Nutrients and intestinal adaptation

Clin Invest Med 1996; 19 (5): 331-45.

[résumé]

Reprint requests to: Dr. Alan B.R. Thomson, Division of Gastroenterology, University of Alberta, 519 Robert Newton Research Bldg., Edmonton AB T6G 2C2; tel 403 492-6490, fax 403 492-7964; alan.thomson@ualberta.ca

• Abstract
• Résumé
• Introduction
• Structural and physiological considerations
• Physiological, cellular and molecular aspects of nutrient uptake
• Importance of diet in modifying nutrient absorption
• Possible signals of diet-associated nutrient adaptation
• A model of the mechanisms of dietary-lipid-associated intestinal adaptation
• Acknowledgements
• References

Résumé

[Table of contents]

Introduction

A growing body of experimental evidence assigns a central role to the presence of food in the intestinal lumen as an important mediator of intestinal adaptation.[2­5] The purpose and function of the regulation of nutrient transport adaptation is to maintain a safety margin among nutrient intake, uptake and requirements:[6,7] up-regulation of transporter activity maintains absorptive capacity at levels modestly above intake, whereas down-regulation saves biosynthetic energy by eliminating unneeded transport capacity. It may be possible to change nutrient absorption through dietary manipulation to achieve a desired therapeutic goal, for example, by varying macronutrient composition or by adding such "gut fuels" as glutamine or short-chain fatty acids.

The patterns of adaptation have traditionally been studied primarily from a physiological and morphological perspective.[8,9] Over the past decade, the powerful tools of recombinant DNA technology have been used to characterize the structure and function of a diverse assortment of transport proteins. This approach has begun to provide us with an unprecedented view of how intestinal-nutrient transporters work and with a framework to define the cellular processes that occur during intestinal adaptation. This review highlights the evolution that has revolutionized our understanding of the effects of luminal nutrients on the mechanisms and signals of the adaptation of intestinal transport of sugars and lipids.

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Structural and physiological considerations

The structural changes that occur in models of intestinal adaptation are accompanied by adaptation of transport processes. For example, an earlier study[15] showed that the mucosal hyperplasia that occurs after partial small-bowel resection is accompanied by increased absorption of nutrients, water and electrolytes in the intestinal remnant. In studies of carrier-mediated transport, increased nutrient uptake usually results from an increase in the maximal transport rate (Vmax), which may reflect increased carrier activity per enterocyte or more transporting enterocytes. The Michaelis affinity constant (Km) is not usually altered in models of adaptation. The measurement of these kinetic parameters is influenced, however, by the presence of an intestinal unstirred-water layer (UWL), and appropriate corrections must be made to obtain valid estimates of these constants.[16,17]

A genetic regulatory program within the intestine provides developmental patterns of cell differentiation along the crypt-to-villus axis. The stem cells are encoded with a specific "positional address" that allows for appropriate spatial differentiation along the crypt-to-villus and the duodenal-to-colonic axes in the gut.[18,19] This reference point may be intrinsic to the stem cell or programmed by interactions between endodermal and stromal or mesenchymal components.

The dynamics of cell turnover are key determinants of the state of cellular differentiation and, consequently, of the number of phenotypically mature absorptive cells on the villi.[15] The crypt-cell production rate and the enterocyte migration rate are altered in various physiological and pathological states, and these changes in cell dynamics ultimately dictate where along the villus enterocytes of a specific age express transporter activity.[20] Thus, absorption may change as a result of an alteration in the number of transporting enterocytes and not solely as a result of variation in the total mucosal surface area.

Environmental factors such as diet play an important secondary modulatory role in determining nutrient-transporter gene expression. The factors responsible for the down- or up-regulation of transporter activity in the upper third of the villus are important to know: about 70% of the uptake of sugars, amino acids and lipids in rats occurs in the upper 30% of the villus, when enterocytes are about 30 hours old.[21,22] Since the messenger RNA (mRNA) levels of, for example, sodium-dependent glucose transporter (SGLT1) do not necessarily parallel this variation in transporter activity,[23] there may be positional factors influencing this apparent post-transcriptional control. Furthermore, the elegant studies of Ferraris and Diamond[6,24,25] suggest that the crypt cells sense the signal for alteration in sugar transport after a change in the carbohydrate content of the diet. In regard to dietary lipid changes and the uptake of amino acids, the signalling process does not appear to influence the production rate of crypt cells or the position along the villus or age of the enterocyte when transport is modified as a result of a change in diet.[21]

The enterocyte transport pool (ETP) comprises the enterocytes whose brush border membrane (BBM) is actively engaged in nutrient transport.[26] The effect of an increase in mucosal surface area on nutrient uptake depends on whether there is a concomitant alteration in the size of the ETP. Recruitment of enterocytes that express SGLT1 in diabetic ileum has been described.[27] A small change in the size of the ETP may result in a large variation in nutrient transport, even in the absence of large changes in the mucosal surface area. It is noteworthy that few studies of adaptation have examined the profile of transporter expression and activity or the changes in the BBM microenvironment along the crypt-to-villus axis. In addition, the denominator used in measuring transport capacity is important: an absorptive mechanism that shows an overall decline when expressed per unit of weight of intestine may display a modest increase when expressed per unit of length or of mass of mucosa, or even a dramatic increase when expressed as total absorptive capacity.[28]

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Physiological, cellular and molecular aspects of nutrient uptake

The current model of intestinal hexose transport is as follows. SGLT1 and the sodium-independent fructose carrier (GLUT5) are located in the BBM of the enterocyte.[34­37] These sugars are then transported across the basolateral membrane (BLM) by the facilitative hexose transporter (GLUT2).[38] The sodium­potassium adenosine triphosphatase (ATPase) in the BLM establishes the transcellular sodium gradient required for the BBM sodium-dependent nutrient cotransporters such as SGLT1.[39]

Molecular studies have demonstrated two patterns of adaptation: in one, changes in the activity of BBM digestive enzymes or transporter proteins are paralleled by alterations in the corresponding level of mRNA; in the other, there is discordance between protein and mRNA. SGLT1 expression is greater in the more proximal regions of the small intestine and parallels the proximal-to-distal gradient in glucose absorption.[40,41] In most species, SGLT1 mRNA levels are most abundant in the differentiated midvillus cells, SGLT1 protein appears to be uniformly distributed along the villus, and only low levels of SGLT1 expression are detected in the BBM of crypt enterocytes and at the villus tips.[40,42] An exception appears to be the small intestine of rabbits, in which there are increases in SGLT1 mRNA abundance and immunodetectable protein levels as cells migrate toward the villus tips.[43] It is noteworthy that Smith, Turvey and Freeman[44] demonstrated increased SGLT1 activity along the length of the villus accompanied by relatively constant levels of SGLT1 mRNA. Freeman and colleagues[39] also observed high levels of SGLT1 mRNA at the crypt-villus junction. Taken together, these findings suggest that the discrepancy between SGLT1 expression and functional activity reflects a post-transcriptional factor or factors that influence the transporter.

Both GLUT5 and GLUT2 are expressed predominantly in differentiated villus cells in the proximal regions of the small intestine.[45,46] The functional expression of GLUT2 and GLUT5 have been defined in the oocyte system of Xenopus species.[37] The GLUT2 cDNA encodes a 524-residue protein (61kD) with no homology to SGLT1. The GLUT5 clone codes for a 501-residue protein (50kD) with 41% amino-acid homology with GLUT2.

In preruminant lambs, BBM glucose transport is highest after birth, and there is a greater than 100-fold decline in glucose transport as lambs are weaned from a milk to a grass diet.[47] The developmental changes in BBM glucose-transport rate in the postnatal intestine of lambs correlate with alterations in BBM SGLT1 protein but not with SGLT1 mRNA.[40,48] These findings suggest that the principal level of SGLT1 regulation is translational or post-translational. In postnatal rats, increases in glucose and fructose uptake have been observed,[7] and increases in hexose uptake in rats after birth are paralleled by similar increases in SGLT1, GLUT2 and GLUT5 expression.[49,50] Thus, the relative importance of transcriptional and post-transcriptional events in determining the expression of these nutrient transporters remains unclear.

In the developmental pattern of sucrase-isomaltase (SI) expression in postnatal rats, the regulation of SI expression appears to be transcriptional.[51­56] SI and amino-oligopeptidase are two examples of concordant patterns: studies in rats,[51­53] rabbits[54] and humans[55,56] demonstrate that the increase in SI enzyme activity is accompanied by a parallel increase in steady-state levels of SI mRNA, suggesting regulation at a pretranslational level. There are also examples of discordant patterns: in early life, a rise in lactase activity is accompanied by an increase in lactase mRNA, implying transcriptional control, although there may also be a post-transcriptional component.[57] Indeed, in humans there appears to be mosaic expression of lactase protein,[58] and in adult rats lactase mRNA is confined to the lower halves of the villi, whereas lactase enzyme is present along the full length of the villi.[59]

Lipid absorption has been reviewed.[60­62] The uptake of lipids is thought to occur largely through a process of passive diffusion. Cholesterol absorption is a passive, diffusionally-mediated process from mixed micelles. Cholesterol exists in the BBM in several kinetically distinct pools,[63] and there is evidence that cytosolic cholesterol is metabolically compartmentalized.[1] Intracellular cholesterol is derived from the lumen and from de novo synthesis; as well, approximately 10% of circulating low-density lipoprotein is catabolized by the enterocyte after BLM uptake, and most of this uptake is mediated by a receptor-dependent mechanism.[64] Distinct BBM-associated proteins may be involved: second-order reaction kinetics and saturation have been demonstrated with the use of BBM vesicles, and a 14-kDa protein has been demonstrated by SDS-Page.[65] Pancreatic cholesterol esterase in the BBM and enterocyte cytosol also plays a role in the uptake of cholesterol,[66] as does acylcoenzyme A cholesterol acyltransferase.[1,67,68]

The passive permeation properties of the intestine are influenced by BBM fluidity and variations in the BBM lipid composition. There may be a dissociation between the BBM lipid composition and fluidity, especially if the fluidity of the inner and outer leaflet of the BBM is not measured separately.[69,70] BBM lipids are synthesized in the enterocyte microsomal membranes (EMM), and the EMM traffic to the BBM, where they are inserted. BBM lipid permeation is influenced, at least in part, by the activity of EMM lipid-metabolizing enzymes, with alterations in EMM lipids being reflected, at least in part, by changes in BBM lipids. Because failure to correct for UWL resistance may lead to an underestimate of the true permeability properties of the BBM,[16] correlation between changes in BBM fluidity or lipid composition and lipid permeation must be attempted only after appropriate corrections for the effect of this diffusion barrier. In addition, there may be protein-mediated components of lipid uptake,[71,72] and these must be taken into account when correlating changes in lipid uptake and BBM lipid composition. Finally, because lipid uptake is greater in the upper than in the lower portion of the villus,[22] correlations between EMM and BBM lipids, and between BBM lipids and lipid uptake, must be made in enterocytes isolated from similar positions along the villus, rather than from homogenates of enterocytes isolated from all portions of the villus.

A fatty-acid-binding protein (FABPpm) has also been identified in BBM; it influences uptake of long-chain fatty acids and of cholesterol in isolated intestinal epithelial cells, with in vivo perfused segments of rat jejunum, with in vitro sheets of intestine and in BBM vesicles.[71,72] The availability of monoclonal antiserum and partial peptide sequence should facilitate the cloning of the FABPpm gene as well as the demonstration of the molecular basis for its control and potential for adaptation and therefore modification of lipid uptake.[73]

An amiloride-inhibitable uptake step for fatty acids across the BBM has been reported.[71] This step is presumably due to the presence of a BBM sodium­hydrogen exchanger (NHE).[74] Depending on the presence or absence of a combined sodium and hydrogen gradient across the BBM, one or another of these protein-mediated steps may be important in lipid uptake (Fig. 1). It is not yet known whether the activity of NHE or the abundance of FABPpm varies when lipid uptake is modified in models of intestinal adaptation. If this activity or abundance does vary, and if these proteins are heterogeneously distributed along the villus, then such findings as the increased lipid uptake in diabetes mellitus would need to be interpreted on the basis not only of known alterations in BBM lipid composition[75,76] but also of alterations in the activity or abundance of these proteins and their corresponding mRNA.

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Importance of diet in modifying nutrient absorption

Diet plays an important role in the regulation of intestinal transport in early[78] as well as later life.[79,80] Although the intestine responds to alterations in the nutrients in the lumen, nutrient absorption is generally considered to be genetically programmed or "hard-wired," and early changes in the composition of the animal's diet may have lasting effects in later life.[76,79,80] Changing the lipids in the mother's diet modifies the absorption characteristics of the intestine of suckling rats.[81] Diet plays a role in determining total and specific maximal activity levels; it also plays a modulating role in the maturation of the longitudinal pattern of, for example, expression of the lactase gene.[82] However, there is less dietary regulation of intestinal nutrient absorption in aging animals than in younger animals.[83] The mechanism of impaired adaptation to diet in older animals is unknown.

In adult rats, intestinal nutrient transporters are adaptively regulated by the dietary level of their substrates.[6] Some studies have examined the differential responses of intestinal hexose transporters to levels of dietary sugars. For example, a high-glucose diet stimulates glucose transport activity and increases the levels of SGLT1 and GLUT2 expression.[84­86] By contrast, GLUT5 expression is increased only by fructose and galactose, and fructose also increases GLUT2 expression.[84,85] The increases in GLUT5 expression after eating fructose appear to be due primarily to post-transcriptional mechanisms.[86] In the case of amino acids, consumption of a high-protein diet increases the Vmax for the uptake of amino acids, with relatively greater changes in the Vmax for the uptake of essential than of nonessential amino acids. Aspartate, valine, lysine and glutamine induce their own transport.[86-89] However, amino acids do not necessarily regulate their own transport. For example, the dipolar amino acids glutamine and valine induce the transport of acidic amino acids;[86] the acidic amino acid aspartate is the best inducer of cationic amino-acid transport, and the cationic amino acid arginine (but not lysine) is a good inducer of acidic amino-acid transport.[88]

Changing the quality of dietary lipids by substituting one type of lipid for another has demonstrated that intestinal transport is modified by the ratio of saturated to polyunsaturated fatty acids, the ratio of n6 to n3 fatty acids and the presence of cholesterol in the diet.[76,77,90] Intake of isocaloric diets supplemented with saturated, rather than polyunsaturated, fatty acids up-regulates the intestinal absorption of sugars and lipids,[91] and the nature and extent of this effect is influenced by the type of lipid in the diet.[92,93] This phenomenon of the dietary lipid modulation of intestinal transport may be used to achieve a desired therapeutic aim, such as enhancing nutrient uptake in the remaining intestine after small-bowel resection, preventing malabsorption of nutrients caused by long-term ethanol ingestion or abdominal irradiation, or reducing the undesired hyperabsorption of nutrients in diabetes mellitus (and thereby diminishing the associated hyperlipidemia and normalizing the serum concentration of hemoglobin A1C).[94­96] Furthermore, dietary lipid changes modify the ontogeny of the intestine. In this regard, a "critical period" phenomenon and a late effect of early nutrition have been shown;[62,79,80,97,98] it is important to note that modifying the lipid content of a nursing dam's diet alters nutrient transport in her suckling offspring.[81]

Variations in the type of lipids in the diet influence the abundance of SGLT1 and its mRNA,[99] which implies an effect on genetic expression. Absorbed fatty acids also act as substrates for the intracellular metabolism of lipids, and the modification of lipid metabolic-enzyme activities through diet alters the composition of the EMMs.[90] These EMM lipids traffic to the BBM and to the BLM. It is believed that these lipids are modified between the times they are inserted into the EMM and into the BBM, since the diet-associated changes in EMM lipids are not reflected exactly by the changes in the BBM lipids (Monika Keelan and associates: unpublished observations, 1996). In other tissues, deacylation­reacylation enzymes modify the composition of membrane phospholipid fatty acids, but it is not known whether this is the case in the intestine. In addition, phosphatidylethanolamine methyl transferase is present in the BBM[69,92] and may influence postmicrosomal modification of BBM lipids.

Before the importance of the role of FABPpm and NHE in the BBM was appreciated,[71,72] it was assumed that any alteration in lipid uptake was due to a modification in the lipophilic properties in the BBM, reflected by variations in BBM lipids. However, an important portion of lipid uptake (about 40%, depending upon the experimental conditions) may be influenced by NHE or FABPpm,[71,72] and lipid uptake varies along the length of the villus.[22] Therefore, attempts to link alterations in the BBM lipids with lipid uptake must involve collection of enterocytes from along the villus and determination of the proportion of total lipid uptake that is passive and can therefore be correlated with BBM lipid content.

The dietary lipid-associated changes in sugar uptake are due to alterations in the Vmax of the sugar carriers[79,100­102] as well as to altered expression of the carriers and their respective mRNA.[99] In diabetes mellitus, the adaptation of sugar transport is achieved by both transcriptional and post-transcriptional means.[42] The signalling of changes in dietary carbohydrates is thought to be read in the intestinal crypt cells.[2,3,25] It is therefore important to establish whether the dietary lipid-associated alterations in nutrient uptake occur in just the crypt cells or also in enterocytes from along the length of the villus.

Most uptake of sugars and amino acids occurs from the upper quarter to the upper third of the villus.[21,22] Therefore, attempts to demonstrate concordance or disconcordance among transporter activity, expression of protein, and mRNA levels of abundance must correlate these components in enterocytes taken from different positions along the villus. Thus, the signals for genetic regulation and post-translational control of carrier activity must also be searched for in the corresponding enterocyte fraction. Furthermore, lipid uptake is greater from the upper than from the lower portions of the villus.[22] Hence, the same villus segment must be used in attempts to explain adaptation of lipid uptake achieved through a modification in the lipophilic properties of the BBM. Similarly, studies to explain BBM lipid changes as a function of alterations in the activities of lipid metabolic enzymes in the BBM itself must be performed in the appropriate villus segment. Although isocaloric changes in diet do not modify BBM cholesterol or phospholipids,[102] it is not known whether these changes alter the BBM phospholipid fatty acids or free fatty acids, and there have been no studies that have specifically examined the transporting enterocytes in the upper third of the villus.

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Possible signals of diet-associated nutrient adaptation

In addition to functioning as metabolic substrates and constituents of complex lipids, including membrane lipids, long-chain fatty acids have been recognized as mediators in signal-transduction pathways.[108] For example, arachidonic acid is a second messenger of certain G-protein-mediated cellular receptors, and palmitic and oleic acids (important dietary lipids) regulate gene expression at the transcriptional level.[109,110] The fatty-acid-induced effects are reversible upon removal of the effector and do not require metabolism of the fatty acid.[111] In addition, long-chain fatty acids act as signals in the induction of liver, fatty-acid-binding protein, peroxisomal b-oxidation and cytochrome P450 4A1.[112,113] This modulation of gene expression by fatty acids may be mediated by ligand-activated transcription factors.[114] Extracelluar and intracellular diet-induced regulation of gene expression in the pancreas has been reviewed.[115] It is unclear how these second messengers alter gene expression, but it is reasonable to speculate that dietary lipids influence the expression of transporter proteins and the enzymes responsible for lipid metabolism by altering some of the second messengers.

At the cellular level, both the direct and indirect mitogenic effects of nutrients appear to be mediated by the induction of ornithine decarboxylase (ODC) activity.[116] The importance of ODC and the polyamines is underscored by the finding that their levels increase with the cell proliferation that occurs in a variety of models of intestinal adaptation.[117] ODC is the key enzyme in the biosynthesis of the polyamines, which bind to nucleic acids, modify growth-regulating genes and stabilize membranes.[118] Polyamines regulate membrane-based enzymes, transport of ions and metabolites, calcium homeostasis, polyphosphoinositide metabolism, PKC, phospholipids and membrane fusion. As well, polyamines regulate growth-related genes such as c-myc, c-fos and H2A.[119,120]

Important growth factors in the gastrointestinal tract include members of the following families: epidermal growth factor, transforming growth factor b, insulin-like growth factor and fibroblast growth factor.[121,122] Additional families of peptides, generally classified on the basis of non-growth-related activities, including the cytokines and colony-stimulating factors, may also play a role in modifying the functional activities of the BBM. Many of these growth factors have been shown to stimulate ODC activity, and their mitogenic effects may be mediated through the actions of polyamines.[123]

Most receptors for peptide growth factors in the gastrointestinal tract possess intrinsic tyrosine kinase activity related to their intracellular domains.[122,124] Activation of this activity within the intracellular domain of the membrane receptor leads to phosphorylation of a wide variety of substrates, many of which are phosphokinases, including MAP and Raf kinases.[124] Growth factors modulate cellular proliferation and phenotype through the alteration of various genes.[125] Growth factor receptors may be coupled with a variety of secondary intracellular-messenger signalling systems, including adenyl cyclase-generated cAMP, G-coupled cyclic guanine monophosphate (cGMP), the products of the phospholipase C-phosphatidylinositol pathways (including diacylglycerol and phosphinositides) closely integrated with intracellular calcium, and the products of PKC.[124,126,127] Alteration in the expression of the nuclear transcriptional factors (e.g., fos and myc) appears to be involved in the induction or suppression of transcription of many genes required for cellular growth and proliferation.[124] This induction or suppression may play a central role in the adaptation of nutrient transport.

Transcriptional control elements have a critical function in modulating the expression of various genes, but the mechanisms of their action are not yet defined.[128] All genes are not transcribed concurrently, indicating that the cell has mechanisms for "silencing" some genes in response to extracelluar stimuli. The mechanisms for repressing genes may be general or sequence-specific[129] and may allow certain cellular functions to proceed unchecked. Thus, positive and negative regulators may interact, as they do during cellular proliferation and differentiation.[130] Many of the mechanisms in which transcription factors are transactivated involve protein dephosphorylation and phosphorylation by protein kinases.[104] The precise mechanisms of transcriptional activation are unknown. It appears that most cells respond to their environment by recruiting subsets of ubiquitous and promoter-specific transcription factors that synergistically produce the desired cellular phenotype.[128,131]

Post-translational processing of proteins, such as originally described with proinsulin, may occur.[132] After completion of protein synthesis in the endoplasmic reticulum, glycosylation, phosphorylation and sulfation may occur in the Golgi apparatus.[133] Transport vesicles have an outer coat of protein (coatamer). The fungal metabolite brefeldin A (BFA) blocks protein transport through the Golgi stack as well as binding of the coatamer complex to budding Golgi membranes.[134,135] As an example, BFA interferes with the post-translational processing of progastrin, which suggests that this pathway is involved in the sorting of prohormones as well as other soluble secretory proteins.[136] The primary amino-acid sequence of SGLT1 contains the crucial information required to target this transporter to the apical membrane domain.[118] GLUT2 cell-surface expression and intracellular transport have been examined in pancreatic b cells.[137] The data obtained from these studies demonstrate that, at least in this cell type, GLUT2 surface expression occurs via the constitutive pathway of protein secretion,[133] its transport can be blocked by BFA, and, once delivered to the cell surface, GLUT2 does not recycle in intracellular vesicles.[137] Whether BFA modifies the movement of transport proteins to the BBM or affects the trafficking of lipids destined for insertion into the BBM in the enterocyte remains to be defined.

Fatty acylation, usually with either myristic or palmitic acid, is a common mechanism for the post-translational modification of proteins[138] and may play a role in membrane targeting.[139] PKC is a candidate for the kinase-mediating PP1-linked receptor phosphorylation and desensitization. PKC is activated by the increases in diacylglycerol generated during the hydrolysis of phosphatidylinositol 4,5-biphosphate.[140] However, it is unknown whether the diet-induced changes in transcriptional and post-translational processing of transport proteins are mediated by that means.

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A model of the mechanisms of dietary-lipid-associated intestinal adaptation

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Acknowledgements

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