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1Department of Human Biology and Nutritional Sciences, University of Guelph, Guelph, Ontario N1G 2W1, Canada; 2Department of Molecular Genetics, Maastricht University, 6200-MD Maastricht, The Netherlands; 3Section of Endocrinology and Metabolism, Wake Forest University School of Medicine and Baptist Medical Center, Winston-Salem, North Carolina 27157; and 4Thrombosis Research Laboratory, Otsuka America Pharmaceutical Inc., Rockville, Maryland 20850
Submitted 16 December 2003 ; accepted in final form 11 May 2004
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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fatty acid translocase; plasma membrane-associated fatty acid-binding protein; cardiac myocytes; transport; plasma membrane; low-density microsomes; perfusion; heart
LCFA transporters and rates of LCFA transport are also altered in obesity and diabetes. In obese Zucker rats (17) and streptozotocin (STZ)-induced diabetes (16), LCFA transport into heart and muscle is increased through the subcellular redistribution of FAT/CD36 to the plasma membrane [obesity (17)] and through the increased expression of FAT/CD36 and FABPpm, resulting in their increased sarcolemmal content [type 1 diabetes (16)]. Because of the many alterations in circulating substrates and hormones in these animal models, it was not possible to determine which factor(s) accounted for the changes in LCFA transporters. But, given that LCFA transporter expression is increased in STZ-induced diabetes (16), it is tempting to suggest that the hypoinsulinemia in this model may have contributed to the upregulation of the FAT/CD36 and FABPpm mRNAs and proteins in the heart (16). Indeed, this is suggested by studies in 3T3-L1 adipocytes, in which insulin rapidly reduced the expression of fatty acid transport protein (FATP)-1 mRNA (21), another LCFA transporter. Whether insulin also regulates the expression of FAT/CD36 and FABPpm is not known. Therefore, in the present studies, we have examined the effects of insulin on regulating the expression of the LCFA transporters FAT/CD36 and FABPpm 1) in cardiac myocytes and 2) in perfused hearts. In addition, we determined 3) the effects of insulin on the subcellular distribution of LCFA transporters, 4) the effects of insulin on the rates of LCFA transport, and 5) the insulin-signaling pathway involved in regulating the expression of LCFA transporters. Our results demonstrate that insulin rapidly upregulated FAT/CD36, but not FABPpm, protein expression, via the phosphatidylinositol (PI) 3-kinase-signaling pathway. This increase in FAT/CD36 expression was accompanied by an increased plasmalemmal content of FAT/CD36, which increased the rate of LCFA transport into giant vesicles.
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METHODS |
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: anti-PKC/ and anti-phospho-PKC/ (Thr410/403; Cell Signaling Technology)]. Goat-anti-rabbit secondary antibodies were purchased from Santa Cruz Biotechnology. [1-14C]palmitate was purchased from Amersham Life Sciences (Little Chalfont, UK). BSA [fraction V, essentially fatty acid free (confirmed in separate analyses)] and phloretin were obtained from Sigma-Aldrich (St. Louis, MO). Collagenase type II was purchased from Worthington (Lakewood, NJ). Insulin (Humulin-R) was purchased from Eli Lilly (Toronto, ON, Canada). All other chemicals were obtained from Sigma-Aldrich. Animals and isolation of cardiac myocytes. Male Wistar Rats (250–300 g) were bred on site and maintained at 20°C on a reverse light-dark cycle in approved animal holding facilities. They had unrestricted access to food and water. This study was approved by the committee on animal care at the University of Guelph.
Cardiac myocytes were isolated from male adult rats according to the procedure described by Fisher et al. (11), as modified by Luiken et al. (19). Briefly, rats were anesthetized using Somnotol (50–60 mg/100 g ip) combined with heparin (300 IU/100 g ip). The hearts were quickly removed and placed in ice-cold Krebs-Henseleit bicarbonate buffer (KHB, pH 7.4) and equilibrated with 95% O2-5% CO2. Subsequently, hearts were perfused (20 min) in a recirculating mode with KHB buffer supplemented with 0.7% (wt/vol) BSA, 15 mM butanedione monoxime, and 0.075% (wt/vol) collagenase type II. CaCl2 was added to a final concentration 0.2 mM during the perfusion. After 20 min, hearts were removed and gently minced. The suspension was incubated for another 10 min at 37°C while the CaCl2 concentration was gradually raised to 1.0 mM. Cells were then filtered through a 0.2-mm nylon gauze and centrifuged for 2 min at 20 g. After isolation, cells were washed twice and suspended in 20 ml of medium A [KHB buffer supplemented with 2% (wt/vol) BSA and 1 mM CaCl2]. At the beginning of the experiments, the percentage of rod-shaped cells excluding trypan blue was determined. For all the experiments >80% of the cardiac myocytes were structurally intact. For determination of cardiac myocyte wet mass, duplicate aliquots of the cells suspensions were centrifuged (2–3 s at 10,000 g). The yield of cardiac myocytes ranged from 500 to 600 mg per single heart.
Effects of insulin on FAT/CD36 and FABPpm and cardiac myocyte viability. The effects of insulin on cardiac myocyte FAT/CD36 and FABPpm were examined during time course studies (10 nM insulin, 0–180 min; typically experiments were conducted over 120 min) and dose-response studies (0–100 nM insulin, 2 h). All studies were performed at 37°C. Viability was assessed in freshly obtained cardiac myocytes immediately after their isolation and after 2–4 h of incubation. Cardiac myocyte ATP content was determined after acidification of cell samples with ice-cold perchloric acid (final concentration 0.5 M), as described by Williamson and Corkey (33). The metabolically competent and dead myocytes were distinguished using a commercially available kit for cell viability (Cytotoxity/Viability Kit L-3224; Molecular Probes, Eugene, OR).
Determining insulin-signaling pathways involved in regulating LCFA transporter expression.
To ascertain the signaling pathways involved in the insulin-induced regulation of LCFA transporters, cardiac myocytes were pretreated for 1 h with selected inhibitors followed by treatment with insulin (10 nM for 2 h). The inhibitors used were as follows: myristoylated PKC/ pseudosubstrate inhibitor (PKC-ps, 10 µM) has been used as a cell-permeable specific inhibitor of PKC/ kinases (24); UO-126 has been used at a concentration of 10 µM as a highly selective inhibitor of the MAP kinases MEK1 and MEK2 (10); LY-294002 was shown to act as highly selective inhibitor of PI 3-kinase and at a concentration of 50 µM does not inhibit lipid and protein kinases such as PI 4-kinase, PKC, or MAP kinase (31).
Effects of insulin on LCFA uptake by cardiac myocytes. To examine the effects of 2-h insulin (10 nM) exposure on palmitate uptake by cardiac myocytes, we used the procedure of Luiken et al. (19). For these purposes, 0.6 ml of a [1-14C]palmitate-BSA complex was added to 1.8 ml of cardiomyocyte suspension (final palmitate concentration 100 µM, palmitate/BSA ratio of 0.3). Palmitate uptake was stopped by adding an ice-cold stop solution [KHB supplemented with 0.1% BSA (wt/vol), 1 mM CaCl2, and 0.2 mM phloretin]. Subsequently, cells were washed twice with the stop solution at 60 g for 2 min. The final pellet was assayed for radioactivity.
Subcellular fractionation of cardiac myocytes. To detect the subcellular distribution of FAT/CD36 and FABPpm, plasma membranes (PM) and low-density microsomes (LDM), were isolated from cardiac myocytes. Isolated cardiac myocytes (50 mg wet mass/ml) were incubated with medium A and constantly gassed with 95% O2-5% CO2 with (10 nM) or without insulin for 2 h. At the end of the experiments, NaN3 was added (final concentration 5 mM), and samples were frozen in liquid N2 and kept at –80°C until analyzed. Subsequently, PM and LDM fractions were obtained as we (19) have previously described. Briefly, on being thawed, cardiac myocytes were centrifuged for 15 min at 17,000 g. The pellet was then washed with TES buffer (20 mM Tris, pH 7.4, 1 mM EDTA, 250 mM sucrose, and 100 µM PMSF) and centrifuged for 20 min at 17,000 g. Thereafter, the resuspended pellet was homogenized (10 strokes) in a glass homogenizer, and the total volume was layered on top of a sucrose cushion (38% wt/vol) in 15 ml of Tris, pH 7.4, containing 1 mM EDTA. Subsequently, samples were centrifuged for 65 min at 65,000 g. The interface was collected, diluted with 20 ml of TES buffer, and pelleted at 48,000 g for 30 min. The final pellet yielded the PM, and this was resuspended in 100 µl of TES buffer. For the collection of intracellular membrane pools, the supernatant fraction from the first 17,000-g centrifugation step was collected and centrifuged for 30 min at 48,000 g. The resulting in supernatant fraction was centrifuged for 65 min at 250,000 g. This yielded LDM, which were resuspended in 100 µl of TES buffer. In the LDM fraction there was no mitochondrial contamination, as determined by the absence of the mitochondrial enzyme cytochrome oxidase (data not shown). We have previously reported that the PM fraction was enriched with the ouabain-sensitive p-nitrophenylphosphatase (13.5-fold enrichment) accompanied by the decrease in sarcoplasmatic EGTA-sensitive Ca2+-ATPase (3.6-fold decline) (19).
Heart perfusion, giant vesicle preparation, and LCFA transport. Isolated hearts were perfused with (10 nM) or without insulin in a Langendorff mode, using continuously gassed (95% O2-5% CO2) medium A. After 2 h, the ventricles were removed and frozen in liquid N2 and stored at –80°C until analyzed for FAT/CD36 and FABPpm by use of Western blot analysis.
Before preparation of giant sarcolemmal vesicles, hearts were perfused with (10 nM) and without insulin for 2 h. Thereafter, the ventricles were removed and placed in KCl-MOPS buffer (140 mM KCl, 10 mM MOPS, pH 7.4). Giant sarcolemmal vesicles were prepared as we have previously reported (18, 20). Briefly, perfused ventricles were scored into strips with a scalpel and incubated for 1 h at 34°C in KCl-MOPS supplemented with 0.142 mg/ml PMSF, 10 mg/ml aprotinin, and 150 U/ml type II collagenase. The incubation medium was collected, and the ventricles were washed with 10 mM EDTA in KCl-MOPS until 7 ml had been collected. Percoll was added to the collected medium in a volume ratio of 7:30. This mixture was slowly pipetted under a density gradient of 3 ml of 4% (wt/vol) Nycodenz, on top of which 1 ml of KCl-MOPS was layered. The samples were centrifuged in a swinging bucket rotor (Beckman) at 60 g for 45 min at room temperature. After centrifugation, the vesicles were collected from the interface between the Nycodenz and KCl-MOPS solutions. The vesicles were pelleted at 12,000 g for 5 min at room temperature. The supernatant was aspirated, and the vesicles were slightly diluted with KCl-MOPS supplemented with PMSF. Vesicles were used immediately for LCFA transport. Some vesicles were also stored at –80°C until analyzed for plasmalemmal LCFA transporters.
LCFA transport was performed as we have previously reported (18, 20). Briefly, a reaction medium [unlabeled palmitate, radiolabeled [3H]palmitate (0.3 µCi), and [14C]mannitol (0.06 µCi) dissolved in 0.1% BSA-KCl-MOPS solution] was added to the vesicles (40–80 µg protein) and incubated for 15 s at room temperature. A stop solution (2.5 mM HgCl in 0.1%BSA-KCl-MOPS) was added and the sample immediately centrifuged (12,000 g, 2 min). The supernatant fraction was aspirated, and the bottom of the tube containing the pellet was cut off and placed in a scintillation vial. Standard liquid scintillation techniques were used to measure the radioactivity.
Western blot analysis.
FAT/CD36 and FABPpm were determined in heart homogenates and in cardiac myocytes, as well as in the PM and LDM fractions derived from cardiac myocytes. In addition, these proteins were also determined in giant vesicle PM prepared from whole hearts. We used routine Western blotting procedures as previously described (5, 16–19) to detect FAT/CD36 and FABPpm, as well as some other proteins to which we refer but for which the data have not been shown. Briefly, all samples were separated using 10% SDS-polyacrylamide gel electrophoresis, and polyclonal antiserum was applied. Membranes were immunoblotted with MO25 antibody against FAT/CD36, FABPpm antisera, anti-phospho-Akt1/2/3 (Ser473 or Thr308), anti-Akt1/2/3, anti-phospho-p42/44 MAP kinase (Thr202/204), anti-p42/44 MAP kinase, anti-phospho-PKC/, and anti-PKC/. Signals obtained by Western blotting were quantified by densitometry.
Northern blot analysis. Total RNA was isolated from cardiac myocytes using TriPure Isolation Reagent (Roche, Indianapolis, IN). Total RNA (3–5 µg) was loaded on a formaldehyde gel for each sample, electrophoresed at 100 V for 2.5 h, and transferred to positively charged nylon membranes (Roche). Equal loading of RNA and even transfers were confirmed by Blot Stain Blue (Sigma-Aldrich, Oakville, ON, Canada). FAT/CD36 and FABPpm digoxigenin (DIG)-labeled probes were generated using a DIG RNA labeling mix (Roche). Membranes were prehybridized for 30–60 min at 68°C in a standard hybridization buffer [containing 25% (FAT/CD36) or 50% (FABPpm) deionized formamide, 5x SSC, 0.1% N-lauroylsarcosine, 0.02% SDS, and 2x Blocking Solution (Roche)]. Membranes were hybridized overnight at 68°C in 1 µg of DIG-labeled probe per 10 ml of hybridization buffer. Membranes were washed, blocked in 1x Blocking Solution for 30 min, and incubated with anti-DIG-AP antibody (1:10 000) for 30 min. Signal detection was performed using CDP-Star chemiluminescent substrate (Roche). Blots were visualized and quantified using the ChemiGenius2 Bio Imaging System (Perkin Elmer, Boston, MA).
Statistics. All presented data are expressed as means ± SE. Depending on the experiment, statistical differences were tested with analyses of variance and Fisher's least significant differences post hoc test or with a t-test. Statistical significance was set at P < 0.05.
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RESULTS |
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Effects of insulin on cardiac myocyte FABPpm and FAT/CD36. We exposed freshly isolated cardiac myocytes to 10 nM insulin for varying periods of time. In the presence of insulin (10 nM), FAT/CD36 protein was increased over the 2-h period (Fig. 1A). No changes were observed within the first 30 min, but after 1 h, FAT/CD36 protein had increased by 25% (P < 0.05), reaching a plateau after 90 min (+51%, P < 0.05; Fig. 1A). When myocytes were not exposed to insulin, FAT/CD36 concentrations were not different from freshly obtained controls (P > 0.05; Fig. 1A).
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We also examined the dose-response effects of insulin (10–12 to 10–7 M). Increasing concentrations of insulin did not alter FABPpm (P > 0.05; Fig. 2). In contrast, there was a dose-dependent relationship between insulin and FAT/CD36 expression (P < 0.05; Fig. 2). Compared with fresh (t = 0), untreated cardiac myocytes, a 2-h exposure to 10–10 M insulin resulted in a 9% increase in FAT/CD36 (P < 0.05). Thereafter, FAT/CD36 protein increased progressively to +20% at 5 x 10–10 M insulin and reached a plateau at 10–9 to 10–8 M (45–48%) insulin (P < 0.05; Fig. 2).
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/, and these insulin-induced phosphorylations were blocked by LY-29004, UO-126, and PKC-ps, respectively (data not shown). Blocking of the PKC/-signaling pathway did not inhibit the insulin-induced expression of FAT/CD36 (P > 0.05; Fig. 7), whereas UO-126 only partially inhibited the insulin-induced FAT/CD36 expression (Fig. 7). In contrast, when the PI 3-kinase-signaling pathway was blocked by LY-29004, the insulin-induced increase in FAT/CD36 expression was completely inhibited (Fig. 7). When the increase in FAT/CD36 expression was blocked by LY-29004, insulin also failed to stimulate LCFA uptake into cardiac myocytes, whereas blocking of the other insulin-signaling pathways failed to inhibit the insulin-stimulated LCFA uptake (Fig. 8).
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DISCUSSION |
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Interestingly, the present studies have also shown that insulin does not regulate the expression of FABPpm, another LCFA transporter. Unexpectedly, we found that FABPpm is present not only at the plasma membrane, as is well known, but also in an intracellular low-density microsome depot. It is known that FABPpm is identical to the mitochondrial aspartate aminotransferase (6, 14, 28). However, the low-density microsome fraction is devoid of mitochondrial contamination (data not shown). The intracellular FABPpm pool, unlike the intracellular FAT/CD36 pool, is not a target for insulin-induced translocation. Possibly, other stimuli induce the translocation of FABPpm.
Except for the report by Man et al. (21), we are not aware of any studies that have examined the effects of insulin on the expression of LCFA transporters. It is worth noting that Man et al. found that insulin repressed the expression of FATP1 mRNA by 66% after 24 h (t1/2 = 4 h) in 3T3-L1 adipocytes, although neither the effects on protein expression nor the effects on LCFA transport were examined. It is important to do so, because there seems to be little relationship between LCFA transporter mRNAs and their protein products and between LCFA transporter mRNAs and rates of LCFA transport (1, 2, 16, 17). In contrast to the studies showing that insulin repressed FATP1 mRNA expression in 3T3-L1 adipocytes (21), we observed in cardiac myocytes that insulin markedly stimulated the protein expression of the LCFA transporter FAT/CD36, but not the LCFA transporter FABPpm. The insulin induction of FAT/CD36 expression was very rapid, with an increased protein expression being observed after only 1 h and continuing to increase further for another 30 min. Thereafter, FAT/CD36 remained stably overexpressed from minutes 90 to 120. We also observed a strikingly similar effect of the insulin-induced expression of FAT/CD36 in cardiac myocytes and in the intact heart, suggesting that our observations are relevant in vivo. In other studies, a rapid increase in protein expression and mRNA by a variety of stimuli has been observed in muscle tissue [i.e., 1.5- to 6-fold increase in uncoupling protein-3 in 30–200 min (34)]. Thus the rapidly induced increase in FAT/CD36 protein expression by insulin within 2 h is well within the timeline of those studies. The increased FAT/CD36 protein expression would appear to be mediated by pretranslational events, as insulin rapidly increases FAT/CD36 mRNA within this time period. An insulin-induced upregulation of FAT/CD36 mRNA has also been reported by others (23). In marked contrast, insulin did not affect the expression of FABPpm protein or its transcript. Thus, in our present study and others (21), insulin has unique effects on the expression of LCFA transporters; this hormone represses FATP1 mRNA (21) in 3T3-L1 adipocytes, does not regulate the expression of FABPpm in cardiac myocytes and the intact heart (present study), and upregulates the expression of FAT/CD36 in cardiac myocytes and the intact heart (present study). Although this may indicate that there are tissue-specific responses to insulin (i.e., 3T3-L1 adipocytes vs. cardiac myocytes), there can be no doubt that in the same tissue (heart) insulin differentially regulates the expression of two LCFA transporters, FAT/CD36 and FABPpm.
Recent studies have provided evidence that different signaling pathways can contribute to protein synthesis in cardiac myocytes (15, 32), and insulin can activate a number of signaling pathways (26, 29). Blocking insulin signaling through the MAP kinase- and PKC/-signaling pathways failed to inhibit the insulin-induced increase in FAT/CD36 expression. In contrast, we observed a complete inhibition of the insulin-induced expression of FAT/CD36 when the PI 3-kinase pathway was blocked. Thus the insulin-PI 3-kinase-Akt-signaling pathway must be activated to stimulate the expression of FAT/CD36. Recently, it was shown that the insulin-induced activation of Akt1 is required for growth (9), and possibly other functions, whereas the insulin-induced activation of Akt2 is essential to maintain normal glucose homeostasis (8). Whether insulin activation of Akt1 or Akt2 is required to induce the upregulation of FAT/CD36 remains to be established.
An important feature of the present studies is that we also examined the metabolic consequences of insulin-induced overexpression of FAT/CD36. For these purposes we 1) subfractionated cardiac myocytes to examine the effects of insulin on the subcellular distribution of FAT/CD36, 2) determined the plasmalemmal content of FAT/CD36 in giant vesicles, into which 3) we had examined the rates of palmitate transport. In agreement with our previous work (18, 19), insulin induced the translocation of FAT/CD36 from an intracellular depot to the plasma membrane within 30 min, before any changes in FAT/CD36 expression had occurred (data not shown). With more prolonged exposure to insulin (2 h) there were two effects: 1) FAT/CD36 expression was increased, and 2) the plasmalemmal FAT/CD36 was also further increased whereas the intracellular depot was decreased. Specifically, if the acute (30 min) insulin stimulation studies provide an index of the insulin-induced FATCD36 translocation to the plasma membrane, when FAT/CD36 expression is not altered (data not shown and Ref. 19), then the greater increase in plasmalemmal FAT/CD36 observed after 2 h of insulin exposure would seem to reflect the sum of the combined effects of 1) the insulin-induced expression of FAT/CD36 protein and 2) the insulin-induced translocation of FAT/CD36 to the plasma membrane. Thus insulin not only increases FAT/CD36 expression, but it also targets a similar proportion of this increase to the plasma membrane.
Our study also provides strong evidence that FAT/CD36, is involved with plasmalemmal LCFA transport. An increase in LCFA transport occurred only when plasmalemmal FAT/CD36 was increased, whereas no change in LCFA transport occurred when the insulin-induced effects on FAT/CD36 expression and translocation were blocked by LY-29004. We have previously shown that blocking FAT/CD36 specifically with a reactive ester (sulfo-N-succinimidyl oleate) inhibited LCFA transport (4, 20). Interestingly, insulin induced similar increases in palmitate transport (+34%) and plasmalemmal FAT/CD36 (+29%), as well as a similar increase in triacylglycerol esterification (+36%; data not shown). These observations underscore the fact that insulin can have a profound effect on LCFA uptake into the heart. This may be most relevant in the postprandial period, when insulin clears not only glucose from the circulation but apparently also LCFAs.
Previously, we (16) had observed in a model of STZ-induced diabetes that FAT/CD36 expression in the heart was increased. Thus it was tempting to ascribe these observations to the hypoinsulinemia in that model. However, the present results indicate that, under controlled conditions, insulin acts to increase the expression of FAT/CD36 in the heart. It would seem, therefore, that, in the STZ-induced diabetes model, the hypoinsulinemia may not have been at the root of the increased FAT/CD36 expression. In this model of diabetes, perturbations in circulating substrates also occur, and it is conceivable that the increased concentration of glucose and/or fatty acids, along with the concurrent hypoinsulinemia, contributed to the increased expression of FAT/CD36. This suggestion awaits confirmation by carefully controlled experiments in isolated hearts and cardiac myocytes.
In summary, we have shown that insulin induces the expression of the LCFA transporter FAT/CD36 in cardiac myocytes and the intact heart. The insulin-induced increase in FAT/CD36 expression is mediated via the PI 3-kinase-signaling pathway. The functional consequence of the insulin-induced increase in FAT/CD36 expression is an increased rate of LCFA transport across the plasma membrane, which was quantitatively similar to the increase in FAT/CD36 expression and the increase in plasmalemmal FAT/CD36 content. Thus insulin not only increased FAT/CD36 protein expression, but this hormone also targeted FAT/CD36 to the plasma membrane. Our studies also revealed that insulin failed to increase the expression of FABPpm. Unexpectedly, we found that FABPpm is present not only at the plasma membrane, but also in an intracellular depot. But, although insulin induced the translocation of FAT/CD36 from the intracellular depot to the plasma membrane, insulin failed to translocate FABPpm.
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The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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800 genes during a hyperinsulinemic clamp. J Biol Chem 278: 18063–18068, 2003.This article has been cited by other articles:
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