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Digestion and Absorption

Barrett: Chapters 15 & 16

Carbohydrates

Proteins

Water and electrolytes

Calcium

Iron

Vitamins

Lipids

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

OF STARCH BY α -AMYLASE amlyase cleaves nonterminal α -1,4 links, but not the α -1,6

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DIETARY CARBOHYDRATES

Starch digestible: amylopectin, glycogen, amylose (α-linked polymers of glucose) indigestible (fiber): cellulose and other β-linked forms Disaccharides sucrose and lactose Monosaccharides glucose and fructose (these plus galactose can be absorbed)

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Intraluminal and brush border enzymes sequentially digest branched starch

Intraluminal and b rush border enzymes sequentially digest branched starch 4
Intraluminal and b rush border enzymes sequentially digest branched starch 4

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Digestion and absorption of carbohydrate at the brush border plasma membrane

of carbohydrate at the brush border plasma membrane Lactase splits lactose into glucose and galactose Sucrase

Lactase splits lactose into glucose and galactose Sucrase splits sucrose into glucose and fructose Glucoamylase splits α-1,4 bonds (even terminal ones) α-Dextrinase (a.k.a. isomaltase) splits α-1,6 bonds at branch points Glucose and galactose absorbed by SGLT1 (secondary active) Fructose absorbed by GLUT5 (facilitated transport)

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CARBOHYDRATE

MALABSORPTION

SYNDROMES

“Carbohydrate intolerance” diarrhea, gassiness Normally 5-10% of carbohydrate is passed on to colon This 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 synthesized as one polypeptide—it is deficient in this disorder Glucose-galactose malabsorption syndrome Defect in SGLT1, very rare

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MONOSACCHARIDE TRANSPORTERS

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DIGESTION & ABSORPTION OF CARBOHYDRATES. Which statements are NOT true and why are they incorrect?

A.

Sucrase and α-dextrinase are synthesized as a single

protein. B. Fructose is transported across the basolateral membrane by a different transporter than the one that transports glucose and galactose. C. In the absence of α-dextrinase, some of the α -1,6 branch points in starch can be cleaved by glucoamylase. D. Glucose-galactose malabsorption syndrome is due to a defect in the SGLT1.

 
 

B is FALSE, by the same protein (GLUT2)

C is FALSE, only the α-dextrinase can cleave these

linkages

 

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PROTEASES IN PANCREATIC JUICE

PROTEASES IN PANCREATIC JUICE 9

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AMINO ACID TRANSPORTERS

The brush border and basolateral membrane have, for the most part, different amino acid transporters Some are Na + -dependent secondary active transporters, others are Na + -independent facilitated transporters There are multiple transporters for neutral amino acids There are transporters for basic and acidic amino acids The IMINO transporter carries proline & hydroxyproline The Na + -dependent transporters of the brush border are unique to epithelia

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DIGESTION AND ABSORPTION OF PROTEINS

 

Pepsins produce oligopeptides Pancreatic proteases produce large and small peptides, some amino acids Brush border peptidases produce single amino acids plus di- and tripeptides Single amino acids and di-and tri-peptides are taken up by brush border membrane Cytosolic peptidases cleave di- and tri-peptides; only amino acids absorbed into blood

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10

 

Brush border amino acid transporters

Na + -dependent

 

B

neutral amino acids

B o+ neutral and basic amino acids + cystine

 
 

IMINO

X - AG

proline, hydroxyproline acidic amino acids

Independent of Na +

b o+ neutral and basic amino acids + cystine

y +

basic amino acids

**Do not memorize these**

 

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Baslolateral membrane amino 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 ASC basic amino acids

y +

L

larger & hydrophobic amino acids

**Do not memorize these**

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DEFECTS OF AMINO ACID ABSORPTION

Hartnup’s disease Defect in B system: defective absorption of neutral amino acids in gut and kidney Cystinuria Defect in B o+ or b o+ system: defective absorption of basic amino acids, cystine, and some neutral amino acids Prolinuria Defect in IMINO transport system: defective absorption of proline and hydroxyproline Due to absorption of di- and tripeptides, malnutrition does not occur in these disorders!

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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 active transport Transports di- and tripeptides Does not transport tetrapeptides well

High rate of transport of di- and tripeptides

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Hartnup’s Disease clinical correlate

• Low levels of tryptophan due to loss of this amino acid in urine

• Normal catabolism of tryptophan has niacin (nicotinamide) as a product

• Patients with Hartnup’s Disease may present 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 tetra- peptides are transported across the brush border membrane of the small intestine.

C.

The Na-dependent amino acid transporters of the brush border membrane are present only in epithelial cells.

D.

Congenital defects in intestinal amino acid transporters 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 develops

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SOLUTE ABSORPTION DRIVES WATER ABSORPTION

 

Tight junctions are very leaky in duodenum and very tight in colon: gradient from proximal to distal bowel In duodenum, usually net flux from blood to lumen due to hypertonicity Large net absorptive flux in jejunum and ileum Net absorptive flux is resultant of larger unidirectional fluxes: tips vs. crypts All water absorption is powered osmotically by absorption of solutes: Na, Cl, sugars, amino acids, etc.

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OVERALL FLUID BALANCE IN THE GI TRACT

OVERALL FLUID BALANCE IN THE GI TRACT 2L/day gastric juice Almost 9 L/day are absorbed by

2L/day gastric juice

Almost 9 L/day are absorbed by the GI tract!

1.5 L/day intestinal secretions

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STANDING OSMOTIC GRADIENT MECHANISM OF FLUID ABSORPTION

STANDING OSMOTIC GR ADIENT MECHANISM OF FLUID ABSORPTION Na pumps and Cl- channels are especially dense

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 AND WATER TRANSPORT

Na + and Cl - are absorbed in every segment HCO 3 - is secreted in duodenum, absorbed in jejunum, and secreted in ileum and colon K + is concentrated due to absorption of water and absorbed passively, except in colon where K + is usually secreted into the lumen Paracellular vs. trancellular transport. Tight junctions loosest in duodenum and tightest in the colon Cells on villous tips are net absorbers, cells in crypts of Lieberkuhn are net secretors of water and electrolytes

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ION

TRANSPORT

IN THE

ILEUM

ION TRANSPORT IN THE ILEUM Brush border Na + -nutrient cotransport Brush border Na + ,

Brush border Na + -nutrient cotransport Brush border Na + , H + countertransport (NHE3) Cl - /HCO 3 - 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 HCO 3

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-

K + ,Cl - K + ,Cl - CO 2 22 ION TRANSPORT IN JEJUNUM
K + ,Cl - K + ,Cl - CO 2 22 ION TRANSPORT IN JEJUNUM
K + ,Cl - K + ,Cl - CO 2 22 ION TRANSPORT IN JEJUNUM
K + ,Cl - K + ,Cl -
K + ,Cl -
K + ,Cl -

CO 2

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ION

TRANSPORT

IN JEJUNUM

Na + -nutrient cotransport is electrogenic Na + , H + countertransport via NHE3

Acidification of lumen drives CO 2 (HCO 3 - ) 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

ION

TRANSPORT IN

THE COLON

ION TRANSPORT IN THE COLON Electrogenic Na + transport at brush border (ENaC, blocked by amiloride)

Electrogenic Na + transport at brush border (ENaC, blocked by amiloride) -- remember this from the distal tubule? Brush border Na + , H + countertransport (NHE3) Brush border Cl - /HCO 3 - exchange (AE1) Luminal negativity drives Cl- absorption via tight junctions K + secretion, usually, due to lumen being -30 mV

H,K-ATPase in brush border secretes H +

Net absorption of NaCl and net secretion of K + (usually), H + , and HCO 3

Tight tight junctions permit large luminal electronegative potential

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-

SECRETION IN CRYPTS OF LIEBERKUHN

SECRETION IN CRYPTS OF LIEBERKUHN Na, 2Cl, K transporter in basolateral membrane Luminal electrogenic Cl- channel

Na, 2Cl, K transporter in basolateral membrane Luminal electrogenic Cl- channel (CFTR) turned on by cyclic AMP Na + secreted via tight junctions Basolateral K + channel turned on by cyclic AMP and by Ca 2+ Osmotic water secretion

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DEFECTS OF SALT AND WATER ABSORPTION

Failure to absorb a nonelectrolyte e.g. Carbohydrate malabsorption syndromes Ion 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 enteropathy

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ABSORPTION OF SHORT CHAIN FATTY ACIDS (SCFA) IN THE COLON

Colonic bacteria produce SCFA (2 to 5 carbons: acetate, proprionate, etc.) by metabolizing carbohydrate SCFA are the most concentrated anions in the colon! SCFA are a good metabolic fuel for colonic enterocytes SCFA promote absorption of Na + Acidification of lumen by Na/H exchanger forms neutral, protonated SFCA, which are absorbed by diffusion SCFA - can exchange for HCO 3 - across luminal

membrane

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HORMONAL CONTROL OF SALT AND WATER ABSORPTION

Aldosterone increases Na + absorption in colon Glucocorticoids increase Na + absorption in small and large intestine Epinephrine increases NaCl absorption in ileum Somatostatin increases salt and water absorption in ileum and colon (decreases cyclic AMP) Opioids stimulate salt and water absorption and

inhibit intestinal motility (e.g. imodium)

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PARASYMPATHETIC CONTROL OF ELECTROLYTE AND WATER ABSORPTION

Parasympathetic impulses cause diminished absorption and increased secretion Cholinergic input to ENS leads to stimulation of secretomotor neurons of the ENS Parasympathetic tone:

ablation of parasympathetics or atropine increases net absorption (therapeutic uses of muscarinic antagonists)

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CONTROL OF ELECTROLYTE AND WATER ABSORPTION BY GI IMMUNE SYSTEM

The GI tract contains numerous immunocytes When stimulated they release a large number of inflammatory mediators Almost all of these mediators decrease net absorption of salts and water and stimulate GI motility The inflammatory mediators act directly on epithelial cells and also via the ENS The ENS also modulates release of mediators from cells of the GI immune system

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SYMPATHETIC CONTROL OF ELECTROLYTE AND WATER ABSORPTION

 

Sympathetic stimulation enhances net absorption Sympathetic tone ablation of sympathetics decreases net absorption “diabetic diarrhea” Sympathetic input to ENS diminishes secretomotor output from ENS neurons Epi and nor-epi diminish response to many

secretatogues

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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 here B. 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 sites of Ca 2+ absorption Absorptive capacity regulated in response to diet Vitamin D required for normal levels of absorption Parathyroid hormone stimulates Ca 2+ absorption

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DEFICIENCY OF VITAMIN D

In vitamin D deficiency, there is defective

absorption of Ca 2+ .

This leads to ricketts.

The best known action of vitamin D is to promote the synthesis of calbindin (aka CaBP) It may be that vitamin D can enhance every step in Ca 2+ absorption and the vesicular pathway as well

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ABSORPTION OF CALCIUM

ABSORPTION OF CALCIUM Ca 2 + channel in brush border membrane IMCal in brush border? Calbindin

Ca 2+ channel in brush border membrane IMCal in brush border? Calbindin keeps Ca 2+ soluble and promotes intracellular diffusion Basolateral efflux via Ca-ATPase and Na/Ca exchange

Vesicular pathway?

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ABSORPTIONABSORPTION OFOF IRONIRON

Only a small fraction of iron ingested is absorbed A typical adult ingests 15-20 mg/day and absorbs only 0.5 to 1 mg Greater absorption by children and pregnant females Hemorrhage leads to enhanced absorption Iron tends to form insoluble salts. Vitamin C complexes iron and keeps it soluble and in the

Fe

2+

state, which is more soluble and better

absorbed Heme iron is better absorbed: 20% of ingested heme is absorbed

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ABSORPTION

OF IRON

Absorption

vs. Storage

ABSORPTION OF IRON Absorption vs. Storage Mucins bind Fe 2 + and Fe 3 + in

Mucins bind Fe 2+ and Fe 3+ in the lumen Brush border transporters for Fe 2+ (DCT1) and heme Iron split off heme via heme oxidase Fe 2+ oxidized to Fe 3+ by cytoplasmic ferroxidase Cytoplasmic iron binding proteins keep Fe 3+ soluble Basolateral proteins (IREG1, hyphaestin) export Fe 3+ to the ECF Transferrin binds Fe 3+ in the plasma Fe 3+ bound to ferritin cannot be absorbed (protective mechanism)

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REGULATION OF IRON ABSORPTION

REGULATION OF IRON ABSORPTION In iron depletion, Fe is not bound to IRP and IRP enhances

In iron depletion, Fe is not bound to IRP and IRP enhances synthesis of DCT1 and IREG1, but decreases synthesis of apoferritin In iron repletion, Fe 3+ binds to IRP, which prevents the effects just noted Thus, in iron repletion, levels of DCT1 and IREG1 decrease, but levels of apoferritin increase

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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 hemochromatosis Iron bound to ferritin is lost into stool. Iron stimulates synthesis of apoferritin Adjustment of ability to absorb iron occurs in crypts; 3-4 day lag period following hemorrhage

 

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ABSORPTION OF IRON. Which statements are 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 Fe 2+ , but not Fe 3+ .

TRUE C. The amount of apoferritin in intestinal epithelial cells increases in response to an iron-deficient diet. FALSE, apoferritin will decrease in ion deficiency

 

D.

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

FALSE: the lag is 3-4 days

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ABSORPTION OF WATER- SOLUBLE VITAMINS

Specific transport mechanisms exist for most water-soluble vitamins If the transporter is defective, most can be absorbed by diffusion if large enough dose is consumed Absorptive capacity of most of them is well in excess of minimum daily amount required The exception is vitamin B 12 , for which the requirement is close to the absorptive capacity

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ABSORPTION OF VITAMIN B 12 (recall Kristen’s Clinical Correlation)

Cobalamins released in stomach and bound to ‘R proteins’ in gastric juice IF secreted by parietal cells has lower affinity for B 12 than R proteins Pancreatic proteases degrade R proteins, B 12 is then bound by IF (resistant to proteolysis) IF dimers bind two B 12 molecules. IF and the IF- B 12 complex are resistant to proteolysis Receptors in ileum bind and internalize IF-B 12 complex Receptors do not bind free B 12 or free IF

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ABSORPTION OF VITAMIN B 12

4 physiologically active forms (cobalamins) Large store in liver (2 to 5 mg) protects against temporary dietary deficiency B 12 is normally present in bile (0.5 to 5 μg/day) Most of this is absorbed in ileum, so only 0.15 to 1.5 μg/day are lost in stool, about 0.1% of hepatic store

Thus store should last about 3 years!

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ABSORPTION OF VITAMIN B 12

ABSORPTION OF VITAMIN B 1 2 Long residence time in cell, 6 to 8 hour lag.

Long residence time in cell, 6 to 8 hour lag. Mitochondria? Exit from cells is poorly understood B 12 appears in plasma bound to transcobalamin II

TC II-B 12 complex taken up by hepatocytes

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MALABSORPTION OF VITAMIN B 12

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 B 12 malabsorption in childhood--rare

1.

Congenital pernicious anemia

2.

Congenital IF deficiency: only IF deficient

3.

Congenital B 12 malabsorption syndrome:

deficit of ileal IF-B12 receptors

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

A. Most water-soluble vitamins are absorbed primarily by

simple diffusion. FALSE, there are membrane transporters for the vitamins B. Absorption of fat-soluble vitamins will be decreased when there is a profound deficiency of bile acids. TRUE C. In the stomach vitamin B 12 is primarily bound to R proteins. TRUE D. Ileal receptors for the IF-B 12 complex also recognize free B 12 at high concentrations.

FALSE, some B 12 is absorbed from high oral loads, but not via the receptor

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

A.

Most water-soluble vitamins are absorbed primarily by simple diffusion.

B.

Absorption of fat-soluble vitamins will be

decreased when there is a profound deficiency of bile acids. C. In the stomach vitamin B 12 is primarily

bound to R proteins.

D. Ileal receptors for the IF-B 12 complex also recognize free B 12 at high concentrations.

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DIGESTION & ABSORPTION OF LIPIDS

Triglycerides are major dietary lipid Because they are insoluble, lipids pose special problems Bile acids first emulsify lipids Then bile acids form mixed micelles with digestion products In the stomach, lipids form an oily phase on top In the duodenum, emulsion droplets (about 1 μm across) form

The 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 emulsion droplets Cholesterol esterase is a nonspecific esterase Phosopholipase A 2 produces FFA and lysophosphatide

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ABSORPTION

OF LIPIDS

ABSORPTION OF LIPIDS Micelles diffuse through the unstirred layer and among the microvilli Micelles keep fluid

Micelles diffuse through the unstirred layer and among the microvilli Micelles keep fluid at brush border saturated with lipid digestion products Lipids enter the cells by diffusion and by transporters Fatty acid binding proteins in cytosol Micelles keep solution in contract with brush border membrane saturated with lipid digestion products

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BILE ACID-LIPID MIXED MICELLES

BILE ACID-LIPID MIXED MICELLES Triglycerides are poor at forming micelles, but 2-monoglycerides are good at this

Triglycerides are poor at forming micelles, but 2-monoglycerides are good at this Other lipids and fat soluble subtances partition into the mixed micelle Micelles are teeny-weeny: about 5 nm across. Can diffuse among

microvilli

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Bile acids must be present at above their CMC

LIPID RESYNTHESIS & CHYLOMICRONS In smooth SR lipid resynthesis occurs Lipid droplets form. They are

LIPID RESYNTHESIS & 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

ABSORPTION OF BILE ACIDS Absorbed in terminal ileum Secondary active transporter for conjugated bile acids Unconjugated

Absorbed in terminal ileum Secondary 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 blood

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MALABSORPTION OF LIPIDS

Bile acid deficiency

Even in complete absence of bile acids, there is

significant hydrolysis of TG.

Short and medium

chain TG are better hydrolyzed. Cholesterol, cholesterol esters, fat-solible vitamins poorly absorbed 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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