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and Adipose SREBP-1c–Regulated Genes1,2
,3
* Department of Biochemical Science and Technology, Division of Nutritional Science, Institute of Microbiology and Biochemistry, National Taiwan University, Taipei, Taiwan
3 To whom correspondence should be addressed. E-mail: cjjhuang{at}ntu.edu.tw.
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ABSTRACT |
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 TOP ABSTRACT MATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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in the liver and downregulate the expressions of lipid storage and lipogenic gene through the suppression of SREBP-1c in the RWAT.
KEY WORDS: • High oleic acid-rich safflower oil diet • PPAR • SREBP-1c • obesity • rats
Long-term consumption of a high-fat diet is associated with obesity and chronic diseases. The adipogenecity of a high-fat diet varies with the type of fat used (1,2). In rodents, diets high in unsaturated fat were shown to be less adipogenic than diets high in saturated fat, and was attributed to a higher oxidation rate (3) and diet-induced thermogenesis (4,5). The metabolic changes caused by dietary fat are regulated at the level of gene expression because lipid-regulated transcription factors such as PPARs, sterol regulatory element-binding protein-1c (SREBP-1c),4 and liver-X-receptor (LXR) (6–8) were discovered.
PPARs are fatty acid–regulated nuclear hormone receptors that control lipid oxidation (9), adipocyte differentiation, glucose and lipid storage, and inflammation (10). The PPAR signaling pathway denotes the successive binding of receptors to specific ligands and then to a specific DNA sequence [peroxisome proliferator responsive element (PPRE)], which in turn activates the transcription of genes downstream of the PPRE. Genes with PPRE, i.e., target genes of PPARs, are an array of enzymes/proteins involved in fatty acid metabolism, lipid transport, and storage (9), such as acyl-CoA oxidase (ACO), fatty acid binding protein (FABP), and mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase (HMGS). PPARs are viewed as monitors of intracellular nonesterified fatty acid (NEFA) (11).
SREBPs are transcription factors that regulate lipid homeostasis by controlling the expressions of a range of enzymes required for endogenous cholesterol, fatty acid, triacylglycerol (TG) and phospholipid synthesis. Intracellular sterol content–dependent proteolytic cleavage of SREBP in the endoplasmic reticulum membrane and the subsequent translocation of the released active SREBP into the nucleus lead to the transcription of genes of lipid synthesis (12). As the predominant subtype in rodents and human, SREBP-1c binds sterol regulator element (SRE) in the gene promoters of many enzymes involved in lipogenesis, such as acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS) (6). Transgenic mice studies suggest that SREBP-1c is involved in fatty acid synthesis and insulin-induced glucose metabolism (particularly in lipogenesis) (12,13).
As a ligand, fatty acid binds directly to PPARs, and trigger the PPAR signaling pathway. In the in vitro binding assay, rat PPAR binds to fatty acids with Kd (in µmol/L) of >30 for 10:0 and 12:0, 5.4 for 14:0, 1.5 for 16:0, 1.1 for 18:0, 0.6 for 18:1 (n-9), 1.1 for 18:2 (n-6), 0.27 for 18:3 (n-6), and 1.2 for 20:4 (n-6) (14). In contrast, PUFAs regulate the nuclear abundance of nSREBP-1c and do not bind directly to SREBP. The hierarchy for fatty acid regulation of SREBP-1c mRNA level is 22:5(n-3) = 20:4(n-6) > 18:2(n-6) > 18:1(n-9) in the in vitro experiment (15). In the in vivo experiment, PUFA-rich corn oil, walnut oil, safflower oil, and fish oil markedly suppressed hepatic mRNA expression of SREBP-1 and its target gene, FAS, but olive oil and lard did not (15,16). Thus, 18:1(n-9) is as active as PUFA for PPAR ligand binding and activation (14,17), but oleic acid, triolein, and olive oil are much less effective in the suppression of lipogenic genes through SREBP-1c.
The demonstration of the fatty acid regulation of genes coded for lipid metabolism through PPARs and SREBP provides a rational basis for the early findings that diets high in unsaturated fat are less adipogenic than diets high in saturated fat (1,2). A high (n-3) PUFA-rich fish oil diet is less adipogenic (18–21) due to a coordinated induction of fatty acid oxidation genes through PPAR (22) and suppression of lipogenic genes through SREBP-1c (23). The (n-6) PUFA-rich oils were also effective in the suppression of lipogenic genes through SREBP-1c (15,16). The effect of a high oleic acid–rich fat diet, however, is controversial. A high oleic acid–rich safflower oil (ORSO) diet was shown to be as effective as high (n-3) and (n-6) PUFA diets in lowering body fat accumulation in meal-fed Sprague-Dawley rats (5). However, a high-rapeseed oil [60% 18:1(n-9) and 20% 18:2(n-6)] diet was ineffective in mice that consumed food ad libitum (21).
Compared with other fat types, ORSO has the advantages of better cooking stability, adequate essential fatty acid [
25% is 18:2(n-6)], very low saturated fatty acid content, and a lower price than olive oil. This study was designed to test the hypothesis that feeding a high-ORSO diet can increase expressions of genes regulated by PPAR and is less adipogenic than a diet high in saturated fat.
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MATERIALS AND METHODS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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The composition of the 4 test diets was modified from AIN-76 (Table 1) (24). The amounts of casein, and vitamin and mineral mixtures in the high-fat diets were adjusted to ensure that the nutrient/energy ratios were equivalent. Rats had free access to food and tap water. Body weight and food intake were recorded weekly. Animal care and handling conformed to accepted guidelines (25), and were approved by the Institutional Animal Care and Use Committee, National Taiwan University.
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Biochemical analyses. Liver lipids were extracted with a mixture of chloroform:methanol (2:1, v:v). Both liver and serum lipids were measured by enzymatic methods using commercial kits for TG (GPO-PAP assay kit, Randox Laboratory) and NEFA (NEFA kit, Randox Laboratory). Serum leptin was measured by ELISA using a goat anti-mouse leptin antibody (R&D systems) with high affinity for rat leptin.
Semiquantitative RT-PCR and quantitative RT-PCR with endogenous standard.
The mRNA expressions of PPAR and PPAR
in the liver were measured by semiquantitative RT-PCR as previously described (27). The mRNA expression of SREBP-1c in the liver and PPAR, SREBP-1c, FAS and ACC in the RWAT were also measured by quantitative RT-PCR with endogenous standard. The sequences of primers used were shown in the supplementary Table 1. The PCR reaction system was modified as previously described (27) and all of the primers (reverse and forward) from target gene and internal control (acidic ribosomal phosphoprotein PO ) were put in one tube. The PCR program was as follows: 5 min at 94°C for 1 cycle, and 1 min at 94°C, 1 min at annealing temperature, 1 min at 72°C for 30 cycles and 7 min at 72°C for 1 cycle. The cycles used were all within the linear range of the dose-response curve. The PCR product was separated by electrophoresis in 2% agarose gel with ethidium bromide and quantitated by the BioSpectrum® imaging system (UVP). Because the sizes of amplified PCR fragments were as expected, and the results of the sequence analysis of amplified PCR fragments were 100% identical to the sequence in the NCBI database, the signals detected by our RT-PCR analysis were justified to be amplified from the cDNA reverse-transcribed from PPAR, PPAR, SREBP-1c, ACC, and FAS mRNA of the tissue extract.
Northern blot analysis for some target genes of PPAR and PPAR.
The method of cDNA preparation was as previously described (27). The sequences of primers used for cDNA preparation are shown in supplementary Table 2. The mRNA expressions of ACO, HMGS, carnitine palmitoyl-transferase 1A (CPT1A), and FABP in the liver and lipoprotein lipase (LPL) and adipocyte fatty acid-binding protein (aP2) in the RWAT were measured by Northern blot analysis. Total RNA was extracted from RWAT using the guanidium isothiocyanate, phenol/chloroform method (28) and from liver using the TRIzol reagent (Life Technologies). The method of Northern blotting was as previously described (27). The amounts of each mRNA were quantitated using a BioSpectrum imaging system (UVP).
Fatty acid composition analysis. Total lipids were extracted from liver and RWAT by a mixture of chloroform:methanol (2:1, v:v), saponified, and treated with BF3/MeOH. The resulted FAME and methyl pentadecanoic acid (Aldrich Chem) added as an internal standard were extracted with n-hexane and analyzed by GC (Varian) combined with flame ionization detection. Temperature programming of the column was as follows: 50°C hold 5 min, 50°C to 150°C (3°C/min), 150°C to 210°C (5°C/min), 210°C to 235°C (30°C/min) and then 235°C hold 10 min.
Statistical analyses. Data are expressed as means ± SEM. To test the significance of the effects of fat type, fat quantity, and their interaction, data from the 5S, 5B, 30S, and 30B groups based on a 2 x 2 factorial design were analyzed by 2-way ANOVA. When interaction (P < 0.05) existed between fat type and fat quantity, the significance of differences among the 5S, 5B, 30S, and 30B groups was further analyzed by Duncan's multiple range test. The significance of differences between 30B and 30S, and between 30B and 30B/S was analyzed by Student's t test. For all statistical analyses, data were transformed logarithmically if the variances were nonhomogeneous. The SAS 8.2 System (SAS Institute Cary) was employed for the statistical analyses.
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RESULTS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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mRNA expressions in the RWAT.
The type and quantity of fat did not affect the expression of PPAR mRNA. Rats fed the ORSO diets had lower LPL expression (P < 0.05, Table 4 and Fig. 1). In addition, the expression of aP2 mRNA in the RWAT of rats fed the 30S diet was lower than that of rats fed the 30B diet (P < 0.05, Table 4 and Fig 1).
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mRNA expressions in the liver.
Rats fed the high-fat diets had higher hepatic PPAR and SREBP-1c mRNA expressions (P < 0.05, Table 4 and Fig 2) in the liver. Rats fed the ORSO diets had higher mRNA expressions of ACO, HMGS, CPT1A, and FABP in the liver (P < 0.05, Table 4 and Fig 2). There were higher mRNA expressions of ACO, HMGS, CPT1A, and FABP in livers of the 30S group than in those of the 30B group (P < 0.05, Table 4 and Fig 2).
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DISCUSSION |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Results of this study indicated that high-fat diets led to obesity, but the extent of the increase in the RWAT, liver TG content, and serum leptin concentration was lower in rats fed the high-ORSO diet than in those fed the high-butter diet. These data agrees with results of Takeuchi et al. (5) that a 20% (wt:wt) ORSO diet was less adipogenic than a 20% lard diet in rats. Results of the present study further demonstrated higher mRNA expressions of hepatic PPAR target genes (ACO, CPT1A, HMGS, and FABP) and lower mRNA expressions of adipose LPL, aP2, SREBP-1c, ACC, and FAS in rats fed the high-ORSO diet than in rats fed the high-butter diet. In addition, the liver TG concentration of the 30S group was about half that of the 30B group (Table 2). These data indicated that feeding the high-ORSO diet induced a higher PPAR signaling in the liver, presumably by providing more 18:2(n-6) and 20:4(n-6) in the fatty acid pool as potent ligands for PPAR and triggering the transcription of its target genes. This in turn might enhance fatty acid oxidation and lead to less hepatic TG accumulation. In addition, the high-ORSO diet might also suppress SREBP-1c–mediated lipogenesis in the RWAT.
The activation of PPARs by fatty acids depends on site-specific availability, the metabolism of particular fatty acids, and the differences in their affinity for specific PPAR subtypes. As the predominant PPAR-subtype in rat hepatic parenchymal cells, PPAR binds 18:1(n-9) and 20:5(n-3) with comparable affinity in vitro (14). However, the addition of 20:5(n-3), but not 18:1(n-9), 18:2(n-6), and 20:4(n-6) to primary rat hepatocytes activates PPAR (29). This was thought to be due to the high relative abundance of 18:1(n-9), 18:2(n-6), and 20:4(n-6) in the intracellular NEFA pool because it was difficult to challenge hepatocytes with exogenous 18:1(n-9), 18:2(n-6), or 20:4(n-6) to significantly increase these fatty acids in the NEFA pool (29). In the present study, the 30% fat diets were fed for as long as 15 wk, and the tissue fatty acid composition was remarkably altered by the 2 different fat sources. In the cotransfection assay using mouse PPAR, the optimal transactivation activity for PPAR was found to be with fatty acids with a chain length of 16–20 carbons and several doubled bonds in the chain (17). Saturated fatty acids were ineffective in this assay (17). This may account, at least in part, for the lower PPAR target gene mRNA expressions in the liver of the 30B group.
High-fat diets, however, increased the hepatic mRNA expression of PPAR and SREBP-1c (Table 4 and Fig 2). The higher mRNA expression of liver PPAR in rats fed the high-fat diets may be related to the obese condition (30–33) and the resulting hyperleptinemia (Table 2). Elevated secretion of leptin from adipose tissues in the obese condition was shown to display antisteatotic and lipopenic action through an enhancement of fatty acid oxidation and suppression of lipogenesis (34,35). Hyperleptinemia in Sprague-Dawley rats fed a 60% (wt:wt) fat diet was shown to be associated with increased PPAR protein, CPT1A mRNA, and fatty acid oxidation in the liver (34). The lipopenic action of hyperleptinemia on white adipose tissue and liver is dependent on PPAR because these effects of hyperleptinemia could not be observed in PPAR-null mice (35). Based on this suggested role of leptin, it seems plausible to speculate that although a high-fat intake induced an excessive adipose tissue accumulation in genetically normal animals, the resulted hyperleptinemia may then upregulate PPAR expression in the liver.
Despite a higher mRNA expression of liver PPAR in the 30B group than the 5B group, the mRNA expressions of PPAR target genes were not higher in parallel. The lack of PUFA as a high affinity ligand might limit the PPAR signaling in the 30B group. Alternatively, a possibility that the level of PPAR protein did not increase in parallel with its mRNA level could not be excluded for the lack of change in PPAR target genes in the 30B group.
The expression of LPL gene is under multiple regulations (36) including PPARs (37) and SREBP-1c (36,38). The coordinated downregulation of SREBP-1c, LPL, ACC, and FAS in the RWAT of the 30S group might be related to the suppression of SREBP-1c mRNA expression by PUFA, more specifically, the higher content of 18:2(n-6) and 20:4(n-6) in the RWAT of the 30S group (Table 3); 18:2(n-6) and 20:4(n-6) were shown to be effective in the suppression of mature form SREBP-1c protein and mRNA (15,39,40) and SRE-dependent gene expression (41). In vivo experiment also showed that 18:2(n-6)-rich corn oil and safflower oil markedly suppressed the hepatic mRNA expression of SREBP-1c and its target genes (15,16). The lower mRNA expression of SREBP-1c and its regulated lipogenic genes (ACC and FAS) in the 30S group of the present study thus might lead to lower lipogenesis and lower RWAT weight. The SREBP-1 is expressed in the very early stage of adipocyte differentiation and was shown to promote adipocyte differentiation (38).
In the liver, however, the mRNA expression of SREBP-1c was higher in rats fed high-fat diets (Table 4 and Fig. 2). Similarly, upregulated liver SREBP-1c was also observed in mice with high-fat diet–induced obesity (42) and mice overfed intragastrically (43). It is unclear how the liver SREBP-1c mRNA expression is upregulated in the high-fat diet–induced obesity condition. One possibility is under the regulation of LXR or PPAR. LXR belongs to a subclass of nuclear hormone receptors that regulates intracellular cholesterol levels by transactivating the expression of cholesterol 7-hydroxylase (44,45), cholesterol ester transfer protein (46), and ATP-binding cassette transporter A1, which modulates cholesterol efflux and mediates reverse cholesterol transport from peripheral tissues. LXR/RXR was recently identified as a dominant activator for SREBP-1c (47). Furthermore, it was found that unsaturated fatty acids bind to LXR (48,49) and interfere with LXR/RXR binding to DNA (50). LXR was shown to be regulated by PPARs (51,52). Evidence for a role of PPAR in the SREBP-1c and its regulated gene expression was provided by the following observations: 1) changes in the SREBP-1c mRNA level with the diurnal periodicity were parallel to changes in PPAR; 2) SREBP-1c mRNA expression was lower in PPAR-null mice than in wild-type mice (53); and 3) SREBP-1c–regulated lipogenic gene expressions were dysregulated in PPAR-null mice (54).
It is not known exactly why the fat type in high-fat diets influenced the mass of RWAT but not EWAT in this study. The cumulative growth of the EWAT was due mainly to hypertrophy, whereas the growth of the RWAT was due predominantly to hyperplasia (55). Moreover, biochemical responses to stimulations and productions of adipokines were shown to be different between subcutaneous and visceral adipose tissue (56). It was speculated that interactions among genetics, local factors (e.g., interleukin, growth factor 1, leptin), systemic factors (nutrition), vascularization, and the degree of innervation by the sympathetic nervous system might produce site-specific normal or pathological growth of adipose tissue (55).
In conclusion, feeding the high-ORSO diet resulted in less RWAT mass, higher tissue 18:2(n-6) and 20:4(n-6), higher mRNA expressions of PPAR target genes, ACO, HMGS, CPT1, and FABP in the liver and lower mRNA expressions of SREBP-1c, FAS, ACC, LPL, and aP2 in RWAT, compared with feeding the high-butter fat diet. These results suggested that the high tissue content of 18:2(n-6) and 20:4(n-6) may upregulate genes coded for enzymes of fatty acid oxidation in the liver through activating PPAR and downregulate genes coded for lipogenesis through the suppression of SREBP-1c, thus leading to lower RWAT mass.
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FOOTNOTES |
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2 Supplemental Tables 1 and 2 are available with the online posting of this paper at www.nutrition.org.
4 Abbreviations used: 5B, 5% butter fat; 5S, 5% oleic acid–rich safflower oil; 30S, 30% oleic acid–rich safflower oil; 30B, 30% butter fat; 30B/S, 30B diet for 12 wk and then switched to 30S diet for 3 wk; ACC, acetyl-CoA carboxylase; ACO, acyl-CoA oxidase; aP2, adipocyte fatty acid-binding protein; CPT1A, carnitine palmitoyl-transferase 1A; EWAT, epididymal adipose tissue; FABP, fatty acid binding protein; FAS, fatty acid synthase; HMGS, mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase; LPL, lipoprotein lipase; LXR, liver-X-receptor; NEFA, nonesterified fatty acid; ORSO, oleic acid–rich safflower oil; PPRE, peroxisome proliferator responsive element; RWAT, retroperitoneal adipose tissue; SREBP-1c, sterol regulatory element-binding protein-1c; SRE, sterol regulator element; TG, triglyceride.
Manuscript received 15 January 2006. Initial review completed 16 February 2006. Revision accepted 14 April 2006.
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