Digest Absorrp-2010 4pdr

8/8/2019 Digest Absorrp-2010 4pdr

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Digestion and Absorption

Carbohydrates

Proteins

Water and electrolytes

Calcium

Iron Vitamins

Lipids

Barrett: Chapters 15 & 16

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DIETARY CARBOHYDRATES

Starchdigestible: amylopectin, glycogen,amylose (-linked polymers of glucose)indigestible (fiber): cellulose and other-linked forms

Disaccharides

sucrose and lactoseMonosaccharides

glucose and fructose(these plus galactose can be absorbed)

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DIGESTION OF STARCH BY -AMYLASEamlyase cleaves nonterminal -1,4 links,but not the -1,6 links at branch points

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Intraluminal and brush border enzymessequentially digest branched starch


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Lactase splits lactose into glucose and galactose

Sucrase splits sucrose into glucose and fructose

Glucoamylase splits -1,4 bonds (even terminal ones)-Dextrinase (a.k.a. isomaltase) splits -1,6 bonds at branch pointsGlucose and galactose absorbed by SGLT1 (secondary active)

Fructose absorbed by GLUT5 (facilitated transport)

Digestion and absorption ofcarbohydrate at the brush borderplasma membrane

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MONOSACCHARIDE TRANSPORTERS

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CARBOHYDRATEMALABSORPTION

SYNDROMES

Carbohydrate intolerance diarrhea, gassinessNormally 5-10% of carbohydrate is passed on to colonThis causes no problems

If more enters colon, symptoms ensue

Lactose malabsorption syndrome: lactase deficiency

Adult: Extremely common, ethnically correlated

Congenital: more rare, but not extremely

Sucrose-isomaltose malabsorption syndrome

Single mutation, rare, sucrase-isomaltase are synthesizedas one polypeptideit is deficient in this disorder

Glucose-galactose malabsorption syndrome

Defect in SGLT1, very rare 8

DIGESTION & ABSORPTION OFCARBOHYDRATES. Which statements are NOT

true and why are they incorrect?

A. Sucrase and -dextrinase are synthesized as a singleprotein.

B. Fructose is transported across the basolateralmembrane by a different transporter than the one thattransports glucose and galactose.

C. In the absence of -dextrinase, some of the -1,6 branchpoints in starch can be cleaved by glucoamylase.

D. Glucose-galactose malabsorption syndrome is due to adefect in the SGLT1.

B is FALSE, by the same protein (GLUT2)

C is FALSE, only the -dextrinase can cleave theselinkages


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PROTEASES IN PANCREATIC JUICE

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DIGESTION AND ABSORPTION OF PROTEINSPepsins produce oligopeptides

Pancreatic proteases produce large and small peptides, some

amino acidsBrush border peptidases produce single amino acids plus di-

and tripeptides

Single amino acids and di-and tri-peptides are taken up bybrush border membrane

Cytosolic peptidases cleave di- and tri-peptides; only aminoacids absorbed into blood

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AMINO ACID TRANSPORTERS

The brush border and basolateral membrane have, forthe most part, different amino acid transporters

Some are Na+-dependent secondary activetransporters, others are Na+-independent facilitatedtransporters

There are multiple transporters for neutral aminoacids

There are transporters for basic and acidic aminoacids

The IMINO transporter carries proline &hydroxyproline

The Na+-dependent transporters of the brush borderare unique to epithelia

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Brush border aminoacid transporters

Na+-dependent

B neutral amino acids

B

o+

neutral and basic amino acids + cystineIMINO proline, hydroxyproline

X-AG acidic amino acids

Independent of Na+

bo+ neutral and basic amino acids + cystine

y+ basic amino acids

**Do not memorize these**


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Baslolateral membraneamino acid transporters

Na+-dependent (transport a.a. into the cell)

A neutral amino acids, imino acids

ASC small neutral amino acids (ala,ser,cys)

Independent of Na+

asc same specificity as ASCy+ basic amino acids

L larger & hydrophobic amino acids

**Do not memorize these** 14

Absorption of di- and tripeptides

Absorbed by a common peptide transporter(PepT1)

Transporter has wide range of specificity

Coupled to influx of H+ ions: secondary activetransport

Transports di- and tripeptides

Does not transport tetrapeptides well

High rate of transport of di- and tripeptides

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DEFECTS OF AMINO ACIDABSORPTION

Hartnups diseaseDefect in B system: defective absorption of neutralamino acids in gut and kidney

Cystinuria

Defect in Bo+ or bo+ system: defective absorption ofbasic amino acids, cystine, and some neutral aminoacids

Prolinuria

Defect in IMINO transport system: defectiveabsorption of proline and hydroxyproline

Due to absorption of di- and tripeptides, malnutritiondoes not occur in these disorders! 16

Hartnups Diseaseclinical correlate

Low levels of tryptophan due to loss ofthis amino acid in urine

Normal catabolism of tryptophan hasniacin (nicotinamide) as a product

Patients with Hartnups Disease maypresent with the symptoms of Pellagra(niacin deficiency)

Note that this occurs with normal dietary

niacin


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DIGESTION & ABSORPTION OF PROTEINS.Which statements are NOT true and why are

they incorrect?A. Small intestinal brush border peptidase activity is

primarily due to a single molecular species.

B. Di-, tri-, and tetrapeptides are transported acrossthe brush border membrane of the small intestine.

C. The Na-dependent amino acid transporters of thebrush border membrane are present only inepithelial cells.

D. Congenital defects in intestinal amino acidtransporters may lead to nutritional deficits.

A is FALSE, there are multiple peptidases

B is FALSE, tetrapeptides cannot be transported

D is FALSE, due to the peptide transporters, no

nutritional deficiency develops18

OVERALL FLUID

BALANCE IN THE GITRACT

2L/day gastric juice

1.5 L/day intestinal secretionsAlmost 9 L/day

are absorbedby the GI tract!

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SOLUTE ABSORPTION DRIVESWATER ABSORPTION

Tight junctions are very leaky in duodenum

and very tight in colon: gradient fromproximal to distal bowelIn duodenum, usually net flux from blood to

lumen due to hypertonicityLarge net absorptive flux in jejunum and

ileumNet absorptive flux is resultant of larger

unidirectional fluxes: tips vs. cryptsAll water absorption is powered osmotically

by absorption of solutes: Na, Cl, sugars,amino acids, etc.

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STANDING OSMOTIC GRADIENT MECHANISM

OF FLUID ABSORPTION

Na pumps and Cl- channels are especially dense near tight junctions

Fluid near luminal end of intercellular channel is hypertonic

Water flows into intercellular channels by osmosis

Fluid flows down intercellular channels due to hydrostatic pressure

gradient


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OVERVIEW OF SALT ANDWATER TRANSPORT

Na+ and Cl- are absorbed in every segment

HCO3- is secreted in duodenum, absorbed in

jejunum, and secreted in ileum and colon

K+ is concentrated due to absorption of waterand absorbed passively, except in colonwhere K+ is usually secreted into the lumen

Paracellular vs. trancellular transport. Tightjunctions loosest in duodenum and tightestin the colon

Cells on villous tips are net absorbers, cells incrypts of Lieberkuhn are net secretors ofwater and electrolytes 22

IONTRANSPORTIN JEJUNUM

Na+-nutrient cotransport is electrogenic

Na+, H+ countertransport via NHE3

Acidification of lumen drives CO2 (HCO3-) absorption

Luminal negativity (slight) drives Cl- via tight junctions

K+ is absorbed passively due to water absorption

Na,K-ATPase only link to metabolic energy

CO2

K+,Cl-

K+,Cl-

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IONTRANSPORTIN THEILEUM

Brush border Na+-nutrient cotransport

Brush border Na+, H+ countertransport (NHE3)

Cl-/HCO3- exchange (AE1)

Luminal negativity drives Cl- via tight junctions

K+ absorption passive, due to absorption of water

Net absorption of Na+ and Cl- and net secretion of H+ and HCO3-

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IONTRANSPORT INTHE COLON

Electrogenic Na+ transport at brush border (ENaC, blocked byamiloride) -- remember this from the distal tubule?

Brush border Na+, H+ countertransport (NHE3)

Brush border Cl-/HCO3- exchange (AE1)

Luminal negativity drives Cl- absorption via tight junctionsK+ secretion, usually, due to lumen being -30 mVH,K-ATPase in brush border secretes H+

Net absorption of NaCl and net secretion of K+(usually), H+, and HCO3-

Tight tight junctions permit large luminal electronegative potential


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SECRETION IN CRYPTS OF

LIEBERKUHN

Na, 2Cl, K transporter inbasolateral membrane

Luminal electrogenic Cl-channel (CFTR)

turned on by cyclicAMP

Na+ secreted via tightjunctions

Basolateral K+ channel

turned on by cyclicAMP and by Ca2+

Osmotic water secretion26

ABSORPTION OF SHORT CHAIN FATTYACIDS (SCFA) IN THE COLON

Colonic bacteria produce SCFA (2 to 5carbons: acetate, proprionate, etc.) bymetabolizing carbohydrate

SCFA are the most concentrated anions inthe colon!

SCFA are a good metabolic fuel for colonicenterocytes

SCFA promote absorption of Na+

Acidification of lumen by Na/H exchangerforms neutral, protonated SFCA, which areabsorbed by diffusion

SCFA- can exchange for HCO3- across luminal

membrane

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DEFECTS OF SALT ANDWATER ABSORPTION

Failure to absorb a nonelectrolyte

e.g. Carbohydrate malabsorption syndromesIon transport deficiency

e.g. Congenital Chloride Diarrhea

Hypermotility of intestine

e.g. Irritable Bowel Disease (IBD)

Enhanced secretion of salts and waters

e.g. secretory diarrheas like cholera

Selective destruction of cells at villous tips

e.g. rotavirus infection, gluten enteropathy28

HORMONAL CONTROL OF SALTAND WATER ABSORPTION

Aldosterone increases Na+

absorption in colonGlucocorticoids increase Na+ absorption in small

and large intestine

Epinephrine increases NaCl absorption in ileum

Somatostatin increases salt and waterabsorption in ileum and colon (decreasescyclic AMP)

Opioids stimulate salt and water absorption andinhibit intestinal motility (e.g. imodium)


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PARASYMPATHETIC CONTROL OFELECTROLYTE AND WATER ABSORPTION

Parasympathetic impulses cause diminishedabsorption and increased secretion

Cholinergic input to ENS leads to stimulation

of secretomotor neurons of the ENSParasympathetic tone:

ablation of parasympathetics or atropineincreases net absorption (therapeutic uses ofmuscarinic antagonists)

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SYMPATHETIC CONTROL OFELECTROLYTE AND WATER ABSORPTION

Sympathetic stimulation enhances netabsorption

Sympathetic tone

ablation of sympathetics decreases netabsorption

diabetic diarrheaSympathetic input to ENS diminishes

secretomotor output from ENS neurons

Epi and nor-epi diminish response to manysecretatogues

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CONTROL OF ELECTROLYTE AND WATERABSORPTION BY GI IMMUNE SYSTEM

The GI tract contains numerous immunocytes

When stimulated they release a large numberof inflammatory mediators

Almost all of these mediators decrease netabsorption of salts and water and stimulateGI motility

The inflammatory mediators act directly onepithelial cells and also via the ENS

The ENS also modulates release of mediatorsfrom cells of the GI immune system

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ABSORPTION OF WATER & IONS. Which statements

are NOT true and why are they incorrect?

A. In the duodenum, large net absorption of water and

electrolytes occurs, predominantly via the loose tight

junctions.

FALSE, net secretion occurs hereB. Bicarbonate is normally absorbed in the jejunum, but secreted

in the ileum.

TRUE

C. Net K+ secretion in the colon is favored by the large negative

electrical potential in the lumen.

TRUE

D. Aldosterone stimulates net K+ and water absorption in the

colon.

FALSE, aldosterone stimulates Na+ absorption, but aldo

stimulates K+ secretion (as it does in distal tubule).


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ABSORPTION OF CALCIUM

Duodenum and jejunum are the major sitesof Ca2+ absorption

Absorptive capacity regulated in response

to dietVitamin D required for normal levels of

absorption

Parathyroid hormone stimulates Ca2+

absorption34

ABSORPTION OF CALCIUM

Ca2+ channel in brush border membrane

IMCal in brush border?

Calbindin keeps Ca2+ soluble and promotes intracellulardiffusion

Basolateral efflux via Ca-ATPase and Na/Ca exchange

Vesicular pathway?

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DEFICIENCY OF VITAMIN D

In vitamin D deficiency, there is defectiveabsorption of Ca2+. This leads to ricketts.

The best known action of vitamin D is to promotethe synthesis of calbindin (aka CaBP)

It may be that vitamin D can enhance every step inCa2+ absorption and the vesicular pathway as well

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ABSORPTION OF IRONABSORPTION OF IRONOnly a small fraction of iron ingested is absorbed

A typical adult ingests 15-20 mg/day andabsorbs only 0.5 to 1 mg

Greater absorption by children and pregnantfemales

Hemorrhage leads to enhanced absorptionIron tends to form insoluble salts. Vitamin C

complexes iron and keeps it soluble and in theFe2+ state, which is more soluble and betterabsorbed

Heme iron is better absorbed: 20% of ingestedheme is absorbed


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ABSORPTIONOF IRON

Mucins bind Fe2+ and Fe3+ in the lumen

Brush border transporters for Fe2+ (DCT1) and heme

Iron split off heme via heme oxidaseFe2+ oxidized to Fe3+ by cytoplasmic ferroxidase

Cytoplasmic iron binding proteins keep Fe3+ soluble

Basolateral proteins (IREG1, hyphaestin) export Fe3+ to the ECF

Transferrin binds Fe3+ in the plasma

Fe3+bound to ferritin cannot be absorbed (protective mechanism)

Absorptionvs. Storage

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ABSORPTION OF IRON

In chronic iron deficiency or after hemorrhage,capacity for iron absorption increases

Intestine protects against too much iron. Iron

overload occurs in idiopathic hemochromatosisIron bound to ferritin is lost into stool. Ironstimulates synthesis of apoferritin

Adjustment of ability to absorb iron occurs in crypts;3-4 day lag period following hemorrhage

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REGULATION OF IRON ABSORPTION

In iron depletion, Fe is not bound to IRP and IRP enhancessynthesis of DCT1 and IREG1, but decreases synthesis ofapoferritin

In iron repletion, Fe3+ binds to IRP, which prevents the effectsjust noted

Thus, in iron repletion, levels of DCT1 and IREG1 decrease, but

levels of apoferritin increase40

ABSORPTION OF IRON. Which statementsare NOT true and why are they incorrect?

A. About 20% of ingested inorganic iron is absorbed.

FALSE, less than 10% is absorbed

B. A brush border protein transports Fe2+, but not

Fe3+.TRUE

C. The amount of apoferritin in intestinal epithelialcells increases in response to an iron-deficientdiet.

FALSE, apoferritin will decrease in iondeficiency

D. In response to a hemorrhage, the iron absorptivecapacity will increase with a time lag of about 1days.

FALSE: the lag is 3-4 days


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ABSORPTION OF WATER-SOLUBLE VITAMINS

Specific transport mechanisms exist for mostwater-soluble vitamins

If the transporter is defective, most can beabsorbed by diffusion if large enough dose isconsumed

Absorptive capacity of most of them is well inexcess of minimum daily amount required

The exception is vitamin B12, for which therequirement is close to the absorptive capacity

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ABSORPTION OF VITAMIN B12

4 physiologically active forms (cobalamins)

Large store in liver (2 to 5 mg) protectsagainst temporary dietary deficiency

B12 is normally present in bile (0.5 to 5g/day)Most of this is absorbed in ileum, so only

0.15 to 1.5 g/day are lost in stool, about0.1% of hepatic store

Thus store should last about 3 years!

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ABSORPTION OF VITAMIN B12(recall Kristens Clinical Correlation)

Cobalamins released in stomach and bound toR proteins in gastric juice

IF secreted by parietal cells has lower affinity forB12 than R proteins

Pancreatic proteases degrade R proteins, B12 isthen bound by IF (resistant to proteolysis)

IF dimers bind two B12 molecules. IF and the IF-B12 complex are resistant to proteolysis

Receptors in ileum bind and internalize IF-B12complex

Receptors do not bind free B12 or free IF44

ABSORPTION OF VITAMIN B12

Long residence time in cell, 6 to 8 hour lag. Mitochondria?

Exit from cells is poorly understood

B12 appears in plasma bound to transcobalamin II

TC II-B12

complex taken up by hepatocytes


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MALABSORPTION OF VITAMIN B12

In absence of IF, 1 to 2% of oral load is absorbed.Different mechanism: short lag time

Pernicious anemia: antibodies vs. parietal cells

gastric mucosal atrophy

deficient secretion of HCl, IF, and pepsins

B12 malabsorption in childhood--rare1. Congenital pernicious anemia

2. Congenital IF deficiency: only IF deficient

3. Congenital B12 malabsorption syndrome:

deficit of ileal IF-B12 receptors 46

ABSORPTION OF VITAMINS. Which statementsare NOT true and why are they incorrect?

A. Most water-soluble vitamins are absorbedprimarily by simple diffusion.

B. Absorption of fat-soluble vitamins will bedecreased when there is a profounddeficiency of bile acids.

C. In the stomach vitamin B12 is primarilybound to R proteins.

D. Ileal receptors for the IF-B12 complex alsorecognize free B12 at high concentrations.

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ABSORPTION OF VITAMINS. Which statements areNOT true and why are they incorrect?

A. Most water-soluble vitamins are absorbed primarily bysimple diffusion.

FALSE, there are membrane transporters for the vitaminsB. Absorption of fat-soluble vitamins will be decreased whenthere is a profound deficiency of bile acids.TRUE

C. In the stomach vitamin B12 is primarily bound to R proteins.TRUE

D. Ileal receptors for the IF-B12 complex also recognize free B12at high concentrations.

FALSE, some B12 is absorbed from high oral loads, but notvia the receptor

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DIGESTION & ABSORPTION OF LIPIDS

Triglycerides are major dietary lipid

Because they are insoluble, lipids pose specialproblems

Bile acids first emulsify lipids

Then bile acids form mixed micelles withdigestion products

In the stomach, lipids form an oily phase on top

In the duodenum, emulsion droplets (about 1m across) formThe greater surface area of emulsion droplets

promotes digestion of lipids


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DIGESTION OF LIPIDS

Digestive enzymes are in pancreatic juice:

Glycerol ester hydrolase (aka pancreatic lipase)cleaves the 1 and 1 fatty acids from triglycerides

Colipase helps pancreatic lipase to bind to emulsiondroplets

Cholesterol esterase is a nonspecific esterase

Phosopholipase A2 produces FFA andlysophosphatide 50

BILE ACID-LIPID MIXED MICELLES

Triglycerides are poor at forming micelles, but 2-monoglycerides aregood at this

Other lipids and fat soluble subtances partition into the mixed micelle

Micelles are teeny-weeny: about 5 nm across. Can diffuse amongmicrovilli

Bile acids must be present at above their CMC

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ABSORPTIONOF LIPIDS

Micelles diffuse through the unstirred layer and among themicrovilli

Micelles keep fluid at brush border saturated with lipid digestionproducts

Lipids enter the cells by diffusion and by transporters

Fatty acid binding proteins in cytosol

Micelles keep solution in contract with brush border membranesaturated with lipid digestion products 52

LIPIDRESYNTHESIS &CHYLOMICRONS

In smooth SR lipid resynthesis occurs

Lipid droplets form. They are covered & stabilized by apo-lipoproteins and form chylomicrons

Chylomicrons are extruded by exocytosis

Chylomicrons are taken up by lacteals and leave gut in intestinal

lymph


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ABSORPTION OF BILE ACIDS

Absorbed in terminal ileumSecondary active transporter for conjugated bile acids

Unconjugated and secondary bile acids absorbed by diffusion

Bound to cellular proteins probably

Cross basolateral membrane?

Leave gut in portal blood54

MALABSORPTION OF LIPIDS

Bile acid deficiency

Even in complete absence of bile acids, there issignificant hydrolysis of TG. Short and mediumchain TG are better hydrolyzed. Cholesterol,cholesterol esters, fat-solible vitamins poorlyabsorbed in absence of bile acids.

Pancreatic insufficiency: must be severe

In complete absence of pancreatic enzymes:malabsorption of all lipids and fat-soluble vitamins

Mucosal atrophy (e.g. gluten enteropathy, sprue)

Malabsorption of all lipids and fat-soluble vitamins

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