【关键词】 receptor
nutrition, metabolism and genomics group (d.p., m.m., s.k.), division of human nutrition, wageningen university, 6700 ev wageningen, the netherlands
department of pathology (j.k.r.), northwestern university, chicago, illinois 60611
abstract
peroxisome proliferator-activated receptors (ppars) are transcription factors involved in the regulation of numerous metabolic processes. the ppar isotype is abundant in liver and activated by fasting. however, it is not very clear what other nutritional conditions activate ppar. to examine whether ppar mediates the effects of chronic high-fat feeding, wild-type and ppar null mice were fed a low-fat diet (lfd) or high-fat diet (hfd) for 26 wk. hfd and ppar deletion independently increased liver triglycerides. furthermore, in wild-type mice hfd was associated with a significant increase in hepatic ppar mrna and plasma free fatty acids, leading to a ppar-dependent increase in expression of ppar marker genes cyp4a10 and cyp4a14. microarray analysis revealed that hfd increased hepatic expression of characteristic ppar target genes involved in fatty acid oxidation in a ppar-dependent manner, although to a lesser extent than fasting or wy14643. microarray analysis also indicated functional compensation for ppar in ppar null mice. remarkably, in ppar null mice on hfd, ppar mrna was 20-fold elevated compared with wild-type mice fed a lfd, reaching expression levels of ppar in normal mice. adenoviral overexpression of ppar in liver indicated that ppar can up-regulate genes involved in lipo/adipogenesis but also characteristic ppar targets involved in fatty acid oxidation. it is concluded that 1) ppar and ppar-signaling are activated in liver by chronic high-fat feeding; and 2) ppar may compensate for ppar in ppar null mice on hfd.
introduction
diabetes mellitus type 2 has become a major health concern worldwide. overt type 2 diabetes is most often preceded by a state of insulin resistance, which describes an impaired response to insulin, either in liver or peripheral tissues. insulin resistance is almost invariably linked to obesity and is often part of a combination of metabolic abnormalities united in the term metabolic syndrome, which also include dyslipidemia, hypertension, and a proinflammatory and prothrombotic state.
an important group of molecular targets for the treatment of insulin resistance are the peroxisome proliferator-activated receptors (ppars). ppars are ligand-activated transcription factors that activate the transcription of genes involved in many different processes, including lipid and glucose metabolism, inflammation, and wound healing. three different ppar isotypes are known to date: , /, and . in analogy with many other nuclear hormone receptors, ppars form heterodimers with the retinoid x receptor and stimulate gene expression by binding to specific elements located in the promoter of target genes. all three ppars bind and are activated by fatty acids, especially polyunsaturated fatty acids, as well as by various eicosanoids (1, 2).
most of the research on ppars has concentrated on ppar because it binds and is activated by an important class of insulin-sensitizing drugs called thiazolidinediones, which include rosiglitazone and pioglitazone. activation of ppar results in stimulation of peripheral glucose disposal and improves insulin sensitivity, possibly by lowering plasma free fatty acid (ffa) levels and affecting plasma concentrations of adipocytokines (3, 4). ppar is mainly present in adipose tissue where it stimulates adipo- and lipogenesis by up-regulating target genes such as fat/cd36, ap2/fabp4, and lipoprotein lipase (lpl). gain and loss of function experiments have demonstrated that ppar is absolutely required for adipocyte differentiation (5, 6, 7). in liver, ppar is only very weakly expressed and does not appear to be influenced by feeding/fasting (8). instead, hepatic ppar is up-regulated in animal models of leptin deficiency and lipoatrophy, concurrent with development of hepatic steatosis (9, 10, 11).
whereas ppar promotes the storage of lipids, the ppar isotype stimulates lipid catabolism. it is highly expressed in liver where it up-regulates numerous genes involved in fatty acid uptake and activation, mitochondrial -oxidation, peroxisomal fatty acid oxidation (rodents only), ketone body synthesis, fatty acid elongation and desaturation, and apolipoprotein synthesis. in addition, it plays an important role in the hepatic acute phase response. ppar is the molecular target for the hypolipidemic fibrate drugs, which are used for the treatment of (diabetic) dyslipidemia (12). apart from lipid catabolism, there is increasing experimental support for an important connection between ppar and glucose homeostasis. indeed, mice lacking ppar display pronounced fasting hypoglycemia, which can be attributed to increased insulin-mediated stimulation of whole body glucose utilization and inhibition of hepatic glucose output (13, 14, 15). lowered hepatic glucose output is probably caused by a combination of impaired energization of gluconeogenesis due to defective fatty acid oxidation, impaired conversion of glycerol to glucose, and decreased glycogen stores (16). it has been reported that the effect of ppar on hepatic insulin resistance may implicate the mammalian tribbles homolog trb-3, which is a negative regulator of intracellular insulin signaling (17).
under physiological conditions, the function of ppar is mainly evoked during fasting, which is associated with increased hepatic ppar mrna expression and increased plasma ffa levels. indeed, whereas in the fed state deletion of ppar has few consequences, in the fasted state it induces a severe phenotype characterized by hypoglycemia, hypoketonemia, hypothermia, and a fatty liver (16, 18). another physiological stimulus that may trigger ppar function is obesity/insulin resistance, which can be modeled in mice by chronically feeding a hfd. high-fat feeding augments fat mass, is associated with attenuated insulin signaling, and results in increased plasma ffa levels and possibly increased hepatic ppar expression levels. to determine whether ppar indeed mediates the effects of chronic high-fat feeding, wild-type and ppar null mice fed a hfd for several months were studied. the data show that 1) ppar and ppar-signaling are activated in liver by chronic high-fat feeding; and 2) ppar may compensate for ppar in ppar null mice on hfd.
materials and methods
chemicals
wy14643 was obtained from chemsyn laboratories (lenexa, ks). recombinant human insulin (actrapid) was from novo nordisk (copenhagen, denmark). sybr green was from eurogentec (seraing, belgium). dmem, fetal calf serum, calf serum, and penicillin/streptomycin/fungizone were from biowhittaker europe (cambrex bioscience, seraing, belgium). otherwise, chemicals were from sigma (zwijndrecht, the netherlands).
animal experiments
sv129 ppar null mice and corresponding wild-type mice were purchased at the jackson laboratory (bar harbor, me). for the fasting experiments, 5-month-old male mice were fasted for 0 or 24 h starting at the onset of the light cycle. for the feeding experiments with wy14643 (chemsyn), 5-month-old male mice were fed 0.1% wy14643 for 5 d by mixing it in their food. for the diet intervention, 2-month-old male mice were fed with a lfd or hfd for 26 wk. the respective diets provided either 10 or 45% energy percent in the form of lard fat (d12450b or d12451; research diets, new brunswick, nj). body weight and food intake were measured at regular intervals throughout the feeding intervention. an additional dietary intervention was performed with c57bl/6 mice (harlan, zeist, the netherlands), which were fed a lfd or hfd providing either 10 or 45% of fat from palm oil. at wk 2, 4 and 16 of the intervention for the c57bl/6 mice or at the end of the dietary intervention for the sv129 mice, tissues were dissected, weighted and directly frozen in liquid nitrogen. blood was collected via orbital puncture. the animal experiments were approved by the animal experimentation committee of wageningen university.
plasma and tissue metabolites
plasma was obtained from blood by centrifugation for 10 min at 10,000 x g. plasma ffas were determined using a kit from wako chemicals (sopachem, wageningen, the netherlands). tissue triglycerides level was determined using a kit from instruchemie (delfzijl, the netherlands).
intraperitoneal glucose tolerance test
intraperitoneal glucose tolerance test was performed after 24 wk on the experimental diets. after a 6-h fast, mice were injected ip with glucose (2 g/kg body weight). blood was collected by tail bleeding after 0, 20, 40, 60, 90, and 150 min and glucose measured using accucheck compact (roche diagnostics, almere, the netherlands). the areas under the curves were determined with graphpad (san diego, ca) prism 4 software.
cell culture
rat hepatoma fao cells were grown in dmem containing 10% (vol/vol) fetal calf serum. serum was depleted to 0.5% 12 h before incubation with insulin. cells were incubated with insulin at 0, 10, or 100 nm for 24 h followed by rna isolation.
rat hepatocytes were isolated by two-step collagenase perfusion as described previously (19). hepatocytes were suspended in william’s e medium (cambrex) supplemented with 10% fetal calf serum, 20 mu/ml insulin, 50 nm dexamethasone, penicillin-streptomycin, and 50 μg/ml gentamycin. after 4 h, medium was replaced by the same medium without insulin. the next day, cells were incubated in the presence or absence of insulin for 10 h.
adenoviral gene transfer
ppar null mice were intravenously injected (tail vein) with virus particles of ad/lacz or ad/mppar1 and killed 6 d later as described (9) (20).
isolation of total rna and quantitative pcr (q-pcr)
total rna was extracted from cells or tissue with trizol reagent following the supplier’s protocol. total rna 35 μg was treated with deoxyribonuclease i amplification grade and then reverse-transcribed with oligo-deoxythymidine using superscript ii rt ribonuclease h. cdna was pcr amplified with platinum taq dna polymerase (all from invitrogen, breda, the netherlands) primer sequences used in the pcrs were chosen based on the sequences available in genbank. primers were designed to generate a pcr amplification product of 100200 bp (13, 21). only primer pairs yielding unique amplification products without primer dimer formation were subsequently used for q-pcr assays. pcr was carried out using platinum taq polymerase (invitrogen) and sybr green on an icycler pcr machine (bio-rad laboratories bv, veenendaal, the netherlands). the mrna expression of all genes reported is normalized to the ribosomal 36b4 gene expression.
microarray
rna was prepared from liver of four mice per group using trizol and subsequently pooled per group. pooled rna was further purified using qiagen (venlo, the netherlands) rneasy columns and the quality verified by lab on a chip analysis (bioanalyzer 2100; agilent, amstelveen, the netherlands). ten micrograms of rna were used for one cycle crna synthesis (affymetrix, santa clara, ca). hybridization, washing and scanning of affymetrix genechip mouse genome 430a arrays was according to standard affymetrix protocols. fluorometric data were processed by affymetrix genechip operating software, and the gene chips were globally scaled to all the probe sets with an identical target intensity value. further analysis was performed by data mining tool (affymetrix).
results
male wild-type and ppar null mice at 23 months of age were fed a low-fat diet (10% fat, lfd) or hfd (45% fat, hfd) for 26 wk. energy intake throughout this period was identical in the four groups (fig. 1a). feeding a hdf caused significant weight gain in the wild-type mice, whereas the effect was much less evident in the ppar null mice (fig. 1b). gonadal fat weight was increased by hfd in both wild-type and ppar null mice, although somewhat less pronounced in the latter group, who already had higher fat weight on the lfd (fig. 1c). liver weight was higher in the ppar null mice, which was further increased by hfd (fig. 1d). this was partially due to elevated hepatic triglyceride levels, which were increased by both ppar deletion and hfd (fig. 1e). in ppar null fed a hfd, almost 15% of liver weight consisted of triglycerides, indicating a severe fatty liver.
during fasting, both hepatic ppar expression and plasma ffa levels are increased, leading to activation of ppar signaling. a similar situation may exist during hfd. indeed, plasma ffas, which serve as ligands for ppar, were significantly increased (26%, p < 0.01) in mice fed the hfd (fig. 2a). furthermore, hepatic ppar mrna levels were modestly but significantly increased by hfd, as determined by microarray and q-pcr (fig. 2b). a similar stimulatory effect of hfd on hepatic ppar expression was observed in mice on a c57bl/6 background (fig. 2c). to examine whether ppar up-regulation by hfd may be connected with insulin we measured the effect of insulin on ppar expression in isolated rat hepatocytes and fao rat hepatoma cells. in both cell types, ppar expression was markedly decreased by insulin treatment (fig. 2, d and e). thus, up-regulation of hepatic ppar by hfd may be attributed to a diminished response to insulin, although other mechanisms cannot be excluded.
to examine whether hfd is associated with increased ppar activity in liver, we measured mrna expression of cyp4a10 and cyp4a14. both are target genes that are extremely sensitive to the presence and activation of ppar in mouse liver and can thus serve as markers of ppar activity. expression of cyp4a10 and cyp4a14 was highly induced by wy14643 and by fasting in wild-type mice, whereas expression was very low throughout and not inducible in ppar null mice (fig. 3, a and b). feeding the hfd resulted in increased expression of both genes in wild-type but not ppar null mice, indicating enhanced ppar activity, although the effects were modest compared with wy14643 and fasting (fig. 3c).
to examine whether this pattern of expression was similar for other classical target genes of ppar, a comparative microarray experiment was performed on liver of wild-type and ppar null mice either fed wy14643, fasted, or fed a hfd. analysis of expression of characteristic ppar target genes involved in peroxisomal and mitochondrial fatty acid oxidation revealed a clear ppar-dependent regulation by wy14643 and fasting (fig. 4, a and b; and table 1). similar to cyp4a10 and cyp4a14, expression of this set of genes was increased by hfd in a ppar-dependent manner, although again the effects were less pronounced compared with wy14643 and fasting (fig. 4c and table 1).
interestingly, when the changes in expression induced by hfd were expressed in relative terms for wild-type and ppar null mice separately, thus correcting for differences in basal expression, the effect of hfd was similar for wild-type and ppar null mice (data not shown and table 1, compare last two columns). this suggests that there might be compensation for ppar in the ppar null mice, perhaps by other ppar isotypes. indeed, whereas ppar/ expression was hardly affected by either hfd or ppar deletion (fig. 5), ppar showed a most remarkable pattern. expression was elevated by both hfd and ppar deletion, resulting in a 20-fold increase in ppar mrna in ppar null mice on hfd compared with wild-type mice on lfd (fig. 5a). in ppar null mice on hfd, levels of hepatic ppar mrna reach almost 80% of that of ppar in wild-type mice (fig. 5b), suggesting that it may be functionally important. in support of a functional role of ppar in ppar null mouse liver, expression of ppar targets cd36/fat, lpl, ap2, and uncoupling protein 2 mirrored that of ppar, suggesting that these genes are up-regulated by ppar in liver (fig. 5a). interestingly, induction of cytosolic glycerol 3-phosphate dehydrogenase and glycerol kinase by hfd was at least as strong in ppar null mice compared with wild-type mice, even though basal expression was lower in the ppar null mice. overall, these data suggest that in mice lacking ppar the effect of hfd on ppar target genes may be mediated by ppar, which is highly up-regulated in ppar null mice on a hfd.
to examine whether ppar is able to up-regulate characteristic ppar target genes involved in fatty acid oxidation and catabolism, expression of these genes was determined in liver of ppar null mice infected with ppar1-expressing adenovirus. under these conditions, expression of ppar was highly up-regulated (fig. 6a), whereas ppar/ was not affected (fig. 6b). it has previously been shown, and which is confirmed here, that ppar1 overexpression causes up-regulation of several ppar target genes, as well as other genes involved in lipo/adipogenesis (fig. 6c) (9, 20). however, ppar overexpression also led to the pronounced induction of numerous characteristic ppar target genes involved in fatty acid oxidation and ketogenesis, including hmg-coenzyme a (coa) synthase, bifunctional enzyme, very long chain acyl-coa dehydrogenase and carnitine palmitoyl-transferase 2 (fig. 6d), plus many others (9). these data demonstrate that, when expressed at a certain level, ppar is able to up-regulate classical ppar target genes in liver.
previous studies had shown that, whereas hfd impairs glucose tolerance in wild-type mice, this is not the case in ppar null mice, which thus appear to be protected from the effects of hfd (22). however, if indeed ppar is able to compensate for ppar in the null mice as in our experiment, one would expect that hfd would cause deterioration of glucose tolerance in ppar null mice as well. indeed, although glucose tolerance was improved by ppar deletion, hfd exacerbated glucose tolerance to a similar extent in wild-type and ppar null mice (fig. 7, a and b). interestingly, the area under the glucose tolerance curve (fig. 7b) showed remarkable similarity with the expression pattern of ppar target genes (fig. 4c), including cytosolic glycerol 3-phosphate dehydrogenase (fig. 5a).
discussion
numerous in vivo and in vitro studies have shown that ppar is activated by fatty acids (23, 24, 25, 26). it has also been clearly established that, in liver, ppar stimulates the expression of a large set of genes involved in fatty acid catabolism (12). accordingly, hepatic ppar is considered to function as a fatty acid sensor that adjusts catabolism of fatty acids to the prevailing plasma fatty acid concentration. this is especially relevant during fasting, when plasma ffas and the flux of fatty acids through the liver increases dramatically (16, 18).
whereas fasting has been an important evolutionary force shaping human energy metabolism, it is rarely encountered in modern industrialized societies. instead, we are dealing with a crisis of overnutrition, giving rise to obesity and associated ailments. obesity and fasting appear to represent two ends of the metabolic spectrum, yet they are both associated with elevated hepatic fatty acid flux and diminished insulin signaling. inasmuch as hepatic ppar mediates an adaptive response to fasting, the aim of this study was to determine whether ppar may mediate some effects of chronic hfd, which is used as a model system for obesity/insulin resistance. using expression profiling, it is observed that hfd results in activation of ppar target genes, probably via a combination of increased ppar mrna and elevated plasma ffa levels. because the effects of hfd on gene expression are small, which is common in nutritional interventions, a pattern only emerges by analyzing all genes together, illustrating the power of microarray analysis. although the effects are modest compared with what is observed after treatment with wy14643 or after fasting, hfd is a much more chronic exposure, suggesting that some of the long-term effects of hfd on lipid metabolism may be mediated by ppar. our data support and extend previous data by kroetz et al. (27), which showed that induction of hepatic cyp4a during streptozotocin-induced diabetes requires ppar.
the up-regulation of ppar mrna by hfd is expected to serve a physiological purpose similar to what happens during fasting. during hfd, increased amounts of fatty acids arrive at the liver and concomitantly there is an increased requirement for fatty acid oxidation. despite up-regulation of ppar and numerous ppar target genes involved in fatty acid oxidation, hfd causes fatty liver, suggesting that the up-regulation is not sufficient to efficiently catabolize the extra load of fatty acids. this is again analogous to what is observed during fasting, when there is spillover of fatty acids into the triglyceride synthesis pathway despite stimulation of fatty acid oxidation, causing a fatty liver (16, 18, 28). importantly, deletion of ppar resulted in more pronounced hepatic accumulation of triglycerides during both fasting and hfd, suggesting that ppar protects from lipid overload in these situations. this observation underscores the notion that ppar in liver becomes especially important when the flux of fatty acids through the liver is increased.
our data clearly demonstrate that insulin represses the expression of ppar in hepatocytes. accordingly, it can be hypothesized that the up-regulation of hepatic ppar by fasting and hfd may be related to attenuation of insulin signaling. supporting our data, de fourmestraux et al. (29) showed that feeding a hfd to c57bl/6 mice resulted in up-regulation of hepatic ppar mrna, together with some of its target genes involved in -oxidation. interestingly, the increase in ppar only occurred in mice developing obesity-related diabetes but not those remaining lean and healthy, suggesting that ppar up-regulation is connected with defective insulin action (29).
recently, lin et al. (30) proposed that the transcription factor sterol regulatory element binding protein (srebp) and ppar coactivator (pgc)-1 may be involved in mediating the effects of hfd on lipogenesis. in contrast to lin et al., we found pgc-1 expression to be decreased after high-fat feeding. it is well established that high-fat feeding is associated with suppression of endogenous fatty acid synthesis. in our experiment, we observed marked suppression of lipogenic genes by hfd, including fatty acid synthase, atp-citrate lyase, acetyl-coa carboxylase and others. as mentioned above, pgc-1 mrna was decreased as well, suggesting that it may mediate suppression of lipogenesis by hfd.
our data clearly show that hepatic ppar is highly up-regulated in ppar null mice on a hfd, reaching an expression level that approximates ppar. at that level of expression, ppar may compensate for ppar by mediating the hfd-induced up-regulation of characteristic ppar target genes involved in fatty acid oxidation in ppar null mice. indeed, ppar does not appear to possess some intrinsic property that prevents it from activating classical ppar targets, as indicated by the marked induction of ppar target genes in liver by adenoviral ppar overexpression. similarly, ppar can act on behalf of ppar because ppar activation by wy14643 causes marked hepatic up-regulation of classical ppar targets lpl, cd36, and ap2, as shown here and in previous studies (7, 31, 32). remarkably, in our study, regulation of lpl, cd36, and ap2 by ppar was not observed under conditions of physiological activation of ppar by fasting. by comparing the role of ppar in mediating the effects of wy14643, fasting and high-fat feeding on gene transcription (table 1), it becomes clear that the function of ppar in normal hepatic gene regulation cannot simply be extrapolated from pharmacological activation of ppar using synthetic agonists. this is an extremely important conclusion that can clarify some of these discrepancies in the literature with respect to role of ppar in hepatic gene regulation.
compensation for ppar by ppar is not necessarily limited to gene expression but may translate into functional consequences, such as fasting blood glucose levels and glucose intolerance, which are reduced in ppar null mice. previous studies by guerre-millo et al. (22) had shown that hfd impairs glucose tolerance in wild-type mice, but not in ppar null mice, which thus appear to be protected from the effects of hfd. however, in our hands ppar null mice were not protected from hfd-induced deterioration of glucose homeostasis, possibly thanks to up-regulation of ppar expression. the reason for the discrepancy is not very clear but may be related to the type of hfd. importantly, compensation by ppar in ppar null might not be limited to hfd. indeed, hashimoto et al. (28) reported that after 72 h of fasting, hepatic ppar mrna was increased in ppar null mice vs. wild-type mice. one can speculate that this may explain why ppar null mice seem to experience a second wind after 24 h of fasting rather than die from the severe metabolic disturbances.
up-regulation of ppar mrna in liver by hfd was associated with increased hepatic triglyceride levels. however, it is not exactly clear in what order they occurred: 1) increased triglyceride levels, either because of impaired fatty acid oxidation (ppar null mice) or increased fat delivery (hfd) causes ppar expression to go up; or 2) increased ppar mrna, either as a compensatory mechanism (ppar null mice) or elicited by hfd, stimulates lipogenesis and triglyceride storage. probably, both mechanisms are working in concert to induce a vicious cycle of enhanced hepatic triglyceride storage. previous studies have demonstrated that ppar overexpression is both necessary and sufficient to induce fatty liver (9, 11, 33). hepatic ppar expression is up-regulated in animal models of severe obesity and lipoatrophy, concurrent with development of steatosis. under those circumstances, treatment with tzd further aggravates hepatic steatosis, whereas deletion of ppar decreases hepatic fat storage. this positive link between ppar and liver fat storage is supported by studies by yu et al. (9), which showed that ppar1 overexpression in liver causes hepatic steatosis and induction of adipocyte-specific gene expression.
in muscle, elevated tissue triglyceride levels are associated with impaired insulin sensitivity, possibly via a mechanism that involves fatty acyl-coa. because in various animal models of obesity/diabetes impaired hepatic insulin sensitivity is associated with a fatty liver, it has been suggested that a similar mechanism may operate in liver. however, ppar null display improved glucose tolerance and insulin sensitivity (13), despite markedly elevated hepatic triglyceride levels. this indicates that in ppar null mice hepatic triglycerides and insulin resistance are disconnected. this is also true in liver-specific ppar null mice, casting doubt on the impact of hepatic triglycerides on hepatic insulin resistance (33).
overall, we conclude that 1) ppar and ppar are activated in liver by high-fat feeding, the latter mainly in the absence of ppar; and 2) in ppar null mice on a hfd, ppar is able to compensate for ppar, which might translate into functional consequences.
acknowledgments
the authors would like to thank rene bakker, jolanda van der meijde, and bart van rossum for technical assistance.
footnotes
this work was supported by the dutch diabetes foundation, with additional support by the netherlands organization for scientific research (nwo), the royal netherlands academy of art and sciences (knaw), and the wageningen center for food sciences.
first published online december 15, 2005
abbreviations: ap2/fabp4, fatty acid binding protein 4; coa, coenzyme a; cyp, cytochrome p450; fat/cd36, fatty acid translocase/cluster of differentiation 36; ffas, free fatty acids; hfd, high-fat diet; lfd, low-fat diet; lpl, lipoprotein lipase; pgc, ppar coactivator; ppar, peroxisome proliferator-activated receptor; q-pcr, quantitative pcr; trb-3, tribbles homolog.
accepted for publication december 7, 2005.
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