GI Flashcards
7 functions the liver performs
Carbohydrate, fat, protein, hormone and toxin/drug metabolism
Storage
Bilirubin metaoblism and excretion
2 storage spaces of iron in the body?
Liver
Reticuloendothelial macrophages
What protein is iron carried by in the plasma?
Transferrin
Where is dietary iron absorbed in the GI tract?
Duodenum
Where is iron sent to from plasma? What is its role?
Muscle cells (plays role in muscle contraction?)
Bone marrow (to form haemoglobin in erythrocytes)
Iron loss from…
Menstruation
Other blood loss
Desquamation
Ferritin structure and location
Subunits form a shell around a central core which contains up to 5000 iron atoms
Found in cytoplasm of cells and also in serum
Ferritin excess means…
Ferritin deficient means…
Could have an excess iron storage disorder
Iron deficiency
Vitamins can act as…(3)
Gene activators
Coenzymes/cofactors in metabolism
Free-radical scavengers (protects cell from damage caused by free-radicals)
2 water soluble vitamins
B and C
4 fat soluble vitamins
A, D, E, K
Why do you require more regular intake of water soluble than fat soluble vitamins?
Water soluble pass through the body much more readily so you can become deficient in them quicker.
Sources of carotenoids and how they produce vitamin A
Carrots, tomatoes, spinach
Oxidation of carotenoids then produces retinol (vitamin A)
Sources of retinol (vitamin A)
cheese, eggs, oily fish
3 functions of vitamin A
Vision (used to form rhodopsin)
Reproduction (spermatogenesis)
Growth
Vitamin A deficiency cause and features
Due to fat malabsorption
Blindness/Xerophthalmia
Chronic Vit A Excess Symptoms
Joint pain, anorexia, hairloss
Acute Vit A Excess Symptoms
Abdominal pain, severe headaches
Carotenemia
Reversible yellow pigmentation of skin from risen beta-carotene levels in blood
How does sunlight exposure lead to vitamin D production
Sunlight stimulates conversion of 7-dehydrocholesterol -> Vitamin D3 which is sent to the liver
Vitamin D dietary sources
D3 - Fish and meat
D2 - Supplements
Why is vitamin D3 transported liver->kidneys?
To be converted to the active form of vitamin D3 that can be used by the body
3 functions of vitamin D
Increased intestinal absorption of calcium
Resorption/formation of bone
Reduces renal calcium excretion
Deficiency of vitamin D causes…
Demineralisation of bone:
Rickets in children, osteomalacia in adults
What carries vitamin K from liver to plasma?
Low density lipoproteins
Sources of vitamin K
Synthesised by plants (K1)
Synthesised by humans in intestinal bacteria (K2)
Synthetic vitamin K (K3, K4)
Vitamin K functions
Activation of some clotting factors
Necessary for specific liver synthesis of plasma clotting factors
Vitamin K deficiency causes…
Haemorrhagic disease of newborn (bleeding from low clotting factors from low vitamin K levels)
Excess vitamin K causes…
Red cell fragility (only in synthetic forms)
Vitamin C source and functions
How much do adults need a day?
Fruit and veg
Collagen synthesis
Antioxidant
Iron absorption
40mg/day
Vitamin E storage, function, and amount needed
Labile and fixed pools in non-adipose cells
Fixed pool in adipose cells
Important antioxidant (protects body against free radicals)
4mg/day in women
3mg/day in men
Vitamin E deficiency caused by…
Fat malabsorption
Result of vitamin C deficiency/excess
Deficiency - Scurvy (easy bruising, gum disease, hair loss)
Excess - >1g/day = GI side effects
How is vitamin B12 protected from stomach acid?
Binds to R protein (released from R protein by pancreatic polypeptide0
How is vitamin B12 absorbed?
Binds to intrinsic factor forming IF-B12 which is absorbed in the terminal ileum and stored in the liver
Vitamin B12 deficiency causes and symptoms
Pernicious anaemia (autoimmune destruction of IF producing cells in stomach), malabsorption, veganism
Causes peripheral neuropathy
Vitamin B12 deficiency causes and symptoms
Pernicious anaemia (autoimmune destruction of IF producing cells in stomach), malabsorption, veganism
Causes peripheral neuropathy
When do individuals have higher folate requirements?
Pregnancy
What are folate functions?
Acts as a coenzyme in methylation reactions and DNA synthesis
Folate deficiency causes and symptoms
Malabsorption, anticonvulsants (interfere with folic acid metabolism)
Can cause macrocytic anaemia and foetal development abnormalities (neural tube defects)
What activates the extrinsic pathway of the coagulation cascade?
Contact between FVII and tissue factor
Clotting factors produced in the liver
I (Fibrinogen)
II (Prothrombin)
IV
V
VI
VII
Performance of clotting pathways measured by…
Prothrombin time (PT) (extrinsic pathway)
Activated partial thromboplastin time (aPTT) (intrinsic pathway)
(prolonged prothrombin time doesn’t confirm you have liver disease but shows how well your liver can synthesise things)
3 colon functions
Absorption of water and electrolytes
Excretion of waste
Producing vitamins
Muscle layers in colon
Continuous circular muscle
3 ribbons longitudinal muscle (taeniae coli)
Cells in colon mucosa
Simple columnar epithelium (lots of microvilli)
Goblet cells
4 phases of defecation
1) Basal
2) Pre-expulsive
3) Expulsive
4) Termination
What occurs in the basal phase of defecation?
Segmental mixing in colon
Tonic contraction of anal sphincter
Contraction of puborectalis (maintaining 90degree anorectal angle)
What occurs in the pre-expulsive phase of defecation?
High amplitude contractions of colon (gastro-colic reflex)
Rectum fills causing distension
EAS maintains contraction, IAS reflex relaxation
Puborectalis remains contracted
What occurs in the expulsive phase of defecation?
Rectum contracts
IAS, EAS, PR relax along with valsalva manoeuvre / posture aids emptying
What occurs in termination phase of defecation?
Traction loss due to sudden EAS contraction (closing reflex)
Nerve supply to colon
Intrinsic - ENS (Myenteric Plexus, Submucosal Plexus)
Extrinsic - Parasympathetic and Sympathetic
Hard stools caused by…
causing constipation
Opioids, low fluid intake, low fibre
How are proteases secreted in stomach?
Chief cells produce pepsinogen
Activated in lumen by pepsin and HCl
Where does inactivation of pepsin occur?
In small intestine by bicarbonate secretion increasing pH (irreversible inactivation)
Zymogen
Inactive protein precursor of an enzyme (pepsinogen)
How is pepsinogen production mediated?
Input from ENS (ACh)
Role of pepsin
Breaks down collagen in meat into smaller pieces with greater surface area for digestion
Receptive relaxation of body and fundus mediated by…
Parasympathetic nervous system acting on enteric nerve plexuses (nitric oxide and serotonin released by enteric nerves mediates relaxation
Any ammonia which evades detoxification as urea can be…
Ammonia + Glutamate -> Glutamine (Glutamine Synthetase)
In the glucose alanine cycle, at the muscle, ALT…
transaminates the amino group from glutamate forming a-Ketoglutarate. The amino group gets attached to pyruvate making alanine (the opposite occurs at the liver)
Stomach Functions (9)
Store/mix food
Dissolve, continue digestion
Regulate emptying into duodenum (due to its larger volume)
Kill microbes
Secrete proteases
Secrete IF (helps in absorption of vit B12 in terminal ileum)
Activate proteases
Lubrication
Mucosal digestion
4 key stomach cell types
Mucous cells
Parietal cells (secrete HCl and IF)
Chief cells (secrete pepsinogen)
Enteroendocrine cells (secrete gastrin)
Neural input to stomach supplied primarily by
Vagus nerve
How much gastric acid secreted per day in stomach?
Approx 2 litres
Arterial supply of foregut, midgut and hindgut
Foregut - coeliac trunk
Midgut - SMA
Hindgut - IMA
Symp/Parasymp innervation from ANS of foregut
S: Greater splanchnic nerve (T5/6-T9)
P: Vagus
Symp/Parasymp innervation from ANS of midgut
S: Lesser splanchnic nerve (T10-11)
P: Vagus
Symp/Parasymp innervation form ANS of hindgut
S: Least splanchnic nerve (T12 +/- L1)
P: Pelvic splanchnics
Where is visceral pain felt in foregut?
Epigastric region
Where is visceral pain felt in midgut?
Umbilical region
Where is visceral pain felt in hindgut?
Suprapubic region
Start and end of foregut
Start - Distal oesophagus
End - Halfway along duodenum (1st and 2nd parts of duodenum are foregut)
Start and end of midgut
Start - Halfway along duodenum (3rd and 4th parts)
End - First 2/3 of transverse colon
Start and end of hindgut
Start - Distal 1/3 transverse colon
End - Upper anal canal
Chemical vs Electrical Synapse
Chemical - Neurotransmitters (majority)
Electrical - direct flow of ions (less abundant)
Explain chemical synaptic transmission
-Axon potential depolarises synaptic terminal membrane
-Opening of voltage-gated Ca channels = Ca influx
-Ca influx triggers neurotransmitter release
Electrical synapse structure
Gap junctions
Channel formed by pores in each membrane
Connexon made up of 6 connexins in a ring which form the pore allowing flow of ions
Dendritic spines
Tiny protrusions from dendrites which form functional contact with other axons
ER found within them (to make proteins)
Arborisation of neurons
Neurons search for appropriate targets by expanding and/or retracting their axons
Oligodendrocytes
Myelinating cells of CNS
Myelin sheath formation
Wrapping of axons by oligodendrocyte processes (membranes)
Highly compacted - 70% lipid, 30% protein
Microglia
Resident immune cells of CNS
Originate from haematopoietic progenitors which migrate to CNS
Resting- Highly ramified, motile processes
Activated - retract processes, motile
Proliferate at sites of injury (phagocytic)
Functions of microglia
Immune surveillance
Phagocytosis (debris)
Synaptic plasticity - pruning of spines
Bad microglia
Proinflammatory cytokines which cause microgla to increase inflammation in neuro-degenerative diseases
Astrocytes
Star-like cells
Most numerous glial cells in CNS
Astrocytes functions
-Structural - define brain micro-architecture
-Envelope synapses
-Metabolic support
-Neurovascular coupling - changes in cerebral
blood flow in response to neural activity
-Proliferation in disease (gliosis or astrocytosis)
Define MND
Adult onset neurodegenerative disease characterised by loss of upper (motor cortex) and lower (spinal cord) motor neurones
Define MS
Autoimmune demyelinating disease where immune cells attack myelin sheath
Tracts of axons that cross midline are called…
commissures
Cell bodies located…
In ganglia (dorsal root ganglia)
Blood-brain barrier
Dyes injected into blood penetrate most tissues, but not the brain (good for disease prevention in brain but problematic for drug delivery)
Formed by endothelial cell tight junctions (few fenestrations), astrocyte end feet and pericytes
Circumventricular organs
Permit hormones to leave brain without interrupting BBB
(e.g - pineal body which secretes melatonin into blood or posterior pituitary which secretes hormones into blood)
4 key cell types in gastric epithelium
Chief Cells - produce proteases
Mucous Cells - secrete mucous
Parietal Cells - secrete HCl and intrinsic factor
Enteroendocrine Cells - secrete hormones
Gastric Acid Secretion
HCl
Approx 2L per day
Neurohumoral regulation (by vagus nerve and variety of hormones)
Pump in gastric parietal cells to decrease lumen pH
Pumps H+ into gastric lumen
Pumps K+ into gastric cell
(K+/H+ ATPase pump)
Which 2 ions passively flow out of parietal cell into gastric lumen?
K+ and Cl-
Where do H+ ions come from in parietal cells?
Cellular respiration
H2O -> OH- + H+
Swapping ions between blood and parietal cells
HCO3- enters blood
Cl- enters parietal cell
How are bicarbonate ions produced in parietal cells?
CO2 + H2O (catalysed by carbonic anhydrase) -> H2CO3 -> H+ + HCO3-
Turning on gastric acid release (cephalic phase)
Parasympathetic nervous system
Sight, smell, taste, chewing stimulates brain to stimulate stomach via vagus nerve
Done through ACh release: acts directly on parietal cells, but also triggers release of gastrin and histamine (which turn on parietal cells)
Turning on gastric acid release (gastric phase)
Gastric distension, presence of peptides / amino acids = gastrin release (acts directly on parietal cells)
Gastrin triggers histamine release (acts directly on parietal cells)
Why do proteins in stomach stimulate gastrin release?
Proteins act as buffer mopping up H+ ions (=pH rise) and therefore decreased production of somatostatin
Role of somatostatin
Inhibit gastric acid release
Turning off gastric acid release (gastric phase)
Low luminal pH = inhibited gastrin secretion indirectly inhibiting histamine release
Stimulates somatostatin release
Turning off gastric acid release (intestinal phase)
In duodenum: low pH, hypertonic luminal contents, duodenal distension, presence of fatty acids and amino acids
Triggers release of enterogastrones: secretin and cholecystokinin (CCK)
Role of secretin and cholecystokinin (CCK)
Inhibit gastrin release, promote somatostatin release
Gastrin, ACh and histamine binding to receptors on parietal cell membranes results in…
Upregulation of H+/K+ ATPase pumps
Somatostatin binding to receptors on parietal cell membranes results in…
Dwonregulation of H+/K+ ATPase pumps
Autocrine factors
Cells releasing a substance that acts on themselves
Paracrine factors
Cells releasing a substance that acts on neighbouring cells (histamine and somatostatin)
Hormone
Acts on cells at distant sites
Define ulcer
Breach in mucosal surface
4 peptic ulcer causes
Heliobacter pylori infection
Drugs (NSAIDS)
Chemical irritants (alcohol, bile salts)
Gastrinoma
4 ways gastric mucosa protects itself from ulcers
Alkaline mucus
Tight junctions between cells
Replaces damaged cells
Feedback loops
Heliobacter pylori causing peptic ulcers
Lives in gastric mucus
Secretes urease splitting urea into CO2 and ammonia
Ammonia + H+ -> Ammonium (toxic to gastric epithelium) = inflammatory response and reduced mucosal defence
NSAIDS causing peptic ulcers
Lessen inflammatory responses by inhibiting cyclo-oxygenase 1 (needed for prostaglandin synthesis and prostaglandins needed for inflammatory response)
Reduce mucosal defence
Bile salts causing peptic ulcers
Duodeno-gastric reflex
Regurgitated bile strips away mucus layer
Reduced mucosal defence
Proton pump inhibitors which prevent over-secretion of gastric acid
Omeprazole, Lansoprazole, Esomeprazole
Role of ranitidine
Prevents histamine from stimulating parietal cell
Mucus secreting cells stimulated by…
Prostaglandins
Chief cells in gastric mucosa produce…
Pepsinogen (which is a zymogen)
Pepsinogen mediated by input from ENS (ACh secretion like HCl secretion from parietal cells)
Pepsinogen activation
In the gastric lumen, pepsinogen and HCl are present (from chief and parietal cells).
HCl cleaves pepsinogen into pepsin
Pepsin can also digest pepsinogen into pepsin (+ve feedback)
Protein -> Peptides
Pepsinogen -> Pepsin most efficient at a pH of…
pH less than 2
How does the duodenum turn off pepsin production?
HCO3- secreted from Brunner’s Glands to increase pH
Role of pepsin in protein digestion
Not essential but accounts for ~20% total protein digestion
Breaks down collagen in meat
Stomach volume variability
Empty - 50mL
When eating, up to 1.5L with little increase in luminal pressure
Receptive relaxation
Relaxation of smooth muscle in body and fundus of stomach to accommodate food
Mediated by Vagus (parasympathetic)
Peristalsis in the stomach
Waves of contraction begin in gastric body More powerful contraction in antrum Pylorus closes as contraction reaches it to churn/mix food in stomach
What are the pacemaker cells of the GI tract?
Interstitial cells of Cajal which depolarise and repolarise (stronger contraction when stomach is fuller)
About 3 contractions per minute
What hormone stimulates increased strength of peristalsis?
Gastrin (due to gastric distension)
Strength of peristaltic contractions decreased by…
-Increased duodenal fat
-Increased duodenal osmolarity
-Decreased duodenal pH
-Increased sympathetic NS action
-Decreased parasympathetic NS action
Overactive stomach results in…
Dumping syndrome of chyme into duodenum
4 saliva functions
-Lubricant for mastication, swallowing and speech
-Oral hygiene (wash, immunity, buffer)
-Digestion
-Remineralisation (Ca(2+) and PO4(3-))
Saliva flow rate
0.3-7ml per minute
Daily saliva secretion in adults from major and minor glands
800-1500ml
Saliva pH range
6.2-7.4
2 salivary secretions are…
Serous secretion - a amylase (starch digestion)
Mucus secretion - (mucins for lubrication of mucosal surface)
Which gland produces the serous saliva secretion?
Parotid gland
Which glands produce both the serous and mucous secretions?
Submandibular and sublingual
Minor glands mainly produce what to contribute to saliva?
mucus
Factors affecting composition and amount of saliva produced
Flow rate
Circadian rhythm
Type/size of gland
Duration/type of stimulus
Diet
Drugs
Age
Gender
What is saliva?
Secretion of proteins and glycoproteins in a buffered electrolyte solution
3 defences of oral cavity
Mucosa - physical barrier
Palatine tonsils - provide immune cells
Salivary glands - wash away food/bacteria/viruses
Activity of glands in oral cavity
Submandibular, sublingual and minor glands continuously active
Parotid - usually fairly inactive but stimulated by thought of food or chewing
What is whole saliva?
salivary gland secretions, blood, oral tissue, microorganisms, food remnants
(can be used for disease diagnosis)
2 distinct types of epithelial tissue in salivary glands
Acinar cells (make saliva)
Ducts (carry saliva out of glands into mouth)
2 types of acini
Serous acini (water and a amylase)
Mucous acini (water and glycoproteins)
Differences in their appearance
Role of myoepithelial cells in a gland
Squeezes the gland pushing saliva out
How do cells lining a duct (from a gland) change as they go down the duct?
Change from intercalated to striated duct cells
Striated duct cells allow exchange of ions (like Na+/Cl-/HCO3-) to produce the final saliva product
Reason for striations in duct lining cells coming from glands
Striations increase SA to house more mitochondria so more active transport of bicarbonate can occur)
Three pairs of major salivary glands contribute what % of total saliva?
Parotid
Submandibular
Sublingual
80%
Minor salivary glands contribute what % of total saliva?
What type of acini do they have?
20% (situated all of submucosa of oral mucosa)
All mucous glands except for the serous glands of von Ebner
What acini are found in the parotid gland?
Serous acini
What acini are found in the submandibular gland?
Mix of serous and mucous acini (referred to as seromucous)
What acini are found in the sublingual gland?
Mix of serous and mucous acini (but more mucous acini)
Stenson’s duct
Major duct that connects parotid gland to oral cavity
Which nerve runs very close to parotid gland?
Facial Nerve
Where do submandibular glands lie?
Under tongue
2 lobes of submandibular glands?
What separates them?
Larger superficial lobe
Smaller deep lobe in floor of mouth
Separated by mylohyoid muscle
Wharton’s duct
Major submandibular duct begins in superior lobe wrapping around posterior border of mylohyoid
Runs along floor of mouth emptying into oral cavity at sublingual papillae
Location of sublingual glands
Between mylohyoid muscle and oral mucosa of floor of mouth
If salivary output falls below 50% of normal flow…
Patient experiences xerostomia (dry mouth)
Glucose pathway from consumption
Absorbed in intestine taken to liver in bloodstream
Distributed to muscle, brain, RBC, adipocytes (storage)
Conversion of glucose to glycogen storage in the liver is stimulated by…
Insulin
What happens to excess glucose in the liver?
Converted into Acetyl Co-A and either fed into Kreb’s or makes triglycerides -> very low density lipoproteins
2 stores of glycogen
Liver and skeletal muscle cells
What happens to glucose sent to brain?
Converted to Acetyl CoA which enters Kreb’s and forms ATP
What happens to glucose sent to RBCs?
Converted to pyruvate (then lactate)
What happens to glucose sent to adipocytes?
Converted to triglycerides (stimulated by insulin)
Triglycerides are insoluble in water so are carried around the body bound to a protein forming a…
Chylomicron or a VLDL
What do chylomicrons travel in back to blood system?
Lymphatic system
What promotes glycogen in liver to be broken down into glucose?
Glucagon (by glycogenolysis)
Where does energy come from when glycogen stores are used up?
-RBCs release lactate to be used as energy
-Amino acids released from muscle breakdown
-Triglycerides in adipocytes broken down into glycerol
(All sent to liver for gluconeogenesis)
During fasting, triglycerides in adipocytes are broken down into…
Glycerol (converted to glucose in liver) and fatty acids (used instead of glucose or converted to ketones in the liver)
This process is lipolysis
Which hormone stimulates breakdown of triglycerides? in lipolysis?
Glucagon
After prolonged fasting, gluconeogenesis decreases leading to an increase in…
Ketoneogenesis - ketones are used by the brain for energy instead of glucose so therefore there is enough glucose available to be used by RBCs
3 hormones released from the adrenal gland?
Adrenaline
Noradrenaline
Cortisol
2 hormones released form the pancreas?
Insulin
Glucagon
Hormone released from thyroid gland? What is the hormone’s role?
Thyroxine - speeds up metabolism
2 hormones released from pituitary gland?
Growth hormone
Somatostatin
Insulin vs Glucagon?
Insulin promotes glycogen and fat storage and protein synthesis (anabolic)
Glucagon promotes glycogenolysis, gluconeogenesis, ketogenesis (catabolic)
3 things that use up energy?
Activity
BMR
DIT
Leptin action in controlling appetite
Normal weight - suppresses appetite
In obesity - High leptin levels = leptin resistance = appetite not suppressed
Ghrelin role in controlling appetite
“Hunger Hormone”
Increases before meals
Stimulates appetite
Xenobiotics
Foreign substances of no nutritional value (can be harmful if not excreted)
Come form food/drink/breathing
Group of enzymes called ….. play major role in process of detoxification
Cytochrome P450 enzymes (specifically in phase 1)
Xenobiotic biotransformation reaction split into 2 phases…
Phase 1 (non-synthetic) - Addition/exposure of small functional groups (amine, hydroxyl etc.) (small increase in hydrophilicity)
Phase 2 (biosynthetic) - Addition of endogenous molecules (large increase in hydrophilicity)
Purpose of xenobiotic biotransformation
Make compounds less toxic and water soluble so can be excreted
Where does detoxification occur?
Mostly in liver but also in lungs and small intestine
Common features of cytochrome P450 enzymes
Present in SER
Oxidise the substrate and reduce oxygen
They’re inducible enzymes
They generate a free radical compound
2 exocrine secretions of pancreas
Aq bicarbonate
Enzyme
2 transport routes of epithelial cells in GI tract
Paracellular pathway
Transcellular pathway
Pancreas endocrine function
Secretes insulin and glucagon from islets of Langerhans
Pancreas exocrine function
Secretion of pancreatic juice
Ethanol metabolism
Only 2-10% excreted as it’s used as a fuel
Used to produce NADH (using alcohol dehydrogenase (ADH))
Cycle of principal blood flow through liver
Heart -> Abdominal Aorta -> Proper Hepatic Artery -> Liver -> Hepatic Veins -> IVC -> Heart
Liver microanatomy
Organised in lobules with a central (hepatic vein) surrounded by a hexagon of 6 portal triads
What constitutes a portal triad
Portal Vein
Hepatic Artery
Bile Ducts
8 Liver Roles
Detoxification - cleans bloods of waste products
Immune Function
Synthesis - clotting factors, glycogen, enzymes
Bile Production
Bilirubin breakdown
Energy storage (glycogen, fats)
Regulating fat metabolism
Ability to regenerate
Liver is regulated by 2 things…
Endocrine glands (pancreas, adrenal, thyroid)
Nerves
Define lipid
Esters of fatty acids and glycerol or other compounds (cholesterol)
What is the storage form of fat in our body?
Triglycerides in adipocytes, hepatocytes, etc.
Saturated fatty acids are…
Unsaturated fatty acids are…
Solid
Liquid
Liver vascular supply
Afferent:
75% portal vein
25% hepatic artery
Efferent:
Hepatic veins
3 Lipid functions
Energy Reserve
Structural (part of cell membranes)
Hormone metabolism
Lipids yield how much energy per gram?
9-10 kcal
How are lipids often transported in blood?
As triglycerides
As fatty acids bound to albumin
How do lipids enter a cell?
TGs can’t diffuse through membrane so FAs are released by lipases to facilitate transport (via several transporter systems like FA binding protein) into cells
In cell, FAs are re-esterified into TGs
Breakdown of triglycerides at adipocytes catalysed by…
Hormone Sensitive Lipase
Breakdown of triglycerides in blood catalysed by…
Lipoprotein Lipase
Breakdown of triglycerides in hepatocytes catalysed by…
Hepatic Lipase
Insulin action in fat metabolism
Fat storage in adipocytes
Stimulates LPL to breakdown TGs releasing FFAs which can be stored in the form TG in the adipocyte
Reduces activity of HSL reducing FA export from adipocytes
Insulin resistance in fat metabolism
Increased lipolysis in adipocytes = increased TG in circulation
Increased offer of FA to hepatocytes = greater uptake = increased glucose level and less demand of lipids to be used
What constitutes a lipoprotein?
A core containing TGs and cholesterol-esters and a surface monolayer of phospholipids, cholesterol and specific protein
How are lipoproteins defined?
By their density (LDL, HDL, chylomicron)
Chylomicrons role
Carry lipids from gut to muscle and adipose tissue
Chylomicrons fate
The remnants taken up by receptor mediated endocytosis
How is cholesterol esterified intracellularly?
acyl-CoA:cholesterol acyltransferase
How is cholesterol esterified in lipoproteins?
By lecithin:cholesterol acyltransferase
What % of cholesterol is endogenous?
90%
What is the major organ in which cholesterol is processed?
Liver
Only method of cholesterol export
Through bile (it’s a constituent of bile)
What is De novo lipogenesis?
Converts excess dietary starch, sugar, protein, and alcohol into specific fatty acids
Rate limiting step of De novo lipogenesis
Acetyl-CoA to Malonyl-CoA catalysed by Acetyl-CoA carboxylase
Fatty acid export from liver
ApoB 100 synthesised in RER
Lipid components (TG, cholesteorlester) synthesise in SER
These are added by TAG transfer protein to ApoB
Transported to GA where ApoB is gylcosylated
Glycosylated Apo-s with lipid componetns bud off GA and migrate to sinusoidal membrane of hepatocyte
Vesicles fuse with membranes and VLDL released
Fatty acid oxidation occurs at 3 locations in the liver… (to produce acetyl co-A)
Mitochondrial beta oxidation
Peroxisomal beta oxidation
ER Microsomal omega oxidation
Peroxisomal b oxidation
Normal ribosomal function
Mitochondrial beta oxidation
Progressive shortening into acetyl-CoA subunits (condensed into ketone bodies which enter TCA cycle)
ER Microsomal omega oxidation
CYP4A enzymes oxidise saturated and unsaturated fatty acids
omega-hydroxylation in the ER
Then, decarboxylation of the omega-hydroxy FA in cytosol
This product then enters b-oxidation pathway
Main source and loss of nitrogen
Source - Dietary protein
Loss - gut and kidneys as urea
Amino acid structure
H
H2N——-C——-COOH
R
Link between 2 amino acids
Dipeptide
Peptide bond (C-N)
How many amino acids in a polypeptide vs a protein
Polypeptide = <50
Protein = >50
Nitrogen said to be in balance if…
N intake (from dietary protein) is roughly equal to N excretion (+/- 4g/day)
Recommended daily dietary protein intake
0.75g/kg/day
3 sources of N loss
Renal excretion (70g/day)
Faecal loss (10g/day)
Skin/hair/sweat loss
Essential vs non-essential amino acids
Amino acids said to be essential if they can’t be synthesised de novo in vivo
Some amino acids are conditionally essential (so only essential under certain circumstances)
Which non-protein molecules are synthesised used N from dietary protein?
Neurotransmitters, nitric oxide, nucleotides
3 roles of albumin
Maintaining appropriate osmotic pressure
Binding and transport of hormones, drugs, etc
Neutralisation of free radicals
Transamination of alanine
Alanine + a-ketoglutarate <–> Pyruvate + Glutamate
(catalysed by ALT)
Cortisol role in AA catabolism
+ proteolysis
- protein synthesis
+ gluconeogenesis
Glucagon role in AA catabolism
+ glycogenolysis
+ gluconeogenesis
+ AA degradation
+ ureagenesis
+ entry of AAs to liver
What is bile?
Lipid rich solution containing water, inorganic electrolytes and organic solvents (bile acids, phospholipids, cholesterol, bile pigments)
Bile secretion per day from gall bladder
500-600ml per day
What circulation means the liver doesn’t have to synthesise as much bile?
Enterohepatic circulation - Most bile acids secreted by hepatocyte have been previously secreted into intestine
3 bile functions
Fat digestion/absorption
Cholesterol homeostasis
Excretion of lipid soluble xenobiotics
Bile acids (major constituent of bile) are synthesised from… in …
Synthesised from cholesterol in hepatocytes
What are the primary bile acids formed from cholesterol (lipid soluble)?
Cholic Acid (CA)
Chenodeoxycholic Acid (CDCA)
(water soluble)
What happens to bile acids before being secreting into bile?
(mechanism to trap them in the lumen of the intestine)
CA and CDCA are conjugated making them more hydrophilic and more acidic which makes them stay in the lumen of the intestine
Bile acids are amphipathic meaning…
Likes water and fat which aids emulsification of lipids (increasing SA) into the aq solution of the lumen
Process of digesting fat within a fat globule
Amphipathic bile salts and phospholipids surround a TG
Amphipathic protein (colipase) allows lipase to get into close approximation to the emulsion droplet and digest the TG
How do FAs and MGs enter the enterocytes?
Fatty acids and monoglycerides associate with phospholipids and bile acids allowing aq diffusion through channels into enterocyte (as the bile acids are amphipathic)
What happens to FAs and MGs once they are absorbed into the enterocyte?
They reform triglycerides and are exocytosed into the blood stream as chylomicrons
What happens to FAs and MGs once they are absorbed into the enterocyte?
They reform triglycerides and are exocytosed into the blood stream as chylomicrons
Fate of bile in fasted vs fed state (enterohepatic circulation part 1)
Fasted - bile acids travel down biliary tract from liver -> gallbladder (where they’re concentrated 10x)
Fed - CCK released from duodenal mucosa which relaxes Sphincter of Oddi and contracts gallbladder releasing concentrated solution of mixed micelles (BA, PL, cholesterol)
Bile acid reabsorption (enterohepatic circulation part 2)
Bile acids conjugated (so remain intraluminal)
Actively transported via apical sodium bile acid transporter (ASBT) into terminal ileum
Re-enters liver via portal circulation
Bile acids taken up by hepatocyte and secreted back towards gall bladder
How many enterohepatic cycles per meal
2-3 cycles
Bile acid negative feedback mechanism in terminal ileum
Bile acid binds to Farnesoid X Receptor in terminal ileum triggering synthesis of FGF 19 (hormone)
FGF 19 then inhibits CYP7A1 reducing bile acid production
Role of CYP7A1
Stimulates conversion of cholesterol into primary bile acids (CA and CDCA) in the liver
Na absorption in intestine
Glucose/Na (SGLT1) co-transporter on apical membrane brings Na into enterocyte
Na+/K+ATPase transporter then moves 1 Na cell->blood and 1 K blood->cell (on basolateral membrane)
Glucose absorption in intestine
Glucose/Na (SGLT1) co-transporter on apical membrane brings Glucose into enterocyte
GLUT2 transporter then takes glucose from cell->blood (on basolateral membrane)
cAMP effect on intestinal secretion
Works to shift Cl- from body into gut lumen
4 factors affecting intestinal absorption
Number and structure of enterocytes
Blood and lymph flows
Nutrient intake
GI motility
What breaks down maltose, sucrose and lactose (disaccharides) into monosaccharides?
Maltase, sucrase, lactase
Enterocytes absorb glucose and galactose by the Na co-transporter but absorb fructose by…
Facilitated transport
4 saliva functions
Lubricates, cleans oral cavity
Dissolves chemicals
Suppresses bacterial growth
Digest starch by amylase
Secretions of the mucous neck cell (in the stomach)
Mucus
Bicarbonate
Secretions of the parietal cells (in the stomach)
Gastric acid (HCl)
Intrinsic factor (complexes with Vit B12 to permit absorption)
Secretions of Enterochromaffin-like cells (in the stomach)
Histamine
Secretions of chief cells (in the stomach)
Pepsin(ogen)
Gastric lipase
Secretions of D cells (in the stomach)
Somatostatin (inhibits gastric acid secretion)
Secretions of G cells (in the stomach)
Gastrin
A lot of gastric acid secretion stimulated by…
Parasympathetic pathway of vagus nerve
Acidosis vs Acidemia
Acidosis - Disorder tending to make blood more acidic than normal
Acidemia - Low blood pH
Alkalosis vs Alkalemia
Alkalosis - Disorder tending to make blood more alkaline than normal
Alkalemia - High blood pH
Transamination reaction between pyruvate and glutamate at the muscle (glucose-alanine cycle)
Alanine aminotransferase (ALT) removes the amino group from glutamate forming alpha-ketoglutarate and adds it to pyruvate forming alanine (opposite occurs at liver)
Link between Kreb’s and urea cycle
Fumarate produced in urea cycle can be fed into Kreb’s
Aspartate produced in Kreb’s can be fed into urea cycle
Where does the urea cycle take place?
Mitochondria and cytosol
