high during consumption of a high-carbohydrate, low-fat diet (10). The more downstream promoter (promoter 2) of the chicken ACC gene contains an SRE that acts in concert with an adjacent triiodothyronine (T3) response element to mediate the stimulatory effects of insulin and T3 and the inhibitory effects of glucagon on ACC transcription in chick hepatocyte cultures (11,12). Because insulin, T3, and glucagon are humoral factors communicating changes in dietary status to the liver, the ACC SRE has been proposed to play a role in mediating the effects of starvation and feeding a high-carbohydrate, low-fat diet on ACC transcription in liver. Information on whether alterations in nutritional status modulate the binding of SREBP to the ACC SRE is currently lacking.
The aims of the present study were to identify and to characterize the chicken homolog of SREBP-1; to determine the effects of starvation and feeding a high-carbohydrate, low-fat diet on the abundance of SREBP-1 in chicken liver; to assess the role of pretranslational processes in mediating diet-induced changes in SREBP-1 levels; and to ascertain the effects of starvation and feeding a high-carbohydrate, low-fat diet on the binding of SREBPs to the ACC SRE in chicken liver.
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MATERIALS AND METHODS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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22) was also subcloned into pSV-SPORT1 to form pSV-SPORT1–cSREBP-1 22. Animals. Newly hatched white leghorn chicks (CBL Farms) were housed in brooders with thermostatically controlled heaters. They had water ad libitum and were fed a commercial chick starter diet (Buckeye Starter Grower; analysis by weight: 71% carbohydrate, 18% protein, 3% fat, 5% crude fiber). A 12-h light–dark cycle (lights on at 0600) was maintained throughout the studies. Ten-day-old chicks were starved for 24 h and then were refed a high-carbohydrate, low-fat diet that contained, by weight, 65% glucose, 25% isolated soy protein (ICN Biochemicals), 1% safflower oil, 6% mineral mix (Briggs chicks salts A, Teklad) (13), 1% vitamin mix (A.O.A.C., Teklad) (14), 2% cellulose, and 0.4% DL-methionine. This protocol was approved by the Animal Care and Use Committee of West Virginia University.
Cell culture and transient transfection.
Primary cultures of chick embryo hepatocytes were prepared as described previously (15) and were maintained in serum-free Waymouth’s medium MD705/1 (Invitrogen) containing 50 nmol/L insulin (gift from Lilly) and 1 µmol/L corticosterone. Cells were transfected 6 h after plating by using 20 µg lipofectin (Invitrogen), 1 µg SRE-TKCAT (11), and varying amounts of pSV-SPORT1–cSREBP-1 (1–464), pSV-SPORT1–cSREBP-1 22, and/or pSV-SPORT1 (empty expression plasmid). The total molar concentration of expression plasmid was the same in each transfection. pBluescript KS(+) was added to bring the total amount of transfected DNA to 2.02 µg/plate. At 18 h of incubation, the transfection medium was replaced with fresh medium. At 66 h of incubation, cells were harvested and cell extracts were prepared as described by Baillie et al. (16). CAT (chloramphenicol acetyltransferase) activity (17) and protein (18) were assayed by the indicated methods.
Western blot analysis. Membrane and nuclear extracts were prepared from liver cells as described (11). Immunoblot analysis was carried out by using mouse monoclonal antibodies against SREBP-1 (IgG-2A4) and SREBP-2 (IgG-1D2) (American Type Culture Collection). IgG-2A4 and IgG-1D2 have been shown to react with the chicken forms SREBP-1 and SREBP-2, respectively (11).
RNase protection assay. RNA probes for chicken SREBP-1, SREBP-2, ß-actin, and 18S ribosomal RNA (rRNA) were generated as previously described (11,12). RNA was extracted from chick tissues by the guanidinium thiocyanate–phenol–chloroform method (19). RNase protection assays were performed as previously described (11).
Gel mobility shift assay.
Mature forms of chicken SREBP-1 and SREBP-2 were translated in vitro by using the TNT SP6 coupled reticulocyte lysate system (Promega). Nuclear extracts were prepared as described in (12). A double-stranded oligonucleotide containing the ACC SRE (–84 to –66 bp relative to the transcription initiation site of ACC promoter 2) was labeled by filling in overhanging 5' ends by using a Klenow fragment of Escherichia coli DNA polymerase in the presence of [-32P]dCTP. Gel mobility shift assays were carried out as previously described (12).
Statistical methods. Differences between pairs of means were determined by the Student’s t test and were considered significant when P < 0.05. All data are reported as means ± SEM.
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RESULTS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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SRE (SRE–TKCAT) and expression plasmids containing or lacking the coding region for the mature form of chicken SREBP-1. Overexpression of mature chicken SREBP-1 from pSV-SPORT1–cSREBP-1 (1–464), caused a marked increase in SRE–TKCAT activity but had no effect on the activity of a reporter plasmid lacking a SRE (TKCAT) (Fig. 2). As an additional control, a dominant negative form of chicken SREBP-1 lacking 22 amino acids in a proline-rich region (amino acids 86–107) was expressed in chick hepatocytes. This mutant, referred to as SREBP-1 22, is unable to dimerize with itself and bind DNA but is able to dimerize with wild-type SREBP-1 and inhibit its DNA binding activity (data not shown). The structure of SREBP-1 22 differs from that of a previously described SREBP dominant negative construct, which contains a mutation in the bHLH-Zip domain (26). Expression of SREBP-1 22 reversed the stimulatory effects of exogenous wild-type SREBP-1 on SRE-TKCAT activity. These data indicate that SREBP-1 functions as an activator of transcription in chick hepatocytes.
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gene in liver (10). The chicken ACC gene contains a SRE that modulates ACC transcription in chick hepatocytes (11,12). To investigate the role of SREBP-1 in mediating alterations in hepatic ACC transcription during starvation and feeding a high-carbohydrate, low-fat diet, the concentration of mature SREBP-1 and precursor SREBP-1 was measured in livers of chicks subjected to this nutritional manipulation. In hepatic nuclear extracts of chicks starved for 24 h, the concentration of mature SREBP-1 was low; feeding a high-carbohydrate, low-fat diet for 5 and 24 h increased the concentration of mature SREBP-1 by 14- and 6-fold, respectively (Fig. 3A). Feeding a high-carbohydrate, low-fat diet also increased the concentration of precursor SREBP-1 in the membrane fraction; however, the magnitude of this effect (1.4- to 3.2-fold) was substantially lower than that observed for mature SREBP-1, particularly at the 5-h time point. This observation suggests that the increase in abundance of mature SREBP-1 caused by consumption of a high-carbohydrate, low-fat diet is mediated primarily by an elevation in the proteolytic processing of precursor SREBP-1 to mature SREBP-1 and/or by a decrease in the turnover of mature SREBP-1.
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In addition to nutritional regulation, the transcription of lipogenic genes is controlled by tissue-specific factors. For example, transcription of the ACC gene in chickens is high in liver and low in brain, heart, kidney, and pectoral muscle (10). These differences in ACC transcription may be mediated by alterations in SREBP-1 expression. To investigate this possibility, the abundance of SREBP-1 mRNA was measured in different tissues of chicks fed a high-carbohydrate, low-fat diet. The abundance of SREBP-1 mRNA was substantially higher in liver relative to brain, heart, kidney, and pectoral muscle (Fig. 4B). These results provide support for a role for SREBP-1 in mediating tissue-dependent differences in ACC transcription in chickens.
Modulation of the binding of nuclear proteins to the ACC- SRE.
Starvation and feeding a high-carbohydrate, low-fat diet modulated the concentration of mature SREBP-1 in chick liver (Fig. 3). Gel mobility shift experiments were performed to determine whether starvation and feeding also modulated the binding of SREBP-1 to the ACC gene. Incubation of a 32P-labeled oligonucleotide probe containing the ACC SRE with hepatic nuclear extracts from chicks fed a high-carbohydrate, low-fat diet resulted in the formation of 4 sequence-specific protein-DNA complexes (Fig. 5). These complexes are designated a, b, c, and d, in order of increasing mobility. Preincubation of nuclear extracts with an antibody against SREBP-1 disrupted the formation of complexes a, b, and c, but had no effect on the formation of complex d. Preincubation of nuclear extracts with an antibody against SREBP-2 disrupted the formation of complex c but had no effect on complexes a, b, and d. Incubation of the ACC SRE probe with in vitro synthesized mature SREBP-1 resulted in a SREBP-1 homodimeric complex whose migration was similar to that of complex a. Collectively, these data suggest that complex a is composed of SREBP-1 homodimers. Complex b also appears to contain SREBP-1 or another protein that is immunologically similar to SREBP-1. The increased mobility of complex b relative to complex a may be due to a decrease in size or a posttranslational modification of 1 or both proteins comprising complex b. Complex c appears to contain both SREBP-1 and SREBP-2, or proteins that are immunologically similar to SREBP-1 and SREBP-2. The mobility of complex c is greater than that observed for homodimeric complexes containing in vitro synthesized mature SREBP-1 or mature SREBP-2. This observation suggests that 1 or both proteins comprising complex c is smaller in size than mature SREBP-1 and mature SREBP-2, or has undergone a posttranslational modification. The identity of the proteins in complex d is presently unclear. Previous work has shown that the SRE of the low-density lipoprotein receptor gene binds multiple protein complexes in crude nuclear extracts and that the transcriptional activity of this regulatory element is correlated only with the binding of nuclear complexes containing SREBP (28,29). Thus, complexes a, b, and c likely account for the activity of the ACC SRE in chick liver.
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SRE. In livers of starved chicks, the binding activity of complex a and complex b was barely detectable, whereas the binding activity of complex c was readily observed (Fig. 5). Feeding a high-carbohydrate, low-fat diet for 5 and 24 h increased the binding activity of complex a and complex b but had little or no effect on the binding activity of complex c. The extent of the increase in the binding of complex a and complex b was greater at 5 h of feeding than at 24 h of feeding. These diet-induced changes in the binding of complex a and complex b paralleled changes in the concentration of mature SREBP-1 (Fig. 3). Collectively, these observations support the proposal that consumption of a high-carbohydrate, low-fat diet increases the binding of mature SREBP-1 to the ACC gene in liver. |
DISCUSSION |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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gene in liver. These observations, in combination with previous work demonstrating that the ACC SRE modulates ACC transcription in chick hepatocyte cultures, provide strong evidence that alterations in the abundance of mature SREBP-1 play a role in mediating the effects of starvation and feeding a high-carbohydrate, low-fat diet on ACC transcription in chick liver. What are the signaling pathways that mediate the increase in abundance of mature SREBP-1 in livers of chicks fed a high-carbohydrate, low-fat diet? Two hormones whose concentrations are elevated by the consumption of a high-carbohydrate, low-fat diet are insulin and T3 (9). In chick hepatocyte cultures, addition of insulin or T3 to the culture medium increases the concentration of mature SREBP-1 (12). The effect of insulin on mature SREBP-1 concentration is rapid (i.e., within the first 6 h of hormone treatment) and is mediated by a posttranslational mechanism. In contrast, the effect of T3 on mature SREBP-1 concentration is delayed (i.e., between 6 and 24 h of hormone treatment) and is mediated by both pretranslational and posttranslational mechanisms. We postulate that insulin plays a role in mediating the increase in mature SREBP-1 concentration observed at 5 h of feeding a high-carbohydrate, low-fat diet and that both insulin and T3 are involved in mediating the increase in SREBP-1 concentration observed at 24 h of feeding. In support of this proposal, the effect of feeding a high-carbohydrate, low-fat diet on mature SREBP-1 concentration is mediated by a posttranslational mechanism at the 5-h time point, whereas at the 24-h time point, it is mediated by both pretranslational and posttranslational mechanisms.
In contrast to SREBP-1, feeding previously starved chicks a high-carbohydrate, low-fat diet had no effect on the concentration of mature SREBP-2 and the binding of SREBP-2 (i.e., complex c) to the ACC gene in liver. These observations suggest that SREBP-2 does not play a role in mediating the effects of starvation and feeding a high-carbohydrate, low-fat diet on ACC transcription. Nevertheless, SREBP-2 may have a physiological function during the starved state, because complex c is the predominant SREBP-containing complex that binds the ACC SRE during this dietary condition. We postulate that during conditions when ACC is not induced by nutritional factors, complex c plays a role in ensuring a basal level of ACC expression for the synthesis of structural lipids in cell membranes.
In rodents, SREBP-1c has been shown to play a critical role in the nutritional and hormonal regulation of lipogenic enzyme expression in liver (6,26). As observed with SREBP-1 in chicken liver, consumption of a high-carbohydrate, low-fat diet causes a marked increase in the concentration of mature SREBP-1c in rodent liver (5,6,8). Insulin treatment also increases the concentration of mature SREBP-1c in rodent hepatocytes (26,30,31). The effects of insulin and feeding a high-carbohydrate, low-fat diet on mature SREBP-1c concentration in rodent hepatocytes are mediated primarily by changes in SREBP-1c mRNA abundance (26). In contrast, we have found that the effects of insulin and feeding a high-carbohydrate, low-fat diet on mature SREBP-1 concentration in chick hepatocytes are mediated primarily by a posttranslational mechanism. Thus, avians and rodents differ in the mechanisms by which nutrients and hormones modulate the concentration of mature SREBP-1 in liver. The reason for these differences is not clear. They may reflect subtle class-dependent differences in the role of SREBP-1 in the regulation of fatty acid synthesis and/or other metabolic processes.
In summary, consumption of a high-carbohydrate, low-fat diet increases the concentration of mature SREBP-1 in chick liver. This effect is mediated primarily by a posttranslational mechanism. Diet-induced changes in the abundance of mature SREBP-1 in chick liver are associated with alterations in the binding of SREBP-1 and the rate of transcription of the ACC gene. SREBP-1 expression is substantially higher in liver relative to brain, heart, kidney, and pectoral muscle, and thus may play a role in mediating tissue-dependent differences in ACC transcription.
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FOOTNOTES |
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3 Abbreviations used: ACC, acetyl-CoA carboxylase-; bHLH-Zip, basic helix-loop-helix-leucine zipper; CAT, chloramphenicol acetyltransferase; mRNA, messenger RNA; 5' RACE, rapid amplification of 5'-cDNA ends; rRNA, ribosomal RNA; SRE, sterol regulatory element; SREBP, sterol regulatory element-binding protein; T3, triiodothyronine.
Manuscript received 11 May 2004. Initial review completed 20 May 2004. Revision accepted 7 June 2004.
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LITERATURE CITED |
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