Gastrointestinal Physio L4-6 Flashcards
What can you find in the liver lobule?
- Portal Triad - Portal venule, Arteriole of hepatic artery, Bile duct
- Sinusoids, hepatocytes, & bile canaliculi
What kind of capillaries are found in the liver?
Fenestrated - This allows the passge of big molecules (glucose, amino acids, etc.)
What are the functions of the liver?
- Carbohydrates metabolism via gluconeogenesis & glycolysis
- Amino acid & protein metabolism (synthesis of plasma proteins)
- Lipid metabolism (fatty acids oxidation, ketone bodies synthesis0
- Storage (glycogen, lipids, vitamins, copper, iron)
- Synthesis & secretion of bile acids, bile formation
- Biotransformation (medicaments, xenobiotics, metabolism byproducts)
- Synthesis of hormones & mediators
- Synthesis of components of the immune system
True or False. The liver does not produce circulating plasma proteins.
False
* The liver does produce circulating plasma proteins.
What are the components the liver produces that is part of the plasma proteins?
- Albumins
- Glycoproteins –> haptoglobin, transferrin
- Nonimmune alfa- and beta-globulins
- Complement facators
- Prothrombin & fibrinogen
- Coagulation factors
- Lipoproteins (VLDLs, IDLs, LDLs, HDLs)
What are the lipoprotein classes according to their density?
- Chylomicrons
- VLDLs
- IDLs
- LDLs
- HDLs
What are VLDLs and what do they do?
- Lipoprotein
- Transport of triglycerids from the liver to adipose tissue/other organs
What are IDLs and what do they do?
- Lipoproteins
- VLDLs remnants after the FFAs have been releases
- 50% become VLDLs & 50% become LDLs
What are LDLs and what do they do?
- Lipoproteins
- Transport of cholesterol esters from the liver to other tissues
- Increased in people eating a diet high in saturated fat obese, and/or sedentary (aka bad cholesterol)
What are HDLs and what do they do?
- Lipoprotein
- Remove cholesterol from the peripheral tissue and transport it to the liver
- It is believed that HDLs can absorb cholesterol that are being deposited in the arteries (aka good cholesterol)
What 4 substances does the live secrete that give it an endocrine function?
- Angiotensinogen - a prohormone that will result in angiotensin
- Thrombopoetin - a hormone (growth factor)
- IGF (insulin-like growth factors) - is produced in response to growth hormone (i.e. IGF-1 and 2)
- Hepcidin - is a small peptide hormone (iron homeostasis)
What is biotransformation?
Group of reactions involved in the conversion of toxic molecules in non-toxic, water soluble & more excretable substances
What is important about most drugs that we can give to patients?
- Most drugs are liposoluble (& would, therefore, stay long in the body)
- Biotransformation is essential for the termination of their action & their elimination from the body
What is the largest site for biotransformation?
The liver
What are the enzymes involved in biotransformation in the liver?
Cytochrome P450 enzymes
True or False. Drug metabolism leads to increase polartiy.
True
* Drug metabolism leads to increase polartiy
* Makes drugs & theit metabolites more water soluble
In the liver, where is the bile produced?
Bile is produced in the hepatocytes and modified in epithelial cells of the gallbladder.
What is the function of the gallbladder?
Storage & concentration of the bile through electrolytes (Na+, Cl-, HCO3-) & water reabsorption.
What is synthesized to make bile acid?
Bile acids are synthesized from cholesterol & conjugated w/amino acids (i.e. glycine, taurin)
True or False. Bile acids are amphipathic molecues.
True
What do bile acids secrete?
- Amphipathic molecules
- Secreted into the duodenum where they emulsify fat droplets in the small intestine (formation of mixed micelles)
When bile acids are secreted into the duodenum & emulsify fat droplets in the small intestine, what is formed?
Formation of mixed micelles
What is the path of bile in liver?
- First excreted into the bile canaliculi (small canals btween hepatocytes).
- Bile canaliculi then gradually feed into larger canals & finally into the common bile duct (ductus choledochus).
What is the muscle that prevents bile from leaking into the duodenum?
Sphincter of Oddi
* sphincter of smooth muscle
* guards the entrance of the bile into the duodenum
When there is no digestion, where is bile stored?
Gallbladder
* rats & horses do NOT have a gallbladder
What causes sphincter of Oddi to relax & release bile?
After a meal, the gallbladder is emptied:
* ↑ amino acids & fatty acids in duodenum → ↑ CCK → contraction of smooth m. & relaxation of Oddi’s sphincter
What is the refractory mechanism that affects the circulation of bile?
Reflexive stimulation →↑ Ach → contraction of the smooth m. of the gallbladder
What is the components of bile?
- Bile acids
- Bile pigment
- Phospholipids
- Cholesterine
- Na+
- K+
- Ca+
- Cl-
- HCO3-
What is the pH of bile?
8.2
What is the general steps of synthesis & circulation of bile acids?
- Cholesterol within hepatocytes interact w/bile acids.
- This then goes through transporters that transport the bile into the bile canaliculi
- Where bile is then fed into the bile duct & eventually released into the duodenum.
- The bile acids are reabsorbed through the intestinal lumen in the ileum through a sodium transporter, & then they go through an additional transporter into the bloodstream.
- This then transports back through to the liver where the bile is collected for reuse.
What percentage of bile is made each time we eat? How much is recirculated?
- 95% is recirculated in small intestine and liver
- 5% is what is made de novo in the liver
After fats are digested & absorbed, where does bile acids go?
After fats are digested & absorbed, bile acids go to the ileum, where they are reabsorbed using an active transport process.
Synthesis & enterohepatic circulation of bile acids have been studied for many years. How does it work (type of diffusion)?
- There are primary active transporters that require ATP, to get into bile canaliculi.
- There is recirculation of bile acids w/transporters in the ileum & hepatocytes, carriers are used.
- NO DIFFUSION
What are the two glandular tissues that compose the pancreas & what do they each secrete?
- Endocrine - secrete hormones
- Exocrine - secrete digestive enzymes & electrolytes
What is the exocrine pancreas?
- Is an acinar gland connected by an arborizing system of ducts.
- The structure resembles a salivary gland
What is the secretion in the acinus of the exocrine pancreas made of?
The primary saliva (i.e. Cl- channel apical; Na+/K+/2Cl- cotransporter basolateral)
In the exocrine pancreas, where does the addition of HCO3- occur?
In the ducts
What are zygomens?
- Inactive forms of proteases (protein-digesting enzymes) which are potentially harmful to pancreatic cells.
- “pro” or “ogen” signifes that enzymes are not in active form
What digestive enzymes are produced in the pancreas?
- Peptidases (produced in inactive form) - Trypsinogen, chymotrypsinogen & proelastase (zymogens)
- Nucleases - Ribonuclease & deoxyribonuclease
- Amylases (pancreatic) - α-amylase
- Lipases
What receptors do pancreatic cells have?
- Acetycholine (Ach)
- CCK
- Secretin
How can diet effect the concentration of specific digestive enzymes?
- ↑ starch → ↑ amylase
- ↑ fast & protein → ↑ lipases & peptidases
What are the phases of regulation for the exocrine pancreas?
- Cephalic phase - smell, sight, imagination
- Gastric phase - dilation of the stomach
- Intestinal phase - ↓ pH → ↑ secretin / ↑ AA, FA → ↑ CCK
What occurs in the intestinal phase of regulation of the exocrine pancreas?
- ↓ pH → ↑ secretin (this is to balance the pH & keep it from becoming too acidic & damage the intestines)
- ↑ AA, FA → ↑ CCK
True or False. Ach & CCK both stimuate secretion of an enzyme & chloride-rich fluid.
True
* Ach & CCK both stimuate secretion of an enzyme & chloride-rich fluid.
True or False. CCK stimulates the production of a bicarbonate-rich secretion.
False
* Secretin stimulates the production of a bicarbonate-rich secretion.
What are two examples of impairment of pancreas secretion?
- Pancreatic insufficiency
- Pancreatitis
What is pancreatic insufficiency and the clinical signs?
- Insufficient production of difestive enzymes by the exocrine pancreas; maldigestion
- Clinical Signs: greasy/oily stools (steatorrhea), polyphagia (eats excessive amt of food), rapid weight loss
What is pancreatitis and the clinical signs?
- In dogs relatively frequent (middle to old age, obese dogs)
- Can be very dangerous, there is inflammation of pancreas & enzymes are activated
- Acini destroyed and replaced by connective tissues b/c of autodigestion
- Increase risk when eating too much fat, human food or garbage
- Example - Beagles
What is the active form of trypsinogen?
Trypsin
What does it mean to be amphipathic?
One side of the compound is hydrophilic while the other is hydrophobic
What are the major dietary carbohydrates?
- Starch
- Glycogen
- Saccharose
- Lactose
After digestion begins in the mouth, how does further digestion occur for carbohydrates?
- Further digestion of carbohyrates is achieved by pancreatic enzymes
- Digestion is finished by enzymes synthesized by the intestinal mucosa
Where does absorption of carbohydrates occur? What is it mediated by and where is the mediator located? What facilitates this action?
- Absorption of carbohydrates takes place in the duodenum & upper jejunum
- It is mediated by a Na+ dependent transport mechanism (SGLT1) present at the apical membrane
- This happens by facilitated transport mechanisms present at both the apical (GLUT5) & the basolateral membrane (GLUT2)
Where are proteins denatured?
In the stomach
What partially hydrolyzes proteins in the stomach?
Pepsin (ca. 12-15%)
Where does the final digestion & absorption of proteins take place?
In the small intestine
What are lipids used for?
- Prostaglandins
- Steroid hormones
- Phospholipids
- Platelet-activating factor (PAF)
- Sphingomyelin: component of myelin in nerve fibers
True or False. Fat has an amphiphatic characteristic.
True
* It has a hydrophillic side and a hydrophobic side of the compound
Where does emulsification occur and what is the goal?
- Occurs in the duodenum
- Aims to reduce the surface area of the hydrophoic lipid droplets (crucial for lipase function which binds at the interface droplet/aqueous solution)
What do bile acids consis of (chemical composition)?
Bile acids (liver) consis of a sterol ring w/a side chain of amino acid (taurine or glycin)
True or False. Bile acids emulsify fat froplets.
True
What are the main dietary lipids?
- Cholesterol esters
- Phospholipids
- Triglycerides
Where do lipid digestion start?
- Partially in the stomach (gastric lipase)
- Bile acids emulsify the large fat drops
- Emulsified fat droplets are still too large to enter the spaces between microvilli
What is the role of pancreatic lipases?
Hydrolize triglycerides into monoglycerides & free fatty acids.
What will form mixed micelles?
- Monoglycerides
- FFA
- Cholesterol
- Liposoluble vitamines
How are mixed micelles absorbed?
Mixed micelles approach the brush border membrane of enterocytes where they will be absorbed
Do short chain fatty acids form mixed micelles? Why or why not?
- Short chain fatty acids do NOT form mixed micelles
- They can be directly absorbed
Once absorbed, what is the path of the mixed LCFA?
LCFA go into the endoplasmic reticulum for re-esterification (re-synthesis) of more complex lipids as follows:
MAG + free fatty acids → TAG
What is the pathway of chylomicrons?
Chylomicrons are released by exocytosis into the lymphatic vessels → thoracic duct → left subclavian vein → blood
Which segment of the small intestine or proximal large intestines has the highest permeability through its tight junctions?
Jejunum
Which segment of the small intestine or proximal large intestines has the lowest permeability through its tight junctions?
Colon
Which segment of the small intestine or proximal large intestines has the highest resistance through its tight junctions?
Colon
Which segment of the small intestine or proximal large intestines has the lowest resistance through its tight junctions?
Jejunum
List in order of lowest to highest permeability the sections of intestine.
Colon → Ileum → Jejunum
List in order of lowest to highest resistance the sections of the intestines.
Jejunum → Ileum → Colon
Where does the water absorption take place in the gastrointestinal tract?
- 85% of water absorption takes place in the small intestine (55% in duodenum & jejunum + 30% in ileum)
- 14% is absorbed in the large intestine
What is required for efficient absorption of water?
- Increase resorption surface
- Mucosa uptake mechanisms
- High blood perfusion
- Permeability
How are monovalent ions absorbed?
- Na+ transport is very efficient since it represents the driving force for most transport processes
- Cl- is absorbed by carriers as well as passice through the paracellular pathway
- K+ is mainly absorbed in the small intestine through the paracellular pathway
Why is Ca2+ absoprtion important in the small intestine, particularly in cows? What vitamin does absorption depend on?
- Important to produce milk
- Depends on Vitamin D from kidneys
What does calcitriol do?
- ↑ apical Ca++ channels
- ↑ Calbindin synthesis
- Ca++ ATPase
Where is Mg++ absorbed?
Through Mg++ channels & paracellularly
How is phosphate absorbed?
Through Na+/Phosphate symporter
Where is Vitamin D produced?
What influences its synthesis?
- Produced in the kidneys
- Synthesis is under the influence of PTH
What is calcium absorption modulated by?
Modulated by Vitamin D in intestine
What occurs to the diameter of the intestine as we move from oral to aboral?
Diameter decreases as we move through the GI tract
What is haptocorrin and what does it do?
- Transcobalamin I
- This protects B12 from stomach acid
What releases B12 from Haptocorrin?
Trypsin
Where is B12 absorbed?
Ileum
Where is iron absorbed?
Small intestines
What breaks down Fe3+ to Fe2+?
Ferriductase
What is iron important for?
The development of RBC/B12
Why is iron oxidized?
So it could be bound to protein (apotransferrin) which is converted to transferrin
What are catabolic pathways?
Energy capture (ATP) as a result of degradation of energy-rich molecules.
What are anabolic pathways?
- Combine small molecules (e.g. Amino acids) to form more complex molecules (e.g. proteins)
- Require energy (ATP → ADP) & oftern chemical reductions (NADH)
What are the energy-poor end products of catabolites?
- CO2
- H2O
- NH3
What are the precursor molecules of complex molecules that are anabolites?
- Some amino acids
- Sugars
- Fatty acids
- Nitrogenous bases
What are the 3 phases of energy metabolism?
- Absorptive phase
- Post-absorptive phase
- Prolonged energy deficiency or Food deprivation
What occurs during the absorptive phase of energy metabolism?
During active digestion & absoprtion of nutrients from the gut
* Insulin is released
* Glucose is taken by the liver & converted to glycogen & fatty acids
* Fatty acids are sent out of the liver in VLDL to adipose tissue or muscle
* Amino acids are used for protein synthesis or are deaminated for gluconeogenesis
What occurs during the post-absorptive phase of energy metabolism?
Nutrients are being mobilized from storage pools to tissues. Between meals.
* Glucagon is released
* Glycogenolysis (formation of new glucose) & gluconeogenesis (reuse of glucose) are stimulated
* Amino acids are mobilized from muscle
What occurs during the prolonged energy deficiency or food deprivation of energy metabolism?
- Glucose & amino acids are conserved
- Fatty acids are mobilized in the form of non-esterified fatty acids (NEFAs)
- Formation of ketone bodies in the liver (mitochondria)
What happens in terms of carbohydrate utilization in glycolysis?
- Once in the portal blood, glucose will reach the liver
- Glucose transport into cells is mediated by GULT
How many GLUT transporters are there, and are they very specific?
> 14 different GLUTs (ghighly tissue-specific, insulin-induced)
What is glycolysis?
- Glycolysis is a central ATP producing pathway as it produces energy w/out O2
- Red blood cells & muscle take advantage of anaerobic glycolysis
What is the net gain w/glycolysis?
2 pyruvate + 2 NADH + 2 ATP
What happens to the pyruvate after glycolysis?
It is converted into lactate:
* Pyruvate → mitochonria
* NADH → electron transport chain → NAD+
* If no oxygen, then fermentation occurs where there is excretion of lactate
Why is NAD+ important?
NAD+ is needed to make more pyruvate
What is anaerobic glycolysis?
2 ATPs are generated for each molecule of glucose converted to 2 molecules of lactate (no net production of NADH)
What is aerobic glycolysis?
- Direct consumption & formation of ATP is the same as in anaerobic glycolysis
- Also NADH production is the same but pyruvate is imported into the mitochondria (to produce ACoA that enters into the Krebs cycle) & NADH can be oxidized (regeneration of NAD+) during the electron transport chain
- During electron transport chain, 3 ATPs are produced for each NADH molecule that has been oxidized
What is the Tricarboxylic Acid Cycle (TCA)?
TCA/Krebs Cycle/Citric Acid Cycle
- The final pathway where carohydrates, amino acids, & fatty acids converge
- TCA is a traffic circle (“roundabout”)
- The energy provided by the TCA is essential for most animals & humans
- TCA occurs close to the electron transport chain
- The process is aerobic b/c oxygen is used as an electron acceptor
- It delievers reduced NADH & FADH2
What occurs in the matrix?
TCA cycle
What occurs in the inner membrane?
- Oxidative phosphorylation
- ETC complexes
What occurs in the intermembrane space?
Proton gradient
Explain TCA overiew.
- Pyruvate from glycolysis is converted to acetyl CoA which enters the cycle
- Step 1 - Acetyl CoA is converted to citrate by combining w/oxaloacetate. The carbons from each are combined so citrate is a 6 carbon molecule.
- It stays as a 6 carbon molecule, until conversion of NAD+ to NADH w/isocitrate converts it to a 5 carbon molecule α-ketoglutarate, as CO2 is released.
- This happens again to get a 4 carbon molecule succinyl CoA.
- This stays a 4 carbon molecule as succinate, then fumarate, then maalte, & eventually oxaloacetate.
What is the overall point of TCA?
- Produce NADH (& FADH) which is used int he electron transport chain to produce ATP
- 3 molecules of NADH are produced in one turn of the TCA cycle.
- Each glucose molecules produces 2 acetyl CoAs, therefore requiring 2 turns of the TCA cycle.
- 1 molecule of glucose = 6 NADH, 2FADH, 2 GTP, 4 CO2
What is gluconeogenesis?
- Production of glucose from non-sugar molecules such as amino acids, lactate, & glycerol
- Important tissues - liver & kidney
What can occur during a prolonged fast?
Hepatic glycogen stores are depleted, glucose is then formed from precursors other than carbohydrates (i.e. lactate, pyruvate, glycerol from TAG, & α-ketoacids from amino acids)
True or False. Gluconeogenesis is a reverse glycolysis.
False
* Gluconeogenesis is NOT a reverse glucolysis
* It is a special pathway that requires enzymes localized in the mitochondria as well as in the cytosol
What are important substrates during gluconeogenesis (& where they enter)?
- Glycerol → glycerol phosphate (glycerol 3-phosphate)
- Lactate → pyruvate
- Amino acids (muscle) → TCA cycle → Oxaloacetate
What is glycogenesis?
- A mechanism to store glucose as glycogen in orger to mobilize glucose in absence of a dietary source
- Main stores in the body: skeletal muscle & the liver
What is glycogenolysis?
The process by whcih glucose is mobilized from glucogen granules in order to be sent into the blood & to other tissues
Where does the pentose phosphate cycle occur & what is another name for it?
- The pentose phosphate cycle occurs in the cytosol
- AKA hexose pathway
- No ATP is consumed or generated
- It does produce a major portion of the NADPH used in the body as well as the pentose ribose 5-phosphate
What are the functions of NADPH in physiologial processes?
- Important source of electrons (reductases in the body)
- Carrying electrons to the electron transport chain complexes
- Reducing the enzyme cytochrome P450 (steroid hormone synthesis, bile acid synthesis, detoxyfication, etc)
- Respiratory burst in phagocytic cells (NADPH oxidase produces reactive oxygen species to kill bacteria)
- Synthesis of NO
What are the fate of dietary lipids in the body?
- Very simplified
- Short & medium chain fatty acids → get into the portal circulation (bound to albumin) & reach, finally, the liver
- Chylomicrons → TAGs will be converted into free fatty acids & glycerol by the enzyme lipoprotein lipase which is expressed at the capillaries of skeletal muscle, adipose tissue, heart, lung, kidney, liver. FFA can be stored as TAG (adipocytes) or can be used to produced energy (in other cells) or remain in the blood (bound to plasma proteins)
- Chylomicron remnants (i.e. cholesteryl ester, phospholipids, liprproteins, fat-soluble vitamins0 will be endocytosed (receptor-mediated) by liver cells
What is the relevance of fatty acids?
- Energy: During a fast period fatty acids are bound to albumin in plasma (free fatty acids) on the way to the tissues (coming from adipose tissue) → oxidation (energu production in most tissues)
- Structural components: Phospholipids & glycolipids in the plasma memvrane
- Hormone precursors: Prostaglandins
- Energy reserve: TAG in adipose tissues
What is the net gain of β-oxidation of fatty acids?
- From 1 palmitoyl CoA that has been oxidized to CO2 & H2O → 8 ACoA, 7 NADH, 7 FADH2
- From these molecules 131 ATP can be generated (minus 2 ATP needed = 129 ATP)
What occurs in ketone body formation?
- The liver (mitochondria) can convert ACoA from fatty acid oxidation into ketone bodies - acetoacetate, 3-hydroxybutyrate (β-) & acetone - which are important sources of energy during fast periods
- During a prolong fast, fatty acids mobilized from adipose tissue come to the liver yielding much more ACoA than necessary (also fatty acid oxidation produces high amounts of NADH which shifts OAA to malate). This result is the utilization of excess ACoA for ketone bodies formation. In periperal tissues, ketone bodies are converted into ACoA which enters the TCA cycle
What are the fates of absorbed amino acids in the liver?
…
What are important molecules in physiology that are derived from amino acids?
- Hydroxxylation of tryptophan yields serotonin (neurotransmitter & paracrine hormone)
- Acetylation & methylation of serotonin → melatonin (hormone which influences reproductive activity)
- Hydroxylation of tyrosine yields dopa, which is subsequently decarboxylated to form the neurotransmitter dopamine (in some neurons dopamine is hydroxylated to form norepinephrine)
- Decarboxylation of histidine yields histamine (mediator of allergic reactions)
What are peptides?
- Biologically occuring short chains of amino acids linked by peptide bonds
- The shortest peptides are dipeptides, consisting of 2 amino acids joined by a single peptide bond, followed by tripeptides, tetrapeptides, etc.
What are glucogenic amino acids?
Those that produce TCA intermediates and can thereby enter the TCA yielding oxaloacetate, a glucose precursor
* Alanine, Arginine, Asparagine, Cysteine, Glutamate, Glutamine, Glycine, Proline, Serine, Histidine, Methionine, Threonine, Valine
What are branch-chain amino acids (BCAA)?
Serve as a source of energy in muscle cells
* Valine, Leucine, & Isoleucine
What happens to BCAA in muscle cells?
- After deamination, BCAA are converted into α-ketoacids which enter the TCA
- At the same time pyruvate serves as an acceptor of the BCAA’s amino group yielding to the formation of the amino acid alanine which leaves the muscle & is used byt he liver for gluconeogenesis
What does alanine from BCAA metabolism represent?
An important way to eliminate ammonia (NH3) from the body through the formation of urea which occurs only in the liver
