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INTESTINAL UPTAKE OF FATTY ACIDS, CHOLESTEROL AND DECANOL IN ILEAL RESECTED RABBITS:

EFFECT OF ISOCAL@ AND PORTAGEN@

A. B. R. THOMSON

Division of Gastroenterology, Department of Medicine, University of Alberta, Edmonton, Alberta. Canada T6G 2G3. Telephone: (403)432-6284

(&z&led 26 February 1985)

Abstract-I. Isocal%, but not Portagen K, is associated with increased villus surface area in control rabbits and in animals with an ileal resection.

2. In control animals, Isocal” feeding was associated with an increased in vitro jejunal uptake of short and medium-chain length fatty acids and cholesterol, whereas Portagen” feeding was associated with a decline in the uptake of short-, medium- and long-chain fatty acids, but an increase in the uptake of choiesterol.

3. In animals with an Seal resection both diets were associated with an increased uptake of long-chain fatty acids and cholesterol.

4. These changes in lipid uptake are not explained by alterations in villus surface area or unstirred water layer resistance.

Previous studies have demonstrated that variations in the macronutrient composition of the diet influences intestinal transport function (Thomson, 1982; Thomson and Rajotte, 1983a,b) and variations in the ratio of polyunsaturated to saturated fatty acids alters nutrient uptake in rats ~Thom~on et al., 1985 (unpublished observations)]. Defined formula diets are widely used in the treatment of nutritional disorders (Jones et al., 1983), but there is only limited information available on their effect upon the morphology and function of the intestinal tract (Young et al., 1980, 1982a,b). In the companion paper (Thomson, 1985), it is reported that Ihe effect of Isocal s increased the mucosal mass of the jejunum of control and ileal resected animals, but there was lack of effect of Isocal’ or Portagen% on mucosal surface area. The effect of feeding the defined formula diets varies with the composition of the diet, the site of absorption, the presence of an intact intestinal tract and the concentration of the sugar studied. These defined formula diets vary in their composition with Isocal” containing more saturated (S) and poly- unsaturated (P) fatty acids than does Portagen”, but with both diets having approximately similar P:S ratios. In this study is reported: (1) the effects of Isocal”‘ and Portagen’” on the jejunat, ileai and colonic uptake of fatty acids, alcohofs and cholesterol in rabbits with an intact intestinaf tract, and (2) the effect of these defined formula diets on the uptake of lipids into the jejunum and colon of animals pre- viously subjected to an ileal resection.

The “C-labeIIed fatty acids, cholesterol and decanol were obtained from New England Nuclear Corp., Boston, Mas- sachusetts and from I.C.N., as also was the ‘H-inulin used as a non-absorbable marker of adherent mucosal fluid. All other compounds were of reagent grade and were obtained from Fisher Scientific Company Ltd, or from the Sigma Company.

The methods used for the preparation of the lipid- containing solutions have been published (Westergaard and Dietschy, 1976). The fatty acids used included: acetic acid (FA 2:0,5 mM), butyric (FA 4:0,5 mM), hexanoic (FA 6:0, 1 mM) octanoic (FA 8:0, 1 mM), decanoic (FA lO:O, 0.5 mM), dodecanoic (FA 12:0,0.2 mM), myristic (FA 14:0, 1 mM), palmitric (FA 16:0, 0.5 mM), and stearic (FA 18:0, 0.2 mM). The cholesterol (0.2 mM) and FA 14:0, 1&O and 18:0 were solubitized in 20 mM taurodeoxychoiic acid.

Determination of races of uptake of lipids

After pre-incubation in Krebs-bicarbonate buffer for IOmin, the chambers were transferred to other beakers containing 3H-inulin and various concentrations of “C-labelled linids in oxvEenated Krebs-bicarbonate buffer at 37°C. Aft& incubation for 6min, the experiment was terminated by removing the chamber and quickly rinsing the jejunal tissue in cold saline for approximately 5 sec. The exposed mucosal tissue was then cut out of the chamber with a circular steel punch, blotted on filter paper, and placed in a tared counting viaI. For the fatty acids and the cholesterol studies, the tissue was dried overnight in an oven at 75°C and the dry weight was determined. The sample was then saoonified with 0.75N NaOH. scintillation fluid was

‘

added and radioactivity was determined by means of an external standardized technique to correct for variable quenching of the two isotopes. For the fatty alcohols, the tissue was weighed wet, digested in Protosol,” scintillation fluid was added, and the ‘%- and %-radioactivity was determined. Paired tissue samples were weighed wet and reweighed when dry. From the wet/dry ratio the dry weights of the tissue samples of known wet weights were calculated.

METHODS

The methods used for intestinal resection, and the com- position of the diet, and the tissue preparation for the in uitro studies are given in the companion paper (Thomson, 1985).

__

The rate of uptake (J,,) was calculated after correcting the total tissue “C-radioactivity for the mass of the probe molecule present in the adherent mucosal fluid. The uptake

819

820 A. B. R. THOMSON

rates were expressed as the nanomoles of the probe molecule taken up into the mucosa per minute per 100 mg dry weight of tissue. The rates of uptake were afso determined in control and resected animals on &he basis of mucosal weight or serosai surface area. However, similar qualitative inter- pretations were achieved with each method, and the results are reported on the basis of intestinal dry weight.

The values obtained from the different groups are re- ported as mean + SEM of the results of six to eight animals. The statistical significance ofthe difference between any two means was determined using the Student’s r-test.

RESULTS

Eflect of ileal resection on uptake of .fatty acids and choiesterol

When animals were fed chow ad ~ib~tum, the uptake of FA 4:0, 10:0, and 12:O was increased (P -C 0.0s) whereas the jejunal uptake of FA 2:0, 14:0, 160 and 18:O was reduced in resected, as compared with control animals (Fig. 1). When animals were fed

Isocal”’ ad libitum for two weeks, the jejunal uptake of FA 2:0 and IO:0 was increased, whereas the jejunal uptake of FA 60, 8:O and 18:O was reduced (P <O.OS) in resected, as compared with control animals (Fig. 2). In animals fed Portagen” ad Ii&turn for two weeks, the uptake of FA 6:0, 8:0 and 12:0 was increased (P < 0.05) in resected as compared with control animals, whereas the uptake of the other fatty acids and cholesterol was unchanged (Fig. 3).

When animals were fed chow ad libitum, the co-

Ionic uptake of FA 12:0 was greater (P < 0.05), whereas the colonic uptake of FA 4:0, 610 and 8:0 was lower in resected as compared with control animals (Fig. 4). In animals fed Isocal ” ad libitum for two weeks, the colonic uptake of FA 2:0 and 8:0 was increased, whereas the uptake of FA 10:0, 14:O and cholesterol was reduced in resected as compared with control animals (Fig. 5). When animals were fed PortagetiE ad libitum for two weeks, the uptake of FA 8:0, 10:0 and cholesterol was greater (P < 0.05) in

Fig. 1. Uptake of short-, medium- and long-chain fatty acids and cholesterol into the jejunum of control and resected rabbits fed chow. The height of the bars represents the mean &SEM of the results of 6-8 animals. The bulk phase was stirred at 600 rpm to reduce the effective resistance of the unstirred water layer. An asterisk (*) indicates that the differences between the mean values of the control and the resected

group is statistically significant, P i 0.05.

Chol ”

Fig. 2. Uptake of short-, medium- and long-chain fatty acids and cholesterol into the jejunum of control and resected rabbits fed Isocal.” The height of the bars represents the mean +SEM of the results of 68 animals. The bulk phase was stirred at 600 rpm to reduce the effective resistance of the unstirred water layer. An asterisk (*) indicates that the difference between the mean values of the control and the resected

group is statistically significant, P < 0.05.

i e z?

Defined formula diets and lipid uptake 821

45 A& 6:0

*i 80

&all 1o:o

Fig. 3. Uptake of short-, medium- and long-chain fatty acids and cholesterol into the jejunum of control and resected rabbits fed Portagen? The height of the bars represents the mean +SEM of the results of 68 animals, The bulk phase was stirred at 600 rpm to reduce the effective resistance of the unstirred water layer. An asterisk (*) indicates that the difference between the mean values of the control and the resected

group is statistically significant, P c 0.05.

Fig. 4. Uptake of short-, medium- and long-chain fatty acids and cholesterol into the colon of control and resected rabbits fed chow. The height of the bars represents the mean +SEM of the results of 68 animals. The bulk phase was stirred at 600rpm to reduce the effective resistance of the unstirred water layer. An asterisk (*) indicates that the difference between the mean values of the control and the resected

group is statistically significant, P < 0.05.

Fig. 5. Uptake of short-, medium- and long-chain fatty acids and cholesterol into the colon of control and resected rabbits fed Isocal.” The height of the bars represents the mean _+SEM of the results of 6-S animals. The bulk phase was stirred at 600 rpm to reduce the effective resistance of the unstirred water layer. An asterisk (*) indicates that the difference between the mean values of the control and the resected

group is statistically significant, P < 0.05.

822 A. B. R

resected as compared with control rabbits, whereas the uptake of the remaining fatty acids was un- changed (Fig. 6).

THOMSON

l?ffeert ofdefinedformulu diets on uptake offatty acids and cholesterol

J&mum. In animals with an intact intestinal tract (i.e. ‘“control” rabbits), differences were noted in the uptake of fatty acids and cholesterol depending upon the animals’ diet. The jejunal uptake of FA 4:0, 6:0, 8:0, lO:O, l&:0 and cholesterol was greater, whereas the uptake of FA 14:0 and 16:0 was lower in animals fed Isocal” than in those fed chow (Fig. 7). The jejunal uptake of cholesterol was higher (P < 0.0% but the uptake of FA iO:O, 12:0, 14:0, and 16:O were lower in animals fed Portagen” than in those fed chow. Differences were also noted in animals fed the defined formula diets; the rates of uptake of FA 4:0, 6:0, 8:0, lO:O, 12:0 and 14:0 were lower in animals fed the Portagen” than in those fed IsocalRT’ (Fig. 7).

In animals with an ileal resection, the jejunal uptake of fatty acids and cholesterol was also influenced by the animals’ diet. The uptake of FA lO:O, 16:0, 1X:0 and cholesterol was greater (P < 0.05) in animals fed Isocal”’ as compared with those fed chow, whereas the uptake of FA:6 was lower (Fig. 8). The uptake of FA 14:0, 16:0, 18:0 and cholesterol was greater (P < 0.05), whereas the up- take of FA 6:O and IO:0 was lower in animals fed Portagen” as compared with chow. The uptake of FA 14:0 was higher, whereas the uptake of FA 10:0 was lower than in animals fed Portagen”’ as com- pared with those fed IsocalH (Fig. 8).

Colon. In animals with an intact intestinal tract, the colonic uptake of FA 10:0 and cholesterol was higher (P < O.OS), whereas the uptake of FA 8:0 was lower in animals fed Isocalk‘ as compared with those fed chow (Fig. 9). The colonic uptake of FA 10:0 and 16:O was higher (P < 0.05), whereas the colonic uptake of FA 8:0 and 12:0 was lower in animals fed Portagen’hj as compared with chow. In animals fed

Fig. 6. Uptake of short-, medium- and long-chain fatty acids and cholesterol into the colon of control and resected rabbits fed Portagen? The height of the bars represents the mean +SEM of the results of 68 animals. The bulk phase was stirred at 600 rpm to reduce the effective resistance of the unstirred water layer. An asterisk (*) indicates that the difference between the mean values of the control and the resected

group is statistically significant, P < 0.05.

Fig. 7. Uptake of short-, medium- and long-chain fatty acids and cholesterol into the jejunum of control animals with an intact intestinal tract fed chow, Isocal ’ or Portagen.“’ The height of the bars represents the mean +-SEM of the results of 6-g animals. The bulk phase was stirred at 600rpm to reduce the effective resistance of the unstirred water layer. An asterisk (*) indicates that the difference between the mean value of the group fed the defined formula diet and the group fed chow is statistically significant. P c 0.05. A dot (0) indicates that the difference between the group fed Portagen R and the group fed

Isocal K is statistically significant, P < 0.05.

Defined formula diets and lipid uptake 823

Portagen’&, the colonic uptake of FA 12:0 and cholesterol was lower (P < 0.05) than in animals fed Isocal.S

In animals with an ileal resection, the colonic uptake of FA 6:0 was increased (P < 0.05), but the uptake of FA 12:O was decreased in animals fed Isocal” as compared with those fed chow (Fig. 10). The uptake of FA 6:0, 8:0, 10:0 and 16:0 was increased, but the uptake of FA 12:O and 18:0 was decreased (P < 0.05) in animals fed Portagen” as compared with those fed chow. The uptake of FA 8:0, IO:0 and 16:0 was increased, whereas the uptake of FA 12:0 and 18:0 was decreased (P < 0.05) in animals fed Portagen”’ as compared with those fed Isocal.‘”

Ileum. The ileal uptake of lipids was also influenced by the defined formula diets. In animals fed Isocal”, the ileal uptake of FA 8:0, 10:0 and 18:0 was increased (P < 0.05), but the uptake of FA 6:0, 14:0

and 16:0 was decreased, compared with animals fed chow (Fig. 11). In animals fed Portagen, ’ the uptake of cholesterol was increased (P < 0.05), whereas the uptake of FA 2:0,4:0, 6:0, 12:0, 14:0, 16:0 and 18:0 was decreased, as compared with animals fed Isocal. ”

There were many qualitatively similar changes in lipid uptake in the jejunum and in the ileum of animals fed Isocal’ or Portagen” (Figs 7 and 11). In comparison with animals fed chow, those fed the defined formula diets displayed similar patterns in the ileum and in the jejunum for the uptake of FA 8:0, lO:O, 12:0, 14:0, 16:0 and 18:0. The reduction in the uptake of FA 14:0 and 16:0 was greater in the ileum than in the jejunum of control animals fed Portagen” than in those fed Isocal.” In contrast, the ileal uptake of cholesterol was increased in animals fed Por- tagen,” whereas the jejunal uptake of cholesterol was increased in animals fed Isocal’” as well as in those fed Portagen.”

Fig. 8. Uptake of short-, medium- and long-chain fatty acids and cholesterol into the jejunum of animals with an ileal resection fed chow, Isocal”’ or Portagen.” The height of the bars represents the mean k SEM of the results of 68 animals. The bulk phase was stirred at 600 rpm to reduce the effective resistance of the unstirred water layer. An asterisk (*) indicates that the differences between the mean value of the group fed the defined formula diet and the group fed chow is statistically significant, P -=z 0.05. A dot (0) indicates that the differences between the group fed Portagen’ and the group fed Isocal” is statistically

significant, P < 0.05.

Fig. 9. Uptake of short-, medium- and long-chain fatty acids and cholesterol into the colon of control animals with an intact intestinal tract fed chow, Isocal” or Portagen. R The height of the bars represents the mean + SEM of the results of 68 animals. The bulk phase was stirred at 600 rpm to reduce the effective resistance of the unstirred water layer. An asterisk (*) indicates that the difference between the mean value of the group fed the defined formula diet and the group fed chow is statistically significant, P < 0.05. A dot (0) indicates that the difference between the group fed Portagen’” and the group fed

IsocalR’ is statistically significant, P < 0.05.

A. B. R. Tnoivtso~

Fig. 10. Uptake of short-, medium- and long-chain fatty acids and cholesterol into the colon of animals with an ileal resection fed chow, IsocalR or Portagen.” The height of the bars represents the mean & SEM of the results of 6-8 animals. The bulk phase was stirred at 600 rpm to reduce the effective resistance of the unstirred water layer. An asterisk (*) indicates that the difference between the mean value of the group fed the defined formula diet and the group fed chow is statistically significant, P ~0.05. A dot (0) indicates that the difference between the group fed Portagen’ and the group fed Isocal” is statistically

significant, P < 0.05.

Fig. 1 I. Uptake of short-, medium- and long-chain fatty acids and cholesterol into the ileum of control animals with an intact intestinal tract, fed chow. Isocal,K or Portagen.K The height of the bars represents the mean + SEM of the results of 6-8 animals. The bulk phase was stirred at 600 rpm to reduce the effective resistance of the unstirred water layer. A asterisk (*) indicates that the difference between the mean value of the group fed the defrned formula diet and the group fed chow is statistically significant, P < 0.05. A dot (0) indicates that the difference between the group fed Portagen K and the group fed

Isocal K is statistically significant, P < 0.05.

Jelunum Colon

Fig. 12. Uptake of decanoi into the jejunum and colon of control and resected rabbits fed chow, Isocal” or Por- tagen.’ The height of the bars represents the mean i SEM of the results of 6-8 animals. The bulk phase was stirred at 600 rpm to reduce the effective resistance of the unstirred water layer. An asterisk (*) indicates that the difference between the mean value of the group fed the defined formula diet and the group fed chow is statistically significant, P < 0.05. A dot (a) indicates that the difference between the group fed Portagen” and the group fed fsocalw is

statistically significant, P < 0.05.

In control animals fed Isocal,’ the uptake of decanol into the jejunum and colon was similar to

values observed in animals fed chow, whereas the uptake of decanol into the jejunum and colon was

reduced in control animals fed Portagen” (Fig. 12). The uptake of decanol into the jejunum of animals with an iieai resection was reduced (P < 0.05) in animals fed Isocal”’ as compared with animals fed chow. Feeding Isocal’K had no effect on the colonic uptake of decanol. The jejunal and colonic uptake of decanol was lower in control and resected animals fed Portagen,“’ as compared with animals fed chow or Isocal.*‘ This lower uptake of decanol reflects higher effective resistance of the intestinal unstirred water layers.

DTSCUSSION

The intestinal uptake of lipids is determined by the effective resistance of the intestinal unstirred water layer and by the permeability properties of the brush

Defined formula diets and lipid uptake 825

border membrane (Thomson and Dietschy, 1981; Thomson and Dietschy, 1984). Changes in the effective resistance of the intestinal unstirred water layer represents one of the mechanisms available for intestinal adaptation, but the process by which un- stirred layer resistance is altered remains unknown (Thomson, 1984). This study shows that ileal re- section by itself does not alter the jejunal and colonic uptake of decanol (Fig. 12) and thus unstirred layer resistance (Westergaard and Dietschy, 1974), but feeding Isocal’“’ or Portagen’% does produce a change in unstirred layer resistance. Feeding these defined formula diets does alter mucosal morphology, but these structural changes do not adequately account for the altered unstirred layer resistance; Isocal,“’ but not Portagen’%’ increases the villous surface area (Thomson, 1985), whereas feeding Portage@ has a greater effect on the uptake of decanol than does the feeding of Isocal’“’ (Fig. 12).

The higher unstirred layer resistance observed in the jejunum of resected animals fed Isocal”’ or Portagen,” or in the jejunum of control animals fed Portagen”’ would be expected to be associated with decreased, rather than with increased uptake of fatty acids. Furthermore, while the uptake of short-, medium- and long-chain fatty acids into the jejunum of control animals fed Portagen” was associated with higher unstirred layer resistance, the jejunal uptake of cholesterol in these animals was increased, rather than decreased, as would have been expected if the only explanation for the altered passive uptake of these lipids was the altered resistance of the unstirred water layer. Thus, it is likely that the altered uptake of the homologous series of saturated fatty acids and cholesterol was due to changes in the permeability properties of the brush border membrane.

The permeability properties of the brush border membrane are influenced by the surface area of the membrane. The surface area of the membrane used for uptake may be much less than the morphological surface area (Smith, 1983): on both a theoretical (Winne, 1978) and an experimental basis (Haglund et al., 1973) it has been proposed that highly permeant lipids, such as long-chain fatty acids and cholesterol, may be absorbed largely by the enterocytes at the tip of the villus. Even though the jejunal mucosal surface area was not significantly altered by ileal resection or by feeding defined formula diets (Thomson, 1985), these maneuvres may have altered the properties or numbers of cells responsible for the uptake of these lipids, independent of any consideration of the total surface area of the villus. Such an alteration in the distribution of functionally mature enterocytes along the villus has been reported with aging (Smith et al., 1983) and with the feeding of a low protein diet (Syme and Smith, 1982).

The villus may be heterogeneous with regard to that portion of the villus available for the uptake of lipids. Such a heterogeneity of the villus is suggested by the variable effect of resection and/or dietary manipulation on the uptake of short-, medium- and long-chain fatty acids and cholesterol. For example, the jejunal uptake of short-, and medium-chain fatty acids is variably affected by feeding Isocal@’ or Portagen”’ in animals with an ileal resection (Fig. 8) but the uptake of long-chain fatty acids and choles-

terol is enhanced by feeding these chemically defined diets to animals with an ileal resection.

The major difference between the formulation of these two defined formula diets is the greater content of medium-chain fatty acids, as well as saturated and polyunsaturated fatty acids in Isocal,” as compared with Portagen.ti Changing the proportion of energy derived from protein, carbohydrate and fat will alter intestinal absorption (Thomson, 1982; Thomson and Rajotte, 1983a,b). Furthermore, changing the ratio of polyunsaturated to saturated fatty acid in the diet will lead to morphological, as well as to functional changes in the intestine (Thomson, 1985, unpublished observations). Therefore it is proposed that one possible explanation of the different rates of lipid uptake in animals fed Isocal” as compared with Portagen”’ is the varying lipid content of the diet which presumably influences the lipid composition of the brush border membrane and therefore the mem- brane permeability properties. Secondly, some of the differences in lipid uptake observed between animals fed chow and animals fed the defined formula diets may be explained by the differences in the fiber content of the chow versus the defined formula diets (Freeman, 1984; Dowling et al., 1967; Elsenhans et al., 1980).

It would be premature to make recommendations for the use of these defined formula diets for condi- tions in which the absorption of lipids is known to be altered, such as diabetes mellitus, chronic ethanol ingestion, or following abdominal radiation (Thomson, 1984; Thomson et al., 1984a,b). Since the pattern of absorptive changes associated with feeding IsocalN’ or Portagen” differs between control rabbits and those with an ileal resection (Figs 14) then it is also not possible to predict the effect of those diets, based on studies performed in control animals with an intact intestinal tract, what effect might be ob- served in resected animals fed the defined formula diets. Finally, IsocalX and Portagen” were only fed for a short interval (two weeks) and the long-term effects of feeding these diets remains to be estab- lished. Future studies must establish whether the long-term use of defined formula diets will play a useful therapeutic role in altering lipid absorption.

Acknowledgemenrs-The author wishes to thank Mrs Susan Evans-Davies for her secretarial assistance. The expert technical assistance of M. Tavernini and L. Poland is warmly acknowledged. Financial assistance obtained from the Canadian Foundation for Ileitis and Colitis and the Medical Research Council, Canada is gratefully acknowl- edged. Major equipment used in this study was funded by a grant provided by the Alberta Heritage Foundation for Medical Research.

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