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Departments of Medicine and Physiology (G.F.L., K.U., L.S.), Division of Endocrinology and Metabolism, and the Department of Laboratory Medicine and Pathobiology (M.N., M.H., K.A.), Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada M5G 2C4
Address all correspondence and requests for reprints to: Gary F. Lewis, Toronto General Hospital, 200 Elizabeth Street, EN11-229, Toronto, Ontario, Canada M5G 2C4. E-mail: gary.lewis{at}uhn.on.ca.
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Abstract |
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Introduction |
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We have recently established the fructose-fed hamster as a nondiabetic model of whole-body and hepatic insulin resistance and metabolic dyslipidemia (13) and have shown that rosiglitazone treatment of the fructose-fed hamster ameliorates whole-body insulin resistance, improves hepatic insulin signaling, and reduces hepatic lipoprotein overproduction (14). The tissue-specific expression of apoB100 (only in the liver) and apoB48 (only in the intestine) is a distinct advantage of the hamster model over other rodent models in permitting the study of intestinal vs. hepatically derived lipoproteins in vivo (15, 16). ApoB48 is an essential structural component of intestinally derived chylomicrons and chylomicron remnants. Thus, the use of the hamster model makes it possible to investigate the mechanisms of chylomicron and chylomicron remnant metabolism in insulin-resistant states because apoB48-containing lipoproteins are almost exclusively secreted by the intestine.
We recently used the fructose-fed hamster model to investigate the role of intestinal lipoprotein production in the development of metabolic dyslipidemia (17). In this model, we found a 2- to 3-fold elevation in apoB48 particle production rate in vivo compared with chow-fed hamsters. The increased secretion of intestinal apoB48-containing particles was confirmed ex vivo in cultured enterocytes derived from fructose-fed hamsters. Similar to hepatic overproduction of apoB100-containing lipoproteins (13), the ex vivo experiments showed that chronic fructose feeding was associated with greater stability of intracellular apoB48, enhanced intestinal enterocyte de novo lipogenesis, and up-regulation of the key protein involved in intestinal lipoprotein assembly, microsomal TG transfer protein (MTP) (17).
In the present study we used the peroxisome proliferator-activated receptor 
agonist and insulin sensitizer rosiglitazone in the fructose-fed hamster to determine whether the administration of this insulin-sensitizing agent is associated with amelioration of intestinal lipoprotein overproduction in the fructose-fed hamster. We measured apoB48 production both in vivo and ex vivo in this animal model of insulin resistance and assessed the response to insulin sensitization with rosiglitazone. We also measured the effect of insulin sensitization on the expression of a key protein involved in intestinal lipoprotein assembly, MTP.
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Materials and Methods |
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In vivo determination of intestinal lipoprotein particle production rates
Methods for the in vivo determination of intestinal lipoprotein particle production have been published previously (17). Briefly, 1 d before these studies, femoral venous and arterial catheters were inserted as described previously (13). The animals were fasted overnight for 16 h. A baseline blood sample was drawn followed by an iv bolus of Triton-WR1339 (Sigma Chemical Co., St. Louis, MO). After Triton administration, blood samples were drawn at 10 and 20 min (total blood volume withdrawn for the entire study was 1.2 ml). The Svedberg unit (Sf) > 400 (large TRL) and Sf 100–400 (smaller TRL) fractions were isolated as previously described (17). ApoB48 was quantified using analytical SDS-PAGE as described previously (20), in which there is no contamination by apoB100. Large and small apoB48 and TG secretion rates were derived by multiplying the slope of the concentration increase of apoB48 and TG, respectively, over time by the intravascular distribution volume estimated as 3.8 ml/100 g body weight (14).
Studies performed in the postprandial state were as described above except that they were manually administered 400 µl of lard at time 0 and then every 20 min over 60 min, to achieve a steady fat-fed condition as previously described (17). The bolus of Triton-WR1339 was given 1 h after starting feeding, and blood samples were drawn as described above.
Triton method validation experiments
We performed additional experiments in three animals in which we compared the slope of apoB48 vs. time after Triton administration, calculated from three vs. five time points. We found no significant difference in the slopes calculated from either three or five time points [5.3 ± 0.45 µg/min vs. 5.1 ± 0.58 µg/min, respectively, for Sf > 400, P = not significant (NS); and 5.5 ± 0.85 µg/min vs. 5.3 ± 0.84 µg/min, respectively, for Sf 100–400, P = NS). To keep blood volumes drawn for each experiment to a minimum we have calculated the slope of the apoB48 vs. time curves using three rather than five time points.
Ex vivo protocols
Isolation of primary hamster enterocytes.
The isolation of viable adult villi from hamster small intestine was based on that described by Perreault and Beaulieu (21) with some modification as reported recently (17).
Characteristics of the isolated enterocytes and their functional viability have been documented previously (17). We have also assessed the stability of primary cultured enterocytes over the time course of the experiments reported in the manuscript. Primary enterocytes were radiolabeled for 20 min after 90, 120, and 150 min of incubation. No significant change was observed in the total amount of apoB48 secreted by cultured enterocytes over these time periods (data not shown), although there is loss of the cell’s ability to secrete apoB48 over time after 2.5 h after isolation. The experiments reported in this manuscript, however, always use cells within 2.5 h of isolation, at which time the apoB48 secretion is high and there is greater than 90% cell viability. Thus we have shown that there is no appreciable loss of cell viability or differentiation over the time course of our pulse-chase experiments reported in the manuscript. We have also tested the effect of rosiglitazone in vitro on primary enterocytes and have found no effect on cell viability as assessed by total protein synthesis.
Metabolic labeling of intact primary hamster enterocytes.
Primary hamster enterocytes were used for pulse-chase experiments as described (17). Briefly, cells were preincubated in methionine-free DMEM for 30 min and pulsed with 50 µCi/ml [35S]methionine (equals 1.85 MBq/ml) for 25 min. After the pulse, the cells were washed and chased in methionine-supplemented DMEM. At 90 min, triplicate dishes were harvested, and cells were lysed in solubilization buffer and the lysates were used for immunoprecipitation, as described (22). As a control, we have monitored changes in total protein synthesis by assessing both acid-precipitable radiolabeled protein (trichloroacetic acid counts) as well as total protein mass assays. No specific protein was used as apoB48 is itself a highly specific protein expressed only by intestinal enterocytes.
SDS-PAGE, fluorography, and immunoblotting of primary hamster enterocytes.
Immunoprecipitates were analyzed by SDS-PAGE and fluorography, essentially as described (23). ApoB48 bands, visualized by fluorography, were quantified by excision from the gel, digestion, and scintillation counting essentially as described (22). The 97-kDa subunit of MTP was measured by chemiluminescent immunoblotting as previously described (22), using a goat anti-bovine MTP antiserum provided by Dr. David Gordon (Bristol Myers Squibb, Princeton, NJ). For MTP blots, we measured total protein content and loaded equal amounts of total protein on each lane of the gel (typically 20 µg). Thus, the MTP data shown in Fig. 4
are normalized for protein content. In addition to the measurement of MTP mass in cultured hamster enterocytes, we also measured MTP mass in total intestinal tissue isolated from three hamsters from each treatment group (i.e. without primary culture of hamster enterocytes). MTP protein mass was quantified by densitometry using FluorChem Imaging software (Alpha Innotech Corp., San Leandro, CA). Lipoprotein fractionation was achieved by sequential ultracentrifugation of the culture medium to isolate large chylomicrons (17, 24).
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Other laboratory methods
Glucose was determined on whole blood using a glucometer (Sure Step, One Touch). Plasma insulin concentrations were determined by RIA using a rat insulin kit from Linco Research (St. Louis, MO). This assay has 100% cross-reactivity to hamster insulin, and the intra- and interassay coefficients of variation were 6.8 and 10.6%, respectively. Plasma free fatty acids (FFAs) were measured by a colorimetric method (kit supplied by Wako Industrials, Neuss, Germany) with a coefficient of variation of 4.7% for intra- and 8.2% for interassay variation. TG was measured using a colorimetric assay (Roche Mannheim GmbH Diagnostica, Laval, Quebec, Canada) with an intra- and interassay coefficient of variation of 3.0 and 4.9%, respectively.
Statistical analysis
All the values are reported as mean ± SEM. For comparison of TRL TG and apoB48 secretion rates between CHOW, CHOW+RSG, FRUC, and FRUC+RSG hamsters, ANOVA was used followed by post hoc analysis with Tukey’s test. A P value < 0.05 was considered to be significant.
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Results |
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) are cumulative data from our laboratory from animals that had undergone identical feeding and rosiglitazone treatment protocols, but these animals did not undergo in vivo studies for assessment of lipoprotein production. There was no significant difference in any of the variables between groups. There was a strong trend for FRUC to have higher TGs, insulin, and glucose, but perhaps because of high inter-animal variability, the differences were not significant.
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Triton WR-1339 studies for determination of in vivo intestinal lipoprotein production in the fasting state (Fig. 1)
There was an approximately 2.5-fold greater apoB48 secretion rate with chronic fructose feeding compared with chow in large TRL (Sf > 400 fraction; P < 0.01) and an approximately 2-fold higher apoB48 secretion rate in smaller TRL (Sf 100–400 fraction; P < 0.05) (Fig. 1, B and D). Treatment of fructose-fed hamsters with rosiglitazone resulted in an approximately 50% lower apoB48 secretion rate than fructose alone in both TRL fractions (for Sf > 400, P < 0.05 vs. FRUC and P = NS vs. other treatment groups; for the Sf 100–400 fraction, P < 0.05 vs. FRUC and P = NS vs. other treatment groups), but treatment of CHOW-fed hamsters with rosiglitazone resulted in no significant change in apoB48 secretion rate in either the large or smaller TRL fraction. There was no significant difference in TG secretion rates between any of the groups in either large or small TRL fractions (Fig. 1, A and C).
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Triton WR-1339 studies for determination of in vivo intestinal lipoprotein production in the postprandial state (Fig. 2)
TG and apoB48 secretion rates were measured in the large (Sf > 400 TRL) and smaller (Sf 100–400) fractions in CHOW, CHOW+RSG, FRUC, and FRUC+RSG hamsters after 60 min of fat feeding. In the Sf > 400 fraction, TG secretion rate tended to be higher in FRUC compared with CHOW and was significantly decreased with rosiglitazone treatment (P = 0.08 for CHOW vs. FRUC; P < 0.05 for FRUC+RSG vs. FRUC and CHOW) (Fig. 2A). There was no significant change in TG production in the Sf > 400 fraction when CHOW-fed hamsters were treated with RSG. In the Sf 100–400 fraction, TG secretion was increased approximately 2-fold in FRUC and normalized with rosiglitazone (P < 0.05 for FRUC vs. CHOW; P < 0.01 for FRUC+RSG vs. FRUC) (Fig. 2C). There was no significant difference in Sf 100–400 TG secretion in the CHOW+RSG.
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). In the Sf 100–400 fraction, apoB48 secretion tended to increase (by 
2-fold) in FRUC (P = NS for all) (Fig. 2D). There was no difference in apoB48 production rate in CHOW+RSG compared with the other treatment groups. TG/apoB48 was assessed in the postprandial state. In this case, the TG secretion rate was increased in FRUC, whereas the apoB48 secretion rate only tended to be increased. For the Sf > 400 fraction, the TG/apoB48 was increased in FRUC vs. CHOW and decreased in FRUC+RSG vs. FRUC (0.005 ± 001 for CHOW, 0.005 ± 001 for CHOW+RSG, 0.009 ± 002 for FRUC, and 0.003 ± 001 for FRUC+RSG; P < 0.05 for FRUC vs. CHOW; P < 0.01 for FRUC vs. FRUC+RSG). In the Sf 100–400 fraction, the TG/apoB48 was also increased in the FRUC group and decreased to normal in the FRUC+RSG group (0.005 ± 001for CHOW, 0.005 ± 001 for CHOW+RSG, 0.008 ± 001 for FRUC, and 0.005 ± 001 for FRUC+RSG; P < 0.001 for FRUC vs. CHOW; P < 0.01 for FRUC vs. FRUC+RSG; and P < 0.01 FRUC vs. CHOW+RSG).
Studies of apoB48 secretion in primary cultured enterocytes (Fig. 3)
Pulse-chase-labeling experiments were used to assess the secretion of apoB48 in villus enterocytes isolated from CHOW, FRUC, and FRUC+RSG hamsters. Figure 3, A and B, shows the extracellular secretion of chylomicron-specific and total apoB48 in enterocytes isolated from CHOW, FRUC, and FRUC+RSG hamsters. Enterocytes from FRUC hamsters secreted approximately 4-fold more newly synthesized chylomicron-specific and total apoB48 over a 90-min chase compared with that in CHOW animals (P = 0.01 for chylomicron-specific and total apoB48 in FRUC vs. FRUC+RSG). In fructose-fed animals, there was a 2-fold reduction in chylomicron and total apoB48 secretion with rosiglitazone treatment (P = 0.02 for chylomicron apoB48, and P = 0.01 for total apoB48 in FRUC vs. FRUC+RSG). Total apoB48 secretion was also assessed in a separate group of hamsters fed either CHOW or CHOW+RSG (Fig. 3C). No significant change in apoB48 was observed in CHOW hamsters treated with RSG. It should be noted that, in Fig. 3, apoB48 synthesis and secretion were normalized for both total cellular protein mass and the incorporation of [35S]methionine into total trichloroacetic acid-insoluble cellular and secreted proteins. Therefore, the stimulation of apoB48 synthesis and secretion was not a consequence of global effects of fructose-feeding on protein synthesis and secretion.
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, A and B) and transfer activity (Fig. 4C) in primary cultured enterocytes and MTP mass and transfer activity measured in intestinal tissue isolated from treated hamsters (not illustrated), in FRUC hamster enterocyte cell lysates, there was a significant increase in protein mass of MTP compared with CHOW controls (20% increase in MTP mass; P = 0.03), which was ameliorated by rosiglitazone treatment (30%; P = 0.008). Interestingly, no significant change was observed in MTP mass between CHOW and CHOW+RSG (Fig. 4B). The MTP transfer activity measured in enterocyte cell lysates mirrored the MTP protein mass data (Fig. 4C), with a significant increase in MTP transfer activity in FRUC vs. CHOW (110.5 ± 2.57 vs. 100.0 ± 2.58%; P < 0.05) and partial amelioration of this FRUC-induced increase with the addition of rosiglitazone treatment (103.2 ± 3.63%; P = NS for FRUC+RSG vs. FRUC). No difference was observed between CHOW+RSG (101.0 ± 1.65%) and CHOW. MTP mass and transfer activity were also measured directly in intestinal tissue (30 µg total protein per lane), but unlike the cell lysates, there was no significant difference in tissue MTP mass between the treatment groups, although there was a tendency for the mass to be higher in FRUC and FRUC+RSG vs. CHOW (MTP mass in CHOW = 100.0 ± 3.0%, FRUC = 110.4 ± 4.3%, and FRUC+RSG =118.7 ± 3.3%; P = NS between groups) (not illustrated). MTP activity measured directly in intestinal tissue was significantly increased by 13% in FRUC vs. CHOW (MTP activity in CHOW = 100 ± 2.94% and FRUC = 112.9 ± 4.83%; P < 0.01). Rosiglitazone did not, however, ameliorate this increase in MTP activity (FRUC+RSG=115.9 ± 4.72%, p=ns vs. FRUC, P < 0.001 vs. CHOW). CHOW+RSG (103.1 ± 1.2%) was not different from CHOW.
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Discussion |
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agonist activity, improved whole-body and hepatic insulin sensitivity and also decreased the overproduction of very-low-denisty lipoprotein apoB by hepatocytes ex vivo (14). In the present study, we have also shown that rosiglitazone treatment reduced the secretion of intestinally derived apoB48-containing lipoproteins in the fasting state and TRL TG secretion in the postprandial state in fructose-fed but not in chow-fed hamsters. The secretion of intestinal apoB48-containing particles was examined both in vivo and ex vivo, and similar results were obtained. Furthermore, rosiglitazone treatment was associated with a reversal of the increased intestinal expression of MTP seen with fructose feeding when measured in intestinal cell lysates, indicating one potential molecular mechanism by which rosiglitazone led to reduction of intestinal particle secretion in this insulin-resistant animal model. Whether this improvement in intestinal lipoprotein particle secretion resulted from the insulin-sensitizing effects of rosiglitazone or from another unrelated action of the drug will require additional study perhaps using relevant knockout and transgenic animal models. In the present study, apoB48 secretion in the fasting state was increased in large (Sf > 400) and smaller (Sf 100–400) TRL fractions, whereas there was no significant difference in TG secretion. The absence of a significant difference in TG secretion between control and insulin-resistant fructose-fed animals in the fasted state suggests that there is increased production of small, lipid-poor, apoB48-containing lipoproteins in these size ranges in the fasting state with fructose feeding. Fructose feeding was indeed associated with the production of smaller particles in the larger TRL Sf > 400 fraction, as evidenced by a reduction in the TG/apoB48 ratio, and a tendency toward smaller particle production in the smaller Sf 100–400 fraction. We speculate that the intestine constitutively secretes small apoB48-containing lipoprotein particles (and a greater number in insulin-resistant states) to be primed and ready for the ingestion of fat. In the fed (postprandial) state, fructose feeding and rosiglitazone treatment manifested in an increase and correction, respectively, of TRL TG, a feature that was not evident in the fasted state, in which predominantly lipid-poor TRLs are secreted. Both chronic fructose feeding and acute fat ingestion also stimulate hepatic very-low-density lipoprotein secretion, as we have shown previously for the former in the fructose-fed hamster (13) and others have shown in humans for the latter after a high-fat meal (27).
The relative proportion of apoB48 as a fraction of total apoB in the Sf 60–100 but not the Sf 20–60 fraction in fasted, chow-fed hamsters was greater than that found in humans and increased proportionately with fructose feeding. Unlike most other rodents, in the hamster liver there is negligible editing of apoB, and we have never been able to detect apoB48 secreted by cultured hamster hepatocytes. The intestine of the hamster, therefore, produces far more TRL apoB48 relative to hepatic apoB100 in this TRL fraction than does the human. Perhaps the hamster, because it nibbles rather than gorges like the human and stores food in its cheek, has evolved to secrete relatively more apoB48 from its intestine relative to hepatic apoB100, compared with the human, to accommodate the transport of fairly persistent food ingestion. These differences between hamster and human caution us not to generalize the present findings in the hamster model to other species such as humans. Future studies will need to examine this phenomenon directly in other species, including the human.
Our ex vivo studies of enterocyte cell lysates showed that treatment with rosiglitazone was associated with a reversal of the increased expression of MTP seen with fructose feeding. Measurement of MTP mass and lipid transfer activity directly in intestinal tissue, however, showed less consistent changes, possibly because of the presence of other cell types masking enterocyte-specific changes in MTP mass and transfer activity. Although these changes in MTP expression are small, there is ample evidence from the literature to support the finding that relatively small changes in MTP levels can result in significant changes in lipoprotein production rates (28, 29, 30, 31). The reduction in MTP levels with rosiglitazone treatment may have been implicated in the reduction of intestinal lipoprotein secretion in the present study. MTP is an important factor in intestinal lipoprotein assembly. In Caco-2 cells, MTP has been shown not only to be involved in the first step of lipoprotein synthesis, i.e. the rescue of apoB from intracellular degradation through early lipidation of the protein, but also to be involved in further steps involving association of lipoprotein particles with TG droplets (32). The promoter region of the MTP gene contains a negative insulin-response element (33), and intestinal MTP mRNA has been shown to be raised in diabetic and insulin-resistant rats (34, 35). It is possible, therefore, that the reduction in MTP levels induced by rosiglitazone treatment was the result of improved insulin signaling at the level of the enterocyte. The precise molecular signaling pathway involved in insulin-mediated modulation of MTP expression is currently unclear. Additional studies are needed to elucidate the role of insulin in modulating MTP expression and in regulating intestinal particle secretion.
Intestinal lipoprotein production has been felt to be regulated predominantly by the amount of fat ingested because of the efficiency of fat absorption and rapid turnover of enterocytes. The mucosal surface of the gastrointestinal tract is remarkable for the very rapid turnover of the epithelial cell population. Enterocytes of the small intestine are replaced rapidly by the division of stem cells at the base of the crypts of Lieberkuhn and movement of cells up the crypts to the villi as they differentiate into mature enterocytes. It is likely that the population of absorptive cells is replaced after 24–72 h. The rapid turnover of intestinal cells, therefore, would seem to preclude a chronic state such as insulin resistance from affecting the intestine’s capacity to produce lipoprotein particles. We have previously performed short-term (2 d) fructose feeding studies in hamsters to investigate the effect on apoB48 lipoprotein formation and found no significant effect on the secreted level of intestinal chylomicron-apoB48, showing that the effect of fructose feeding on intestinal lipoprotein production is a chronic process (17). It has been suggested that consumption of high-fat diets during maturation causes adaptation of the enterocytes so that they have an increased capacity to absorb lipid and secrete chylomicrons (36, 37). Such intestinal adaptation may also underlie the effect of an insulin-resistant state on the intestine’s capacity to produce lipoprotein particles.
In conclusion, we have shown that whole-body insulin sensitization with rosiglitazone treatment is associated with a reduction in intestinal MTP overexpression and apoB48-containing particle hypersecretion in the fructose-fed insulin-resistant hamster. Although we cannot be sure that the beneficial effect of rosiglitazone was mediated by insulin sensitization, our findings suggest that therapeutic measures that effectively ameliorate insulin resistance, or that reduce MTP overexpression in insulin-resistant states, could be part of the strategy to correct the intestinal particle oversecretion associated with insulin resistance. This could have significant implications in the management of the dyslipidemia and possibly atherosclerosis of type 2 diabetes mellitus and insulin resistance. Additional studies examining the link between insulin resistance and intestinal lipoprotein overproduction need to be conducted in humans to determine whether this process is relevant to human disease states.
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Footnotes |
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First Published Online October 14, 2004
Abbreviations: ApoB48, Apolipoprotein B48; FFA, free fatty acids; MTP, microsomal transfer protein; NS, not significant; Sf, Svedberg unit; TG, triglyceride; TRL, triglyceride-rich lipoprotein.
Received August 27, 2004.
Accepted for publication October 6, 2004.
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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agonist, rosiglitazone, protects against nephropathy and pancreatic islet abnormalities in Zucker fatty rats. Diabetes 47:1326–1334[Abstract]
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, P = 0.008 for FRUC+RSG vs. FRUC). No significant change was observed in MTP mass between CHOW and CHOW+RSG. For MTP transfer activity (C), there was a significant increase in MTP activity in FRUC compared with CHOW (11% increase in MTP activity; *, P < 0.05 for FRUC vs. CHOW), which tended to improve with rosiglitazone treatment (7% decrease; P = NS for FRUC+RSG vs. FRUC). There was no difference in the MTP activity between CHOW and CHOW+RSG.
