GI Therapeutics - transport mechanisms in the GI tract Flashcards
Digestion and Absorption: Summary
• Pancreatic enzymes cannot digest all nutrients
• Final digestion takes place on the lumenal surface of enterocytyes which are epithelial cells that line GI tract
- Brush border enzymes on enterocytes
• Intracellular digestion in enterocytes
- Absorption and hydrolysis of di- and tripeptides
• Digestive enzymes are secreted as pro enzymes
• Secretion is regulated by many secretagogues
Examples of secretagogues
• Acetylcholine -
neurotransmitter that is secreted from para sympathetic neurons
• Histamine - secreted from secretory cells with GI tract
• Gastrin - secreted from secretory cells with GI tract
• Secretin - secreted from secretory cells with GI tract
-regulatory factors
Carbohydrates and Proteins -
- enzymes breakdown carbohydrates into monosaccharides and proteins into AAs - pancreatic anzyme, intestinal enzyme
- monosaccharides are absorbed into enterocyte via active transport
- via facilitated diffusion AAs and monosaccharides move out of the enterocyte
- Via diffusion they enter the capillary to hepatic portal system to build proteins or provide energy
What is the hepatic portal system
blood vessels that run from the gut to the liver
Lipids
- fat globules (lipids) churned up in stomach
- bile salts attach onto the globules to form emulsion droplets which have a large SA: Vol
- emulsion droplets are digested by lipases in the intestinal lumen and converted into free fatty acids (monoglycerides) and bile salts
- they then form micelles and bile salts
- the micelles enter enterocyte and become triglyceride and bind with proteins to form chylomicrons
- secreted into vesicles into lacteal
What is the lacteal
part of lymphatic system
Digestive Enzymes Organ:
Enzymes:
Organ: Salivary glands
Enzymes: Amylase, Lysozyme
- amylase is used to break down starch into shorter oligosacchairde chain
- lysozyme remove some polysaccharide chain from bacteria which stops them from interacting with each other and multiplying
Digestive Enzymes Organ:
Enzymes:
Organ: Stomach
Enzymes: Pepsin A, Gastric lipase
- pepsin a is a portease enzyme, pepsinogen (inactive pro enzyme)
- gastric lipase breaks down triglycerides into monoglycerides
Digestive Enzymes Organ:
Enzymes:
Organ: Pancreas
Enzymes: Trypsin, Chymotripsin, Elastase, Carboxypeptidase A, Carboxypeptidase B, Pancreatic lipase
All break down proteins
Where are enzymes mostly secreted from
Pancreas
Enzymes of the Brush Border
Brush Border Enzyme
- Maltase
- Sucrase
- Glucoamylase
- Trehalase
- b-Glucosidase
- Lactase
- Endopeptidase
- Aminopeptidase A
- Aminopeptidase N
- Dipeptidyl aminopeptidase IV
- Leucine aminopeptidase
- gamma-Glutamyltransferase
- Enteropeptidase
- Alkaline phosphatase
Substrate
- Maltose
- Sucrose
- Amylose
- Trahalose
- Glucosylceramide
- Lactose
- Protein
- Oligopeptide
- Oligopeptide
- Oligopeptide
- Peptides
- Glutathione + amino acid -Trypsinogen (turns into active trysin)
- Organic phosphates
Which brush border enzymes break down carbohydrates to simpler carbohydrates
- Maltase
- Sucrase
- Glucoamylase
- Trehalase
- b-Glucosidase
- Lactase
Which brush border enzymes break down proteins
- Endopeptidase
- Aminopeptidase A
- Aminopeptidase N
- Dipeptidyl aminopeptidase IV
- Leucine aminopeptidase
SI Epithelial Cells (Enterocytes) - Lumenal
-Morphological appearance - Ordered microvilli (brush border)
-Enzymes - Di- and oligosaccharidases, Aminopeptidase, Dipeptidases, gamma-Glutamyltransferase, Alkaline phosphatase, Guanylate cyclase
(all help in digesting food)
-Transport systems - Na+-monosaccharide cotransport (SGLT-1), Facilitated fructose transport (GLUT-5) , Na+-neutral amino acid cotransport, Na+-bile cotransport (ASBT),
H+-peptide cotransport (PepT1)
SI Epithelial Cells (Enterocytes) -
Contralumenal
- Morphological appearance - Few microvilli
-Enzymes - Na+/K+ ATPase (provides driving force for absorption of digested micro nutrients), Adenylate cyclase
-Transport systems - Facilitated monosaccharide transport (GLUT-2),
Facilitated neutral amino acid transport
Na+/K+ ATPase: the engine for endothelial transport
most important enzyme in this process
-Lumen of GI tract - where digested food is
draw diagram slide 10
Na+/K+ ATPase: the engine for intestinal uptake
• Na+/K+ ATPase creates an electrochemical gradient with low Na+ inside the cell
– Similar to potential difference in an electrical circuit
• Array of channels and transporters on lumenal and capillary sides of epithelium
– Allows Na+/K+ ATPase to drive a range of different transport processes
In the large Intestine, Cl- follows the current created by Na+/K+ ATPase
-main purpose of LI is to remove water from stuff eaten - if it doesn’t work leads to diarrhoea
what is Cl- used for
surrogate for water transport across GI membrane
draw diagram - slide 12
In the large Intestine, Cl- follows the current created by Na+/K+ ATPase
• Epithelial Na+ Channel allows lumenal Na+ ions to flow into cell
– Down electrochemical gradient
– Creates an electrical potential across the lumenal
membrane
• Chloride ions flow into the cell to neutralise this potential difference
– Passive, uncoupled chloride channel
In the small intestine, Na+/K+ ATPase is coupled to electrically neutral Na+ and Cl- transport
- CA turning water and co2 into bicarbonate ions and protons in the inside and those are pumped out by the DRA and NHE3
- CA recombines them to and splits them into co2 and water so co2 can flow across the membrane
- draw diagram slide 14
Small intestine Na+/K+ ATPase coupled
to neutral Na+ and Cl- transport
• Na+ entry coupled to H+ efflux via coupled Na+/H+ antiport
– H+ provided via carbonic anhydrase
• Carbonic anhydrase also creates HCO3- ions
– HCO3- gradient drives Cl- uptake via another antiport
Na+/K+ ATPase drives NaCl secretion as well as uptake – no Na+ channel on lumenal membrane
- sometimes water needs to be moved into the gut
- draw diagram slide 16
What happens in Cystic fibrosis
- in cystic fibrosis CFTR breaks down
Cystic Fibrosis
- An autosomal recessive hereditary disease affecting the lungs, sweat glands and the digestive system
- Cl- transport is severely impaired in CF sufferers
- ~1 in every 25 caucasians carries the CF gene, each having one ‘normal’ gene and one CF gene
- CF carriers enjoy some protection against cholera
- Natural response is for GI epithelial cells to open their Cl- channels, causing loss of water
- CF carriers are at reduced risk of dehydration as less fluid is released to clear the bacteria, avoiding diarrhoea
Na+/K+ ATPase drives NaCl secretion as well as uptake
• In this system, there is no Na+ channel in the lumenal membrane
• Na+/K+ ATPase drives high cellular Cl- levels via the Na+/K+/2Cl- cotransporter
– Found on capillary membrane
• Cl- flows into lumen via CFTR
– High lumenal Cl- creates electrical potential
– Draws Na+ into lumen via paracellular route
Absorption: Carbohydrates
draw diagram - slide 20
‘Uphill’ Glucose Transport
active transport system
draw diagram - slide 21
Absorption: Peptides
Draw diagram - slide 22
Absorption: Lipids
Draw diagram - slide 23
Absorption: Lipids -What does digestion mean
digestion means the breakage of the ester bonds between glycerol and fatty acid elements of triglyceride to break that down into free fatty acids and monoglycerides (glycerol molecule with a single fatty acid in 2 position)
What is the environment of intestinal lumen
aq enviornment
What are bile salts
bile salts = detergents for ingested fats, help to dissolve fats by binding to the outside of the fat globules. increases SA and allows digestion
Digestion and Absorption of Lipids
Draw diagram - slide 24
Bile salts
• Cholesterol derivatives secreted from the liver
– Important role in solubilising lipids and aiding absorption
• Recirculated between the liver and the intestine
– Secreted from liver in bile; form micelles in small intestine; reabsorbed in distal ileum nearest to LI
– 20-30g secreted in bile/day; total amount in body only 3-5g (non toxic amount)
– Important as bile salts toxic at high concentrations
Enterohepatic circulation of bile acids
Diagram - slide 26
TC and PC during enterohepatic circulation
Diagram - slide 27
Enterohepatic Circulation and Xenobiotics
- Xenobiotics conjugated by excreted via biliary route.
- Enterohepatic recirculation delays the elimination of xenobiotics and can increase toxicity. (particularly hepatic toxicity)
GI-tract pathology
• Acid-related disorders
– Peptic ulcers; gastroesophageal reflux disease
• ChronicBowelDisorders
– Irritable Bowel Syndrome (recurrent abdominal pain; no clear pathology or etiology)
– Inflammatory Bowel Diseases
• No single cause of disease: hereditary; autoimmune disorder; stress and trauma; diet
• Inflammation of mucosa and submucosa
• Ulcerative colitis – large intestine
• Crohn’s disease - any part of GI system
Summary
- The absorption and transport of nutrients across the GI epithelial cells is a complex process that involves both active and passive diffusion
- For peptides, digestion continues within the cell after the nutrients have been absorbed
- Fats are absorbed and transported using a different circulatory system and are associated with bile within the lumen of the GI tract
