Membrane function : Its relationship to intestinal absorption and malabsorption

It is now clear that both chemical composition and physical properties of the intestinal microvi llus membrane are critically important in determi ning its transport function. Recent advances in this field have been made in research labora to ries arou nd the world, and it is importan t that such data be put in a clinical perspective. T he concept of membrane flu idity and the ability to regulate this membrane parameter either pharmacologically o r by diet is now an importan t concept in systemic and local gastrointestinal disease. This review gives an overview of membrane physical properties, how they are measured, and their relationsh ip to nutrien t absorption in the intestinal tract. It is not in tended to be all inclusive and expressly attempts to make these concepts simple. Can J G astroenterol 1990;4( 1 }:39-46

T l II <,TLJDY OJ, CELL Ml:MBRANFS HA 'i become popular once again in the 1980s This has resulted in large pan from the abandonment of the concept that the plasma membrane simply sep• arates the inside and outside of the cell.Plasma membranes are now rccogntzcd to he th e site off unous acuvny, di rect• ing the interaction between the cell and its external environment Although thb 1s true of all cells, knowledge concern-111g recent research 111 th is area is of special interest to gm,trocntcrologisn, as it 1s directly tied to a f undamcn tal app reciation of the process of mtcstinal absorp• non and, hence.malahsorpt1on.
T he process of 111tl'St111al nutrie n t ah -sorp11on has foscmated gcnerauons o f phys1olog1sts.h1ochcm1sts and cli111ciam, alike However, despite volumes of published papers and ncvcr-cnd111g textbook chapters, there arc glaring gnps in our undcrsia ndmg llf how nutrients ul11matcly cross the mtcstinal m1crovillm membrane and gain access to the body The 1mportann• of this to the cl1111c1an 1s embodied in one of Mu rphy's famous laws "whenever •,ometh111g can go wrong, ll will" Historically, there have been examples of malahi,orption involving most, 1f not nll. of thl ical perspective it remains equally clear that in many cases the cause of ma labsorption is obscure and the methods used to deal with it are best described as limited.T'nus. in order to keep abreast of fu ture clinical developments it is wise to have a basic understanding of the cu rrent research efforts aimed at the fundamental principles of membrane nutrient transport.This article will outlin e some recent advances in knowledge concerning the mechanism by which both lipids and more water-soluble nutrients cross the intestinal microvillus membrane.Specifica lly, this discussion will foc us on the microvillus membrane and how its chemical structure and physical properties may combine to modula te nutrient absorption.Although th is may initially appear esote ric to some, in the near future the information now in research circles m ay have im portant clinical applications.
The approach to this discussion will be first to describe, in general terms, what is known about membrane nutrient transport and relate this to the structure of the microvillus membrane.S ince membrane biophysical properties appear to be of importance in the regulation of nutrient absorptio n, what is meant wh en a researcher refers to 'membrane fluidiry' will be described and an attempt made to point out the relation ship between this artificial measurement and the natural process of nutrient absorption.Finally, these concepts will be su mmarized a nd their significance to the clinical problems o f malabsorprion and its treatment no ted.

INTESTINAL NUTRIENT TRANSPORT
In its simplest form we can picture the small intestine as a single large membrane extending from the duodenum proximally to the cecum distally.Obviously, this formulation igno res the intercellular spaces through which much absorption occurs; however, for the sa ke of simpliciry this contribution to absorption will not be considered here.In order fo r any nutrient to gain access to the body it must first cross the microvillus membrane .Herein lies the importance of understanding me mbrane structure and function.The microvillus membrane is simply a plasma membrane specially adapted for the efficient movement of nutrients from the intestinal lumen to the cytoplasm o f the enterocy te .Importantly, it is now recognized that these adaptations involve not only protein transporters (or carriers) but also the lipid environment in which they are em bedded .
Two majo r forms of membrane trans-port exist, generally termed the carrierdependen t and the carrier-independent rou tes (Figure l) ( l ).The evolu tion of these probably ste mmed from the existence of two im portan t classes of biological nutrients: chose that arc water soluble and those which are not.The latter generally fall into the class of compounds labelled lipids and represent a significant component of the daily diet.Since lipid s a re more or less soluble in organic solvents, they can permeate directly th rough most biological membranes, including the in testi na l microvillus membrane which in its simplest form approximates a slightly polar organic solvcnt(2).This allows these nutrients a distinct advantage over their counterparts, the water-soluble nutrients.Since lipids do not require the assistance of a membrane transporter they enjoy the luxury of an almost infin ite su rface area for absorption .Consequently the amount of li pid absorbed depends upon only two factors: th e existi ng concentration gradient across the membrane and the intrinsic permeability p roperties of the microvillus membrane (3.4).However, when a nutrient such as glucose approaches the membrane it is in a much more difficult predicament.Being highly water soluble and, the refore, insoluble in the nonpolar interior of the b il ayer, g lucose can n ot ga in access di rectly to the in terior of the enterocytc.S ince many of the n u trien ts we require fall into this class of water-soluble compounds we have evolved a diverse class of carrier proteins that faci litate the movement of such molecules across cell membra nes using a bewild eri ng variety of steps.In general these carrier molecules arc tra nsm embrane proteins, or groups of proteins, that may or may not be directly li nked to a metabolic energy source such as ATP.Since it is a timeand energy-consum ing process to manufac ture such car riers there are gcncr all y a limited n um ber of such si tes, carefully quanritated over the course of cvo-1 u tion co approximate the number required to deal with a certain amountof nutrient.Therefore.for nutrients using th e carrier-dependent ro ute, only a severely limited surface area of membrane is ava ilable for absorption.The net result is tha r the amoun t of nu trient absorbed, in contrast to the carrierindependent route. is not linearly related to increasing concentration.A finite number of carriers imp lies that all available carriers can be saturated if enough nutrient is ingested.This create5 a prohlem for ,1nimals.including humans, for whom n variable amount of dieta ry nutrient is the ru le.How can the cell ensure char no rnctabolirnlly cxpensiw transporters go to waste and still ahsorh all available nutrients?One possible solution would allow a small percentage of ingested nutrient to be ignorcJ when dietary nutrients arc plentiful and support only enough carriers to cope with the average meal.This solution has the advantage that the animal need not carry a large number of underused rnrriers.However. the optimal solution would a llow for some sensing of the diernry nutrient load and a corresponding increase or dec rease in activity of the required carriers.
At first glance it would seem that such a system could be accomplished most simply by regulating the factor not yet considered: time.Under conditions in whi l1 an increased dietary load is ingested, a simple delay in intestinal mmsit would allow a saturated transport system to operate for a longer time.Although appealing and ;ipplicablc to m;iny conditions this solution does not cover all eventualities.It is quite e;isy to im;iginc situations in which the amount of one nutrient falls and another increases, making intcscin;il transit time a poor choice as the regulatory step.It would seem that a well designed system would incorpora te mu ltiple checks and balances that include the ability to change the activity of individual transport processes.
An initial step would involve up or down regul;ition of the synthesis of different transporters.This has now been conv incingly demonstrated to occur in a variety of experimental systems.The prolonged feeding of a single nutrient in high concentrations induces the appearance of a greater n u mber of transporters specific for that nutrient (5) Howeve r, such a mecha ni sm does not allow for minute-to-m inute adjustments in transporter activity depending on luminal or serosal conditions, since the syn-thesis of new proteins is time consuming.The disturbing fact is th;it such regulation Joes indeed occu r.Acute perfusion of the intestinal lumen with high glucose concentrations immediately up regulates the functional activity of the glucose transport system (6).Furthermore, acute hyperglycemia, induced by glucose infusion, produces a similar resu lt in the experimental animal (7).Thus, acute exposure to glucose.at either the luminal or ~crosal surface can trigger mechanisms resulting in rapid adaptation that allow the cell to make better use of this nutrient.
The mechanisms by which such rapid rcgul;ition of transport processes occur are presently being unravelled, and although multiple mechanisms probably exist.it is now clear that the physical state of the microvillus membrane may have a major impact on nutrient absorption Within the last 10 years the concept of biological membranes has undergone a drammic shift.No longer arc they viewed as static, unchanging barriers that simply serve to support cellular shape.The older view of a 'picket fence' membrane has gradually given way to one in which the membrane is seen as a dynamic structure.Within the m1crovillus membrane lipid molecules arc in constant motion.rapidly changing both position and form on a minute-to-minute basis.It is appropriate a t th is point to consider a simplified view of membrane structure.

MEMBRANE STRUCTURE AND PHYSICAL PROPERTIES
Since the original proposal by Singer and Nicholson (8) of the fluid-mosaic model for membrane structure, it has become accepted that most biological membranes arc formed from two hcmilcaflcts (Figure I).Each hemileaflct contains lipid and protein; the protein component can span both leaflets, as in the case of membrane transporters.However, it is the lipid composition of biological membranes that is responsible for the diversity of membrane structure that is now being appreciated.From one perspective only two lipid types form the vast maiority of membrane lipids: cholesterol and phospholipids.However, the subclasses of phospholipids are extensive.The chemical structure of a typical phospholipid i~ shown in Figure 2. The head- F igure 2) Structure of a rypical phos/1holi/11d Phos/1ho/1pids are formed from a Klycerol hackhone w which is allacht!d a h~wlgroup t•ia a phos/1/u.uelinkage.This group 1s 1/111strated as R3 and can he one of many groups.Six are listed in the figure.The diversity of phospholip1d structure becomes af,parent when the fatty acyl gro11ps !RI and R2) are considered There arc many different fauy acids that can combine w produce 111dii11duul pliospholipid 1pec1cs.Not all of the /)()ssibil1ties are listed In general.jauy acids in the RI position are saturared while those substitutmRfor R2 arc mono-or polyunsaturated MEDOINGS group of these molecules (R3) defines the class of the phospholipid; most membranes contai n at lease five majo r classes.The incredible diversity in membrane li pid compositio n becomes apparent when the phospholipid acy l chains arc examined .A typical phospholipid has two fatty acids attached to the glycerol base, generally o ne saturated (RI) and one unsaturated (R2) acyl chain.H owever. the number of possible choices for each fatty acid is huge and the resulting combinations seemingly endless, thereby affording a high degree of flexibility to the system.
It is also important to recognize chat once a membrane is fo rmed its lipid structure is not etched in stone.On a minu te-to-m inute basis changes can occur, primarily in the phospholipid species with a lterations of both h e adgro ups and fatty acy l c h a in s .Suc h cha nges are mediated by a variety of enzyme systems located in the plasma membranes of most cell types.Only a few of the stimuli that precipitate these changes are known, but the fact remains chat membrane lipids can be altered over a rapid cime<;calc, the resultant change affecti ng me mbran e function.The major impediments to further research in th is area are twofold.First, it is difficult to isolate and characterize membrane lipids with any degree of precision.Second, the sheer diversity of m embrane lipid types makes a meaningful interpreta tion of such data almost impossible.Following almost any stimulus a given membrane may have numerous lipid species e ither inc rease o r decrease in number.An investigator can a lm ost se lec t the number of significant alterations he or she wishes to find by performing the lipid analysis either supe rficially or in great depth .The more sophisticated the analysis, the greater th e number of differences that can be identified .The question then becom es whether o r not small yet statistica lly significant changes have functional meaning.This problem has led many investigato rs co seek cools chat provide an overall assessme nt of membrane lipid structure which might he lp to evaluate the significance of many small co mpositional changes.One of the leading candidates is the measurement of' membrane fluidity'.

42
Figure 3) TyJ>cs of mo11011 wuhm b1olog1cal membranes.Set•eral types of molecular mo11011 are de p1cted A Lateral diffusion: B Wobble; C Rotation.D Bobbing: E Flip-flop A cornerstone in the model of biological membra nes is molecula r motio n : membranes arc dynamic.The degree of motion in a particular membrane is defined by chat membrane's chemical structure and, therefore, if ' me mbrane motion ' could be measured o ne would have a global measurement of membrane structure.The major problem with ch is approach is the definition of membrane motion.Numerous types o f movement are possible in a membrane (Figure 3 ).Molecules can move laterally within the plane of the membrane, rotate, wobble, 'bob' or even flip fro m one leaflet co the other.Therefore, co tru ly assess motional freedom in a given membrane, each type of motion should be exa min ed .This becomes a timeconsu ming task but is considerably simpler and more meaningful than the alternative -complicated lipid analyses.Furthermore, to correlate alterations in transport function with changes in the membrane there are theoretical arguments suggesting chat transport rates should in fact be d etermined by the physical state of the membra ne rather than by specific lipid composition itself (9).Thus, it m akes sense to measure the fluidity or rigidity of a particular membrane and assess whether this property of cellular me mbranes is regulated .
There are very simple m ethods, both in theory and practice, no w available to measure chis function of bio logical me mbranes.Ideally, one wou ld like to label a particular molecule, locate its exact position at time zero and a short time later measure how far it has moved.In practice it is usually not possible to use an endogenous molecule; rather an exogenous molecule is added and its mouon ca refully measured.le is assumed that th e motion of this molecule approxi• mates that of endogeno us membrane lipids.The tech n iques most prevalent today use fluoresce nt lipid molecules as rracers to assess three types of motion the amount of wobble allowed in a membrane, the rotational freedom of a probe, and the amou n t of lateral diffusion that can occu r within the plane of the bilayer These techniqu es can be further extended to p rovide information at vari• o us depths within the bi layer and many labo ratories, including the author's, rou• tinely quantitate rotational freedom at va rious depths within the bilayer.These estimates o f motio nal freedom are relatively sim ple co obtain and provide an estimate of membrane fluidity.Although not strictly correct, fo r the purpose of this review 'fluid ' can be thought of as the inverse of viscous.Thus, a fluid membrane allows more moveme nt of any type th an a rigid o r viscous membrane.In most instances all three types of motion are in agreemen t; however, there is no a priori reason why la teral diffusio n cannot decrease while rotational freedom increases.A fin al caveat must be kept in mind .When fluo rescent probes are introduced into a membrane sample they e nter the bilayer randomly.Therefore, the signal obtained represe nts an overa ll average from all regi o ns that the p robes have e ntered .Thus, if a large change has occurred in a localized region of the membrane, fo r instance in the lipid immediately adjacent co the glucose transporter, this change might be missed sincr 1t represents a small fraction of the whole st!{nal.
Given thnt an estimate can be made of the fluidity of a particular membrane, the next question 1s the relation of this to membrane function.One area of particular interest is nutrient transport across the intestinal microvillus membrane and the following discussion will be limited to this area At present only a handful of laboratories hnve examined these questions and, therefore.the following data leans heavily upon work char has emerged from only a few groups.

RELATIONSHIP BETWEEN MEMBRANE TRANSPORT AND FLUIDITY
Along the length of the small intestine, ar both macro-and microscopic levels, there arc a variety of axes' over which transport (unction nppcars to vnry.These include the JCJu n nl-ilcal axis and th e crypt-villus tip ax is.Fat and glucose absorption a re typically complete by the end of the JCJunum.while bile acid and 8 11 absorption take place in the ileum Villus tip enterocytes a rc absorptive, whil~:.ryptcnterocytcs arc said to be predominantly secretory and not co ahsorb nutrients such as gl ucose.If a relationship exists between the physical properties of the m1crov1llus mcmbrnne and its transport activity one would, therefore.expect the phys1c:1l properties of this membrane to v:-iry over these axes. When this is examined It 1s found to be true.In a number of species it now appears that the m1crovillus membrane becomes progressively mo re rigid as cells are sampled from jqunum to ileum ( 10, 11 ).This is true for all types of mo• tion within the b ilayer th:-it have been exa mined.Furthermore.over the lifespan o f several experimental animals the microvillus membrane becomes more rigid with age ( 12).Although only a small amount of data relating to transport function in aged animals is available.an a nalogous situation occurs along the crypt• villus axis.Following its 'birth ' 111 the intestinal crypts the enterocyte migrates up the vi llus and after reach ing the villus tip is sloughed in to the intestinal stream Techniques are now available to isolate seque ntial fractions of these cells and compare mature villus up cells to imma-ture crypt cells.It is now clear in two species that the microvillus me mbrane becomes more rigid as the cnterocyte matures and moves up the crypt-villus axis ( 13,14) Thus, in many situations fo r which membrane transport function differs there arc also differences in membrane physical propernes.

LIPID ABSORPTION
It is not e nough simply co correlate one variable with another to prove a relationship.For instance, even though ileal microvillus membrane is more rigid than jejuna!microvillus membrane is this the reason that lipid absorption is less eff1c1ent 111 the ileum than m the jejunum ?Many factors regulate the rate of lipid absorption.Smee lipids simply permeate through the micmvillus memb rane 1t seems tntuitive that che rate of permeation muse depend upon some physical characteristics of the membrane It has been proposed, from mathematical arguments, chat the race-limiting step for transmembrane lipid permeation should be the density of membrane lipids m che outer third of che bilayer, JUSt beneath the p hospholipid headgroups.Physical properties can now he measured at different depths in the bilayer to answer this questmn.The measurement of rates of fatty acid pcnneaoon across jejuna!and ilea! microv1llus membranes reveals that the lipid permeability properties o f jcJunal microvillus membrane far exceed those of ilea! m1crovillus membrane.lleal microvillus membrane 1s generally more rigid than Jejuna!m1crovillus membrn ne This difference is locali zed. in large part, to the superficial regions of the membrane ( 11 ).Thus.th ese experiments appear to bear out the proposed cheorettcal relationsh ip between membrane physical properties and lipid permeability.However.once again these a rc simply corre lative studies wh ich Jo not provide firm evidence to support the hypothesis.ln order ro test this hypothesis one would need to alter the physical properties experimentally within this region of the bilayer, a nd demonstrate altered membrane lipid permeability.
The Immediately below this group a re the four carhon rtngs that form the basis of all sterols.This region of the molecule 1s highly rigid and forms strong hydrophobic interactions with neighbouring phospholipid side chai ns.In order to alter physical properties in the outer third of the h ilayer.the cholesterol ring structure must be modified .Fortunately, pharmaceutical companies have recen tly developed a variety of compounds which intl'rfe re with the biosynthes1s of cholesterol and fo rce the p roduction of alternate sterols having d iffe re n t ring structu res.Usmg one of these in hibitors it 1s possible to replace m 1crov1llus membrane cholesterol completely, 111 vivo.with a precursor of cholesterol.Animals treated with this agent appear grossly normal and develop much like control a nimals, thereby excluding gross derangements in intestinal transport function However, as expected their jejuna!microvillus memhrane 1s significan tly more rigid than that of control animals.Furthe rmore.this difference is limited to the outer regions of the membrane, the region implicated in the control of lipid permeation races.These animals could thus be used to test the hypothesis outlined above.When lipid permeation rare~ were measured in these animals the more rigid microvillus membrane of the treated a n imals had a much lower lip id permeability than that of the controls, thereby confirming the prediction t 15) It now seems safe to conclude chat at least one more regulatory step in the rate of lipid absorp tion is the physical state of the outer bilayer of the microvillus membrane From a physio logical and cl1111cal perspective it is 11nportant to ask whether the body regulates lipid permeation rates by altering the physical properties of the m1crovillus membrane in vivo.If this were 1he case one wou ld anticipate chat unde r condi tions of a high dietary lipid content th e microvillu:, membrane would be kept fa irly flwd and as the dietary content of lipid decreased the membrane would become more rigid.This is exactly the sce na rio that occurs when an infant drinking breast milk weans and begms to ingest solid food Breast mil k has most of its caloric content as lipid, after weaning the ma1orny of calorics arc found in carhohydrate.It was, therefore. of interest to study the development of the in testine in the experimental animal over this time cou rse ( 16) In the suckling rat the jeiunal microvi ll us membrane is h ighly permeable to lipid and this permeability rapidly decreased at the ti me of wean ing.From a structural viewpoint this coincided with a remarkable ch ange in the lipid composition of the microvill us membrane.Major alterations were seen in the amou nt of membrane cholesterol, the type of membrane phospholipids and their fatty acyl composition.In fact the compositional changes are so numerous that they become con fusing.However.when the physical properties of the microcroviJlus membrane were examined over the same time course th is apparently confusing situation became more clear.During the suckling period the jejuna I microvill us membrane is ex tremely fluid, especially in its outer regions, and with in days of weaning to a solid diet tt becomes d ramaticall y more rigid.These alterations occurred over the same time course as the observed changes in membrane lip id permeability.
Therefore, it now appears that the degree of membrane fluidi ty can not only regulate the lipid rransport p roperties of the microvillus membrane, but also allow the animal.and p resumably h umans.to adapt to a lterations in d ietary n utrients under certain condition~.

CARRIER-DEPENDENT NUTRIENT ABSORPTION
Since ca rrier-independent tra n sport processes occur d irec tl y through th e substance of the bilayer, it is relatively simple to convince oneself that the physical properties of the b ilayer will be important in determining rates of transport.Carrier-dependent procc scs requ ire the intervention of a protein carrier and th us it is not immediately appa rent that membrane lipids wi ll affect the function of this protei n .However, still incompletely apprecia ted is th e exact mechanism by w h ich a carrier p rotein binds to its substrate an<l moves gl ucose, fo r instance, across the membrane.It seems reasonable that this movement requ ires a change in conformation of the protein, and it is e ntirely con-ceivable that the degree of conformational change may be lim ited by the fluid ity o f the microvillus membrane.Most car rier-dependent transport systems are characterized on the basis of two parameters; the affini ty of the transporter fo r its substrate (inversely proportional to the Michaelis-Mcntcn constant [Km] of the system) an d the max imal transport velocity Um.ix).T he latter is determi ned by two further parameters: the nu mber of transporters and their turnover number, which is a reflection of how rapid ly the transporter can move substrate from one side of the membrane to the ot h e r a n d return to its starting position.
[n th e case of the glucose transporte r located in the m icrovillus membrane, it is now known that the step initiating glucose movemen t is the b ind ing of a sodium ion to its active site on the transporter ( 17).The protein has been shown to u ndergo a conforma tional c h a n ge associa ted with th is b ind ing that presumably exposes the glucose bind ing site, since the affinity for glucose bind ing increases dramatically with prior sodiu m bi nd ing.What occu rs fo llowing b ind ing of glucose at the exterior of the membra n e is unclear.Somehow glucose bou nd to the transporter on the outside of the membrane moves to the inne r su rface of the m icrovillus mem brane and is released.The exact steps that accompany this translocation arc unknown .However, it is likely th at they involve further conformational changes in the protein.From a theoretical perspective, if the degree of conformational change limited the ph ysical state of membrane lip ids surrou nding the protein then the degree of membrane flu idity would affect both the Jrn,x and the Km of the glucose transport process.
Docs th is occu r with the in testinal sodium-dependent glucose transporter7 There arc SL'veral studies that h ave examined the function of this transport system following alteration of the lipid co ntent of the microvillus membrane.usually by dietary means (18)(19)(20).In many cases alterations in the activity of the transport system were observed, suggesti ng that th is transporter migh t be sensitive to changes in the lipid e n vironmen t.However, no clear demonsrration of a relation-sh ip ro membrane fluidity has emerged unti l recently Proceeding in a manners1milarco that presented for lipid permeability, enrcrocytes from along the crypt-vill us axis have recen tly hecn isola ted and the kinencs of glucose transport across the microvillus membra ne of the:.c cells examined It is quite clcarthat rates of glucose movement are dra m at ically reduced across crypt m ic rovillus membrane compared to vi ll us tip microv ill us memhranc.Furthermore, the d ifferences in glucose transport rate involve both the maximal glucose transport rate a~ well as the affinity of the transporter for gl ucosc Although the crypt transporter has a much lower maxima l transport velocity, tt has an affinity for glucose that is almost twice ns high as that seen in villus tip cnterocytcs ( 14).Remember that crypt microvillus membrane is for more flu id than its counterpart in the matu re villus ti p entcrocyte.T he question.therefore, becomes w h ether th ese differences can be accou n ted for by the diffe rence in membrane lipid e nvironment or whether the crypt transporter is funda mentally differe n t from the one seen in the villus tip.
In answering th is question the first consideratio n is the affi nity o f the transport system.It has now been shown that the Km of the glu cose tran sport system fo r glucose is close to I 00 µ M. Furthermore, th is is depen dent u pon the concentration of sodiu m ions in the medium.If sod ium is grad uall y removed, the affi n ity of the transporter for glucose falls a nd the Km increases to something in the order of 200 µM.In crypt cells the Km of the transporter is close to I 00 µ M while in the vill us tip cells it approximates 200 µM.O ne explanation fo r these data is that the conformational change induced by sodium binding can occu r only in the fluid environ ment of the crypt microvill us membrane; the villus tip micro• villus me mb rane is too rigid to allow chis degree of movement.To test this hypothesis the K,,, of the crypt transport system has been examined at va rio us sodium ion concen trations.At low concentratio ns th e Kn, for the system does indeed increase to 200 µ M , suggesting that this is the sa me tra nsporte r as fo und in villus tip cells.simply in a different lipid environment (14) Further support for chis hypothesis came from experiments where villus tip m1crovillus membrane was artificially made as flu id ;1s crypt microvillus memhrane and the effect of this manipulation upon gluco:;c transport kineucs cxam111cd Usmg hemyl alcohol as a membrane flu1d1zcr it hns hecn demonstrated th.1t tluidi~at,on of villus t1p microvillus mcmbranc has tw0 major ef.
feces on the kinetics of glucose trnnsport First.as l'XpcCtl•d, It 111creases th<" affmity of tht' transport system for glurnse The Km for the transport process decreases from 200 to LOO µM.providing further support for thl' argument that 11 b the physicnl stnte of thl• membrane lipids th:it dctcrmmcs the degree of conformational change that can occur when sodium binds Second.fluidizmg villus tip microvillus membrane profoundlv re duces thl' maximal velocity of glucose transport (J,,,,,_l to levels seen 111 natin• crypt microvillm memhrane Thus, it now appl•nrs that the physical proper• t1esof chc micro\•illus mcmhra,w arc important in the modulation of not l,nh earner-independent transport processes but a~ in one important example of carrier-dependent nutrient ah,orpt1on SUMMARY What docs all this mean to the practising gastroenterologist I At the present 11me there rrn1y be more theory than practical rmplicauons.The important point is that compelling evidence now exists which suggests that the physical properties of the microvillus membrane can affect rates of nutrient transport Such knowledge gives a better appreciation of the process of normal absorption and hopefully makes one consider the pathophysiology of malabsorption more carefully.One might find by lookmg at cases of 1diopath1c malabsorpnon more closely that some have defects in the control of microvillus membrane REFERENCES I.  then: .He !Hl\\ ,1\'ailable drugs such as lovastatm that potently inhibit the :1bil-11y of cdb to synrhes1ze cholesterol.Wi th chc understand111gnfl1p1d permeahdiry across the microvillus membrane out• l1m'd nhow it 1s possible to design man• eu, res to 111h1b1t cholc~tcrol ah:;orpt1on These coupled with the use of drugs such as lovas1atin onl' could theoretically produce a situation which would drama ti• cally reduce the scrum LDL cholesterol concentration Thus there will soon he a variety of thl'rapcutic options that can alter small intest111al transport funcucm hy directly affecti ng the lipid environment of the m,crovillu~ membrane In order to use these efficil'ntly and wisely it 1s important to have at least a pas..sing knowledge of the in teraction between membrane lipids and membram• transport processes.
primary determinant of memb rane fluidi ty in the o uter region of the b ilayer is cho lestero l This molecule has a si ngle polar hydroxyl group that aligns CAN J GA~TROENHROL Vn1 4 Nl> I j ANL, ARY/FUIRuARY 1990 Membrane fluidity and Intestinal absorption itself at the membrane water interface.
1c:1l problem commonly faced is rlw con• trnl of postpnrnd,::il hyperglycemia m diahcucs that is s,•rnndary to 'hyperah-sorpt1on • of luminal glucose While numnous stra tl'gres have hcen proposed tn control this prohkrn.it would seem logic:il to direct thl'rapy at the cause Recent work in experimental diabetes has demonstrated that the markl•d mtest1• nal glucose absorption can be controlled hy altcrntinn of the structurl' tl membrane lipids through dietnry rnan1pul:1-t1on ( l 8) Furthermore, in Western countries the dietary intake of cholesterol and saturated lipids is cxn'ss1vt•.One of the problems associated \\'1th this 1s the high circulating conct'n tratlon of low dl•nsiry lipoprotein ( LDL) cholestl'rol and its a,socrated high 111c1dence of coronary arrcry disease.What is not generally appreciated is that the small intestine is a log1• cal place ro look (or a solution Outside the liver the small 1ntcst1nl' has the greatest number of LDL rccepo( 1111,•sttn,1[ nlU.:1,s,11 urtakl' of short and medium ch.1in fatty acids and alcohc,ls.J l 1r1d Re, 1973.14 475-84. 1 Thomson ABR .D1l'ischy JM lntc,rinal lipid ahsorpnon M.1jor extracellular and mtr,Kellul.irl'H'nlS In Johnson I R. ed Physiology of the Gastrointcstmal Traci Nl'" Y1,rk Ran•n Pr<'"• 1981 1147 Zlt\ CANj GASTRmNTLR{)I V\11 4 Nt) I jANUARY/Ft:BRLJARY [990 Membrane fluidity and intestinal absorption tors in the hody (21) This is probahly due w the fact th;it dw epithelium turns ovl'r rap1dlv and therefore requires a con• nnuous source of cholcstl•rol for the synthesis o f new mcmhr;ine Thl' enteroeyte has three sources of cholesterol.First.dietary cholesterol enters across tht• rn1crovill us membrane Sernnd , 1.hokstnol can be synthesized intraccllularly from acetate and third.the enterocyte can use LDL cholesterol absorhed :icross the hasobreral membrane with the help of the LDL receptor.A s1gn1ficant rcduc• tion in plasma LDL cholesterol concl'n trntion cou ld be achieved if the enten,cytl' could he stimulated to up regu L11e the number of these receptors, thereby incrc:ising the amount of LDL cholesterol cleared from the plasm:i ( 22) From a rheoretical perspectiw this could he achieved by mhibiting the syntht•sis of new cholesterol within the enterocyte and the absorption of dietary cholesterol.If one simply n•moves cholesterol from tlw drl't the cnterocytes' first chc,ice is to increast' syntlwsis of new cholesterol rather than I DL clearance However.