REVIEW ARTICLE
Small Bowel Review
Normal Physiology Part1
A.B.R.THOMSON,MD,PhD,*M.KEELAN,PhD,*A.THIESEN,MD,*M.T.CLANDININ,PhD,*
M.ROPELESKI,MD,†and G.E.WILD,MD,PhD†
In the past year there have been many advances in the area of small bowel physiology and
pathology and therapy.In preparation for this review,over1500papers were assessed.The focus
is on presenting clinically useful information for the practising gastroenterologist.Selected
important clinical learning points include the following:(1)glucose absorption mediated by
SGLT1is controlled by mRNA abundance,as well as by posttranscriptional processes including
protein trafficking;(2)inducers of cytochrome P-450decrease glucose and fructose absorption
and increase glucose consumption in the intestine;(3)the regulated release of nutrients from the
stomach into the upper intestine ensures that the modest intestinal transport reserve capacity is
not exceeded;(4)hepatocyte growth factor and short-chain fatty acids may enhance intestinal
adaptation and prevent the atrophy seen when total parenteral nutrition is infused;(5)inhibitors
of pancreatic lipase and phospholipase H2may be useful clinically to reduce absorption as part of
a treatment program for obesity and hyperlipidemia;(6)several membrane-bound and cytosolic
proteins have been identified in the enterocyte as well as in the hepatocyte and may be the target
for the future therapeutic manipulation of bile acid metabolism and control of hyperlipidemia;(7)
suspect bile acid malabsorption in the patient with otherwise unexplained chronic diarrhea;(8)a
proportion of lipid absorption is protein-mediated,and this opens the way to targeting these
proteins and thereby therapeutically modifying lipid absorption;(9)a high protein diet may be
useful to increase the intestinal absorption of drugs transported by the Hϩ/dipeptide cotrans-
porter;(10)a metal transporter DCT1has been identified,and this may open the way to a better
understanding of disorders of,for example,iron and zinc metabolism;(11)the nutrient trans-
porters such as SGLT1are responsible for a portion of the intestinal absorption of water;(12)the
influence of nitric oxide on intestinal water absorption and secretion depends on its concentra-
tion;(13)a trial of bile acid-sequestering agent may prove useful in the treatment of the patient
who experiences diarrhea while taking an enteral diet;(14)a proteolytic extract from pineapple
stems may prove to be useful to treat diarrhea,although the mechanism of this effect remains to
be established;and(15)the antisecretory effect of the new peptide,sorbin,needs to be tested in
a clinical situation on patients with diarrhea.Other new and promising antidiarrheal agents
include bromelain,an extract from pineapple stems,and igmesine,afinal sigma ligand.
KEY WORDS:small bowel;physiology;pathology;therapy;absorption;metabolism.
ABSORPTION
Carbohydrate
The intestinal brush border membrane enzyme lac-tase-phlorizin hydrolase digests lactose,the main car-bohydrate in milk.Lactose is an important constitu-ent of the diet of human children and adults.In people living in many parts of the world,lactase-phylorizin hydrolase activity declines in early life. However,in descendants of northern European an-cestry,enzyme activity may persist into adult life.The persistence of lactase-phylorizin hydrolase activity is dominant to non-persistence.The genetic difference responsible for the persistence/nonpersistence poly-morphism,which determines high or low lactase-phylorizin hydrolase mRNA expression,respectively, is cis-acting to the lactase gene.Using retrospective analysis of enzyme activity and prospective study for lactase–phylorizin hydrolase mRNA analysis,it was
Manuscript received December4,2000;revised manuscript re-
ceived June1,2001;accepted June3,2001.
From the*Cell and Molecular Biology Collaborative Network in Gastrointestinal Physiology,Nutrition and Metabolism Research
密特朗总统Group,Division of Gastroenterology,Department of Medicine, University of Alberta,Edmonton,Alberta,Canada,and†Division of Gastroenterology and Department of Anatomy and Cell Biol-
ogy,McGill University,Montreal,Quebec,Canada.
撞月Address for reprint requests:Dr.Alan B.R.Thomson,519
Newton Research Building,University of Alberta,Edmonton,Al-
berta,Canada.
Digestive Diseases and Sciences,Vol.46,No.12(December2001),pp.2567–2587(©2001)
determined that the genetically programmed down-regulation of the lactase gene is detectable in children from the second year of life(1).
Enzymes that which are highly expressed in the brush border membrane at birth such as lactase-phylorizin hydrolase decline,while others,which are low or undetectable in thefirst two postnatal weeks, such as sucrase-isomaltase,show increases beginning early in the third week and then reach adult levels. These enzymatic changes coincide with weaning and enable the switch from a milk to a solid diet.The changes are not cued by the dietary change,but instead are initiated by an intrinsic timing program that is modulated by changing the hormonal mileu in the postnatal period.Glucocorticoid hormones and thyroxin act synergistically to elicit a precocious in-crease of sucrase-isomaltase activity that is paralleled by increased sucrase-isomaltase mRNA The syner-gism between these hormones is due to greater accu-mulation of sucrase-isomaltase per epithelial cell(2). Feeding a high-starch diet causes an elevation on sucrase–isomaltase mRNA in rat jejunum within12h of a sucrose load,and perfusion of the intestine with fructose results in increased sucrase-isomaltase activ-ity and mRNA levels as well as the mRNA for the fructose transporter in the brush border membrane, GLUT5(3).The premature increases in sucrase–isomaltase activity and mRNA as well as maltase activity in response to insulin are dose-dependent and are associated with increases of the intracellular poly-amines spermine and spermidine(4).
The mRNAs for brush border membrane lactase–phylorizin hydrolase and sucrase–isomaltase are l
o-calized in the brush border membrane of the villus enterocytes,whereas the mRNAs for intestinal alka-line phosphatase and for-actin are detected both apically and basally relative to the nucleus(5).Lac-tase–phylorizin hydrolase carries two hydrolytic sites, and there is multistep proteolytic processing of pro-lactase–phylorizin hydrolase to mature brush border membrane lactase–phylorizin hydrolase(6).Females with lactose malabsorption may have signs of the irritable bowel syndrome,premenstrual syndrome, and mental depression(7).
The gene expression of lactase–phylorizin hydro-lase and sucrase–isomaltase has been studied exten-sively.These enzymes are anchored in the brush border membrane of the enterocyte,and are crucial in the digestion of dietary carbohydrates.Lactase–phylorizin hydrolase hydrolyzes lactose from milk, which is the primary energy source for newborn chil-dren.Sucrase–isomaltase is essential in thefinal hy-drolysis of starch and becomes more important in later life when starch has become the predominant carbohydrate source in the diet.The precursor form of the sucrase–isomaltase complex is synthesized as a single polypeptide,which is transferred to the brush border membrane where it is cleaved into sucrase and isomaltase subunits for maturation by the action of pancreatic proteases such as trypsin and elastase.In the senescence-prone mouse the sucrase–isomaltase complex may be unstable against pancreatic proteases (8).Both lactase-phylorizin hydrolase and su
crase–isomaltase protein levels correlate with their respec-tive mRNA levels and are thus transcriptionally reg-ulated.Aging from one to eighteen years does not result in significant changes in mRNA or protein levels of either lactase–phylorizin hydrolase or su-crase-isomaltase(9).
Glucocorticosteroids play a role in the rise in su-crase–isomaltase activity at the time of weaning.A decline in lactase–phylorizin hydrolase activity and the accelerated appearance of sucrase–isomaltase in suckling rat pups may be associated with orogastri-cally administered insulin-like growth factor(IGF)-1 (10).The liver is the main source of circulating IGF-1, and there may be an altered profile of IGF-1binding protein in hepatic cirrhosis.In cirrhotic rats,D-galactose absorption is reduced,and IGF-1may cor-rect these changes by modulating the cytoskeletal organization in the enterocyte(11).Sucrase–isomaltase activity is increased in diabetic patient. Insulin also reduces the mRNA level of the sucrase–isomaltase complex in intestinal explants(12).Kera-tinocyte growth factor is afibroblast-derived member of thefibroblast growth factor family that down reg-ulates sucrase–isomaltase mRNA and protein expres-sion in Caco-2cells(13).
The3Ј-untranslated region of all sorted mRNAs studied thus far contain cis-acting sequences that are responsible for the localization and sorting of specific mRNAs to distinct cytoplasmic regions,and are a mechanism of protein localization.The expression of lactase–phlorizin hydrolase mRNA in hum
ans with adult-type hypolactasia is patchy,whereas this patch-iness does not occur in individuals who are lactase-sufficient.Some homologies between human lactase–phylorizin hydrolase and sucrase–isomaltase3Ј-untranslated regions have been identified.It remains unclear whether these sequences play a role in the intracellular localization of these mRNAs.
A method has been developed for assaying intesti-nal brush border membrane sucrase–isomaltase in an intact intestinal preparation(14).The topic of human
THOMSON ET AL
glucose transporters has been reviewed(15).The mRNA for human sodium-dependent glucose trans-porter in brush border membrane(SGLT1)is local-ized to the apical region of the enterocyte(16).The octyl-glucosides are specific inhibitors of SGLT1(17). SGLT1may act as a molecular pump for water,and can account for almost half the daily re-uptake of water from the small intestine(18).
The satiety factor leptin decreases the maximal transport rate(V max)for glucose transport in the rat small intestine(19).Leptin,a167-amino acid protein transcribed from the ob gene,is strongly correlated with the body fat mass.Leptin acts on the hypothal-amus to regulate body weight by decre
asing food intake and by increasing physical activity and energy expenditure.Leptin is produced in fat cells as well as in skeletal muscle.Leptin has been described in the stomach,where it may be involved in early cholecys-tokinin-mediated effects activated by food intake (20).Leptin activates STAT3,the signal transducer and activator of transcription3in the hypothalamus, mediating increased satiety and increased energy ex-penditure.A leptin receptor has been described in the jejunum of the mouse.Intravenous injection of leptin rapidly induces nuclear STAT5DNA binding activity in the jejunum of ob/ob mice,but has no effect in the diabetic db/db mouse that lacks the leptin receptor isoform(21).Leptin also induces the immediate-early gene c-fos in the jejunum and causes a twofold reduc-tion in the apolipoprotein(apo)A-IV transcript level in the jejunum90min after a fat load.This suggests that the jejunum is a direct target for the action of leptin.
The intake of food is suppressed in a dose-responsive fashion by nutrients in the intestine.This suppression varies with the load(amount per minute) of nutrient entering the intestine,independent of the nature of the nutrients themselves.In rats,the secre-tion of apo A-IV is a putative signal of hypothalamic satiety.Calorie-dependent inhibition of food intake depends on feedback from sensors in the proximal and distal bowel contacted after high intakes of nu-trients(22).When rats are ingesting food,infusion of fat rather than sucrose suppresses their continued intake of fat(23).
西塞罗The apical uptake of␣-methyl-D-glucoside,a non-metabolizable glucose analogue,falls with aging(24). The␣-1,4-glucose linkages of dietary starch are effi-ciently hydrolyzed by luminal␣-amylase and by brush border membrane␣-glucosidase in the upper small intestine.The released glucose is absorbed by the brush border membrane-independent glucose trans-porter,SGLT1,and by a facilitated sodium-indepen-dent glucose transporter,GLUT2,at the basolateral membrane.The structure–function relationship of SGLT1has been studied in COS-7cells in culture. The replacement of an alanine residue by an␣-cys-teine residue at position166decreases transporter turnover rate,possibly because the mutation alters the movement of sodium with the transporter(25). Dextran,an␣-1,6-linked glucose polymer,is not nor-mally present in the diet.It is resistant to␣-amylase, but there is some residual activity of mucosal isoma-ltase towards␣-1,6-glucose linkages.Feeding dextran increases SGLT1-mediated glucose uptake after short-or long-term exposure to luminal dextran or to a hydrolytic product(26).
The topic of regulation of intestinal sugar transport has been reviewed elsewhere(27,28).Messenger RNA sorting in polarized cells exists in human en-terocytes.The mRNA for villin(a microvillus cy-toskeletal protein)sorts to the basal region of the enterocyte,the mRNA for SGLT1is localized to the apical region,and the mRNA for the liver form of the fatty-acid-binding protein(L-FABP)is distributed diffusely thoughout the cytoplasm(29).
There is increased SGLT1expression in obese II (non-insulin-dependent)diabetic rats,which may be partially associated with postprandial hyperglycemia (30).In cirrhotic rats there is a reduced V max of glucose uptake,which can be corrected by giving IGF-1(11).Enteric glucagon-37(also called oxynto-modulin),but not pancreatic glucagon-29,potently stimulate intestinal glucose absorption by SGLT1 (31).Vascular infusion of gastric inhibitory polypep-tide(GIP)or glucagon like peptide(GLP-2)in-creases glucose uptake(32).
The activity of SGLT1is increased within30min of infusion of GLP-2when studied using isolate brush border membrane(33).This stimulation by GLP-2is the result of an increase in the value of the V max of SGLT1and is associated with an increased abun-dance of the SGLT1protein.This effect of GLP-2is blocked by luminal brefeldin A or by wortmannin. This suggests that the trafficking of SGLT1from an intracellular pool to the brush border membrane may be altered rapidly and involves phosphoinositol3-ki-nase in the intracellular signaling pathway.
Clinical Learning Point:Glucose absorption medi-ated by SGLT1is controlled by mRNA abundance,as well as by post-transcriptional processes including protein trafficking.
When administered in a vascular perfusion system in rats,cholecystokinin octapeptide reduces the rate
SMALL BOWEL REVIEW:NORMAL PHYSIOLOGY1
of glucose and of3-O-methyl-D-glucose absorption. Cholecystokinin octapeptide also diminishes the SGLT1protein abundance(34).This suggests that cholecystokinin octapeptide,in addition to delaying gastric emptying,may directly regulate the rate of glucose absorption across the small intestine.
The facilitated diffusion of glucose through the plasma membrane of mammalian cells is mediated by members of the GLUT glucose transporter family of proteins,and six isoforms have been described.The GLUT protein crosses the plasma membrane12 times,and the transmembrane stretches show highly conserved primary amino acid sequences between the various isoforms.By introducing single amino acid mutations,it has been shown that certain portions of the transmembrane stretches are important for bind-ing.The domains responsible for the fructose speci-ficity of GLUT5have been investigated by creating chimeras of GLUT5with the selective glucose trans-porter GLUT2.The GLUT5domain from the amino terminus of the third transmembrane domain and between thefifth and eleventh transmembrane stretches are necessary for fructose uptake(35). The turnover of GLUT5protein is diurnally influ-enced(36).The rat intestine up-regulates the hexose transporters prior to the onset of feeding,and this diurnal pattern of expression is hard-wired because GLUT5is up-regulated in the absence of dietary fructose.The phenomenon of diurnality has been link
基因调控网络ed to the daily differentiation process whereby crypt cells migrate past the crypt–villus junction of mature enterocytes.The crypts are thought to be the initial site for the reception of dietary signals. Inducers of cytochrome P-4501A1(CYP1A1)re-sult in an increased rate of glucose consumption,as well as the modification at the protein and mRNA abundance level of the expression of a number of differentiation-associated proteins involved in the up-take,transport,and metabolism of glucose.These include decreased expression of sucrase–isomaltase, SGLT1,GLUT2,and GLUT5,without modifications of the morphological differentiation of the cells or the expression of other differentiation-associated pro-teins such as villin.In Caco-2cells inducers of CYP1A1also decrease the activity of␥-glutamyl-transpeptidase(␥-GTP)activity and mRNA(37,38). It is unclear whether the CYP1A1inducers or the signal transduction system,which controls CYP1A1, is involved in the regulation of the expression of ␥-GTP through a mechanism involving glucose me-tabolism.The authors suggest that there may be a physiological interpretation of the signal-transduction pathway responsible for CYP1A1induction. Clinical Learning Point:Inducers of cytochrome P-450decrease glucose and fructose absorption and increase glucose consumption in the intestine.
In humans,fructose is transported across the brush border membrane by GLUT5-facilitated diffusion
as well as paracellularly via glucose-activated solvent drag.GLUT5contains a transmembrane domain that is responsible for fructose transport(35).GLUT5 mRNA protein levels are increased within4hr of fructose exposure,an effect that occurs in the mature enterocytes.The protein synthesis inhibitor cyclohex-imide blunts the diurmal and fructose-driven increase in GLUT5mRNA expression in the morning but not in the evening(36).This suggests there may be two mechanisms of regulation.When the dietary nutrient load and intestinal capacity are varied in mice in studies involving intestinal resection,there is an in-crease in food intake,digestive efficiency,and glucose uptake.This allows for better survival of the animal, but greater degrees of resection are not necessarily associated with survival,possibly because the intesti-nal reserve uptake capacity has been exhausted(39). The V max of glucose and amino acid transport ex-ceeds daily intakes by a factor of about2.Gastric emptying is regulated by feedback control by the small intestine,in which nutrients enter the duode-num and jejunum and inhibit gastric emptying.The degree of this inhibition depends on the concentra-tion of nutrients and the length of intestine exposed to nutrients,ie,the intestinal load of nutrients.In addition,the presence of nutrients in the ileum slows gastric emptying(the“ileal brake”).This feedback control of gastric emptying provides an additional reserve capacity for absorption(40).
Clinical Learning Point:The regulated release of nutrients from the stomach into the upper intestine ensures that the modest intestinal transport reserve capacity is not exceeded.
“Safety factors”are defined in engineering terms as the ratio of a component’s designed strength or ca-pacity to the maximum load that it is designed to bear. The safety factors of enzymes and transporters are defined as the ratio of the maximal reaction rates at high substrate concentrations(V max)to the reaction rate under actual physiological conditions.Capacities both of sucrase–isomaltase and of SGLT1increase with sucrose load and remain approximately matched to each other except when animals are on a carbohy-drate-free diet(41).Neither sucrase–isomaltase nor
THOMSON ET AL
SGLT1is the rate-limiting step for sucrose digestion; both steps are equally limiting.
防老剂dnpAfter an80%resection of the small bowel in rats, a14-day infusion of hepatocyte growth factor up-regulates SGLT1mRNA and GLUT5mRNA(42).It is unknown whether hepatocyte growth factor-enhanced gene expression of carbohydrate transport-ers may be useful for patients with short bowel syn-drome.Short-chain fatty acids are the by-products of dietaryfiber fermentation in the colon.Acetate,pro-pionate,and butyrate account for about85%of these short-chain fatty acids and are
produced intralumi-nally in a nearly constant molar ratio of60:25:15.One week of short-chain fatty acid supplementation re-tards total parenteral nutrition-associated intestinal atrophy in rats with intact bowels and as early as three days after an80%intestinal resection.Short-chain fatty acids lead to rapid changes in ileal proglucagon mRNA abundance after24h of total parenteral nu-trition plus short-chain fatty acid infusion,and as well increase GLUT2mRNA and protein but not GLUT5 and SGLT1(43).
幸福契约Clinical Learning Point:Hepatocyte growth factor and short chain fatty acids may enhance intestinal adaptation,and prevent the atrophy seen when total parenteral nutrition is infused.
Epidermal growth factor(EGF)is a53-amino acid peptide derived from numerous sources in the gastro-intestinal tract including saliva,bile,Paneth cells,and Brunner’s glands.It is a mitogen that promotes DNA synthesis and transcription of RNA,leading to pro-tein synthesis.EGF increases intestinal nutrient and ion absorption by the recruitment of a pool of pre-formed brush border membrane.EGF increases glu-cose absorption by enhancing the insertion of pre-formed membrane and SGLT1into the brush border membrane through a mechanism involving the poly-merization of actin(44).Milk contains a number of peptide growth factors such as EGF,growth factors IGF,and somatostatin.Milk EGF is usually degraded in the intestinal lumen.The defatted and decasein-ated s
upernatant of bovine milk prevents the degra-dation of EGF in both gastric and duodenal luminal fluids.Dietary derived protease inhibitors,such as soya bean trypsin,also prevent EGF degradation in the duodenal lumen(45).
Interleukin-1,known to be a hypoglycemic cyto-kine,is produced by activated macrophages,B lym-phocytes,and endothelial cells.The administration of interleukin-1(IL-1)to normal or diabetic mice in-duces hypoglycemia without hyperinsulinemia,possi-bly by inhibiting the mucosal uptake of glucose by inhibiting the Naϩ,ϪKϩϪATPase in the basolateral membrane(46).Atrial natriuretic peptide binds to specific receptors along cell surfaces,and the signal-ling of two of these receptors is coupled to guanylate cyclase.Atrial natriuretic peptide inhibits sodium, water,and glucose absorption in the intestine by increasing the value of the affinity constant(K m) without modifying the V max(47).
The topic of glucose–galactose malabsorption has been reviewed(48).Denervation of the canine jeju-noileum decreases the in vivo and in vitro uptake of glutamine,alanine,leucine,and glucose(49).Mi-crovillus inclusion disease is a congenital disorder characterized by severefluid and electrolyte losses from the gastrointestinal tract.There is villous atro-phy,loss of microvilli,and internalized inclusions of microvilli within the cytoplasm of the enterocytes.It is not known if this contributes to the clinical features of the disease.These patients have reduced brush bor-der membr
ane expression of the sodium/hydrogen exchangers(NHE2,NHE3)and SGLT1(50).
In the rabbit model of chronic ileal inflammation, there is inhibition of coupled NaCl absorption due to a reduction of ClϪ/HCO3Ϫbut not of Naϩ/Hϩex-change;inhibition of SGLT1via decreasing the num-ber of contransporter;a decrease in Naϩ–amino acid cotransporter affinity;and reduced Naϩ–bile acid co-transport as a result of a decrease both in the affinity and the number of cotransporters.The glucocorticoid methylprednisolone has no effect on SGLT1in nor-mal rabbit ileum,but in the presence of chronic ileal inflammation methylprednisolone reverses the reduc-tion in SGLT1in villus cells seen with inflammation and also reverses the decrease in Naϩ,Kϩ-ATPase (51).The thyroid hormone T3stimulates SGLT1 cotransport activity in Caco-2cells by involving both transcriptional and translational levels of regulation (52).Two interrelated levels of regulation may coex-ist:a differentiation-related control due to the induc-tion in the crypt cells of SGLT1,and modulation of SGLT1protein and mRNA abundance in already mature enterocytes.
Fat
The topic of the intestinal absorption of fatty acids has been reviewed previously(53).The lipid content of the intestinal brush border membrane changes with fasting:there are decreased ratios of c
holesterol/ phospholipid,sphingomyelin/phosphatidylcholine, protein/lipid,decreased oleic and linoleic acids,and increased brush border membrane total phospholipid, double-bond index,as well as an increased percentage
SMALL BOWEL REVIEW:NORMAL PHYSIOLOGY1
of stearic and arachidonic acids(54).These changes alter the physicochemical properties of the brush border membrane and may modify its transport prop-erties.
The diffusion of cholesterol from the lipid-rich phases of the intestinal contents across the unstirred water layer to the brush border membrane is depen-dent on its emulsification and micellar solubilization by biliary lipids and by the detergent by-products of dietary lipid glycolysis.Phosphatidylcholine is an emulsifier of dietary cholesterol.Biliary cholesterol, the major portion of cholesterol entering the intes-tine,cannot be effectively solubilized in bile without biliary phosphatidylcholine.Although phosphatidyl-choline solubilizes cholesterol,it suppresses choles-terol absorption by a phosphatidylcholine-dependent shift of the lipid–water partitioning of cholesterol towards the micellar phase.Inhibition with phos-phatidylcholine-containing micelles results in reduc-tions in the absorption,esterification,and secretion of cholesterol,without any influence on the absorpt
ion of oleic acid,its conversion to acylated lipids,or triacylglycerol secretion(55).Pancreatic phospho-lipase A2(pPLA2)enhances cholesterol absorption from phosphatidylcholine-containing micelles,sug-gesting that inhibitors of pPLA2may be useful to reduce cholesterol absorption.Orilistat is an inhibitor of pancreatic and other lipases.It is used in the treatment of obesity by inhibiting intestinal fat ab-sorption(56,57).
Clinical Learning Point:Inhibitors of pancreatic lipase and phospholipase A2may be useful clinically to reduce absorption as part of a treatment program for obesity and hyperlipidemia.
Bile acids are synthesized from cholesterol in the liver and are secreted with bile into the small intes-tine.In the terminal ileum the luminal bile acids are actively reabsorbed by enterocytes and are returned to the liver via the portal circulation.This process is known as the enterohepatic circulation.About95% of bile acids are conserved in each cycle as a result of the presence of high-affinity transporters located at the brush border membrance of the enterocyte and at the sinusoidal membrane of the hepatocyte.
A small fraction of the more lipophylic conjugates of bile acids is absorbed passively in protonated form in the acid pH of the duodenum.Conjugated bile acids are absorbed in the jejunum by anionic e
x-change and by an antiport transport mechanism(58). The ileal Naϩ-dependent bile acid transporter has been cloned and has homology to the Naϩ-dependent transporter for conjugated bile acids that is present in the basolateral membrane of the hepatocyte.
The topic of the physiology and molecular basis of the intestinal absorption of bile acids has been re-viewed elsewhere(59).Photoaffinity labeling tech-niques have identified many putative proteins in-volved in the ileal bile acid transport system.After the Naϩ-coupled99-kDa protein-mediated uptake,bile acids are transported by actin(43kDa)or by cytosolic proteins(14and35kDa),either to the microsomal 20-kDa protein or directly to the basolateral mem-brane.Here the bile acid leaves the cell by an anionic exchange process mediated by a54-kDa integral ba-solateral protein,and exit is possibly preceded by the binding of bile acid to a59-kDa basolateral associated protein.The cDNAs encoding rat ileal apical Naϩ-dependent bile acid transporter have been cloned. The apical Naϩ-dependent bile acid transporter con-tains a glycosylation site,and a novel apical sorting signal is localized to the cytoplasmic tail of the apical Naϩ-dependent bile acid transporter(60).
A14-to15-kDa cytosolic binding protein,the intestinal bile acid-binding protein,belongs to a fam-ily of hydrophobic ligand-binding proteins,the fatty acid-binding proteins.In Caco-2cells incubated with bile acid,there is a7.5-fold increase in intestinal bile acid-binding protein mRNA levels occurring in a time-
and dose-dependent manner,and this mRNA increase is associated with enhanced abundance of cytosolic intestinal bile acid-binding protein protein (61).This implies transcriptional regulation.This stimulatory effect of bile acids is prevented by the pretreatment of Caco-2cells with actinomycin D or cycloheximide.The binding of bile acids to ileal lipid-binding protein(ILBP)increases the affinity of ILBP for bile acids(62).This may be a substrate-load modification of transport activity and a positive-feedback regulation for active uptake of bile acids in the ileum.The ileal bile acid transporter(IBAT)is up-regulated by administration of glucocorticoste-roids,and the enhanced V max corresponds to an in-crease in both IBAT mRNA and protein(63).Inhi-bition of IBAT inhibits the development of hypercholesterolemia in rabbits in a manner similar to bile acid sequestrants(64).
Clinical Learning Point:Several membrane-bound and cytosolic proteins have been identified in the enterocyte as well as in the hepatocyte and may be the target for the future therapeutic manipulation of bile acid metabolism and control of hyperlipidemia. Common bile duct ligation or feeding a bile acid-binding compound may be used to reduce ileal brush
THOMSON ET AL
豫公网安备41160202000603
站长QQ:729038198
关于我们
投诉建议