secretion and exretion in the liver Flashcards
summarise the functions of the liver
- STORAGE of carbs, lipids, vitamins
- SYNTHESIS of glucose, ketone bodies, amino acids, cholesterol, fatty acids
- PHAGOCYTOSIS of particulates (Kupffer cells)
- DEGRADATION of endogenous compounds and xenobiotics (NH3, drugs and toxins)
^^ all above portal blood - MANUFACTURE of plasma proteins
- INACTIVATION (+ ACTIVATION) of hormones
- EXCRETION of lipophilic waste products
- SECRETION of emulsifiers
^^ later functions closely tied in with role of liver in bile production
where are Kupffer cells found?
lining the walls of the liver sinusoids
what vitamin is hydroxylated in the liver and kidney to produce the active form?
vitamin D
where does the liver get its blood from?
- 75% from portal vein — rich in absorbed nutrients, refuels bile acids/salts. has limited oxygen
- 25% from hepatic artery — regular systemic arterial blood, oxygenated
both feed into hepatic sinusoids (run between layers of hepatocytes)
what is the single venous drainage pathway from the liver?
central vein —> hepatic vein —> IVC
what do portal triads contain?
hepatic artery, portal vein, bile duct
what is the name given to an area of the liver served y a single portal triad?
acinar
sinusoids run between plates towards what?
central vein
what run into the bile duct?
bile canaliculi
describe zone 1 and what happens here
- periportal = most oxygen here = things that require most oxygen happen here
- amino acid catabolism
- gluconeogenesis
- cholesterol synthesis
describe zone III and what happens here
- pericentral - things happening here require less O2
- lipid synthesis
- ketogenesis
- glutamine synthesis
- drug metabolism
fibrosis first occurs aroudn what?
central vein - where there is less O2, cells here least able to regernate
what are hepatocytes?
polarised epithelial cells
what does a fenestrated epithelium mean?
has holes in the cells allowing quite large substances to pass from the intestitial fluid which fills then Space of Disse in the liver
what are the basolateral and apical membranes also called in hepatocytes?
basolateral = sinusoidal membrane
apical = canalicular membrane
what separates the canalicualr membrnae from the basolateral membrane?
zona occludens
where are junctional complexes?
at the ends of a bile canaliculus
what is secreted into the canalicualr space?
bile
how much bile is secreted by the liver each day and how much of it reaches the duodenum?
1000ml a day secreted by liver, 500 ml reaches the duodenum
decreased volume due to absorption of fluid from bile while it is stored in the GB
what does bile contain?
- bile acids/salts (+phsopholipids and choelsterol)
- conjugated bilirubin
- metabolites of hormones and drugs
- heavy metal ions (usually come in directly to liver in the portal blood, toxic to kidneys)
- electrolytes (HCO3- neutralise acid) and water (as a vehicle)
what are bile acids produced from?
cholesterol
primary vs secondary bile acid synthesis
- ‘primary’ bile acids synthesised in liver. they are weakly ionised (BAH = undissociated)
- secondary = bacterial modification in terminal ileum and colon
most bile acids exist in what form?
undissociated form with a proton attached (very little bile acid will exist in dissociated form at a neural pH)
how are bile acids converted to a bile salt? what is the effect on the dissociation constant?
bile acids are conjugated with amino acids Itaurine, glycine supkaye, glucuronate) in a condensation reaction — makes them more water soluble and charged
—> this greatly reduces the pKa dissociation constant — at neutral pH much more of the bile salt will exist in dissociated form therefore better at performing its function (get a greater amount of dissociated bile salts in bile by reducing the constant)
what 2 ways are unconjugated (BA-) and conjugated bile salts (BA-X) apically secreted?
- bile salt export pump (BSEP)
- multi drug resistant associated protein 2 (MRP2)
—> these are both ABC transproters with wide substrate specificities
what are ABC transproters?
ABC stands for ATP Bindign Casssette transporters
= huge family of pumps using ATP hydrolysis to import or export a wide range of substrates
examples
ABCA — ABCA1 = cholesterol transporter
ABCB — MDR1 (P-glycoprotein), BSEP
ABCC — CFTR, MRP2, sulphonylurea receptor (SUR1)
describe MRD1
- multi drug resistance-associated protein 1
- ABCB
- important in drug resistance in cancer cells — over expressed in cancer cells, can remove cytotoxic drug from cell
at any one time, ow much bile acids/salts are there in the body but how much is needed to digest a fat-rich meal?
3g in body but >15g needed to digest a fat-rich meal
enterohepatic circulation of bile acids: what are passively reabsorbed across the proximal intestinal wall and why?
some unconjugated bile acids are passively absorbed because they are lipid soluble and so can pass through the lipid cell membranes of intestinal cells
enterohepatic circulation of bile acids: where and how does active uptake of conjugated bile salts occur?
occurs in the terminal ileum via Na+ bile salt cotransporter ASBT and organic solute transporter (OST)
most bile produced is stored in between meals in the gall bladder in what form?
conjugated bile salt form
how does bile salt leave the enterocyte in terminal ileum?
via facilitated diffusion on an organic solute transporter (after entering enterocyte in terminal ileum via ASBT)
what happens to hte bulk of bile salts and acids?
get back into portal blood and can be transported back to the liver and are resecreted
how is the loss of bile acids in faeces compensated for?
synthesis of new primary bile acids in the liver (from cholesterol)
what do enterocytes in the terminal ileum express?
ASBT = Na+ coupled bile acid transporter
undissociated bile acid can be absorbed how?
by passive absorption - simple diffusion
bile arrives back at the liver in ______ blood and needs transporters on the _______ side to bring bile into the hepatocyte
- portal
- sinusoidal
uptake of recycled bile salts is via what? (basolateral uptake of bile acids/salts in the liver)
- simple diffusion of unconjugated, neutral BAH (bile acids)
- cotransport with Na+ via Na+-taurocholate cotransporting peptide (NTCP)
- exchange with Cl- via organic anion transporting entire (OATP)
don’t worry about names of transproters!!
the biliary tree is lined with epithelial cells called what?
cholangiocytes
30-50% of hepatic bile is secreted by what? describe the bile
- cholangiocytes lining the bile duct
- HCO3- rich
- isosmotic fluid
mechanism of secretion of bile in the biliary tree
- secondary active transport of Cl- and HCO3-
- paracellular Na+ transport with isosmotic water flow
what is bile secretion stimulated by?
secretin, VIP, glucagon
what is bile secretion inhibited by?
somatostatin
what is the effect of ACh on bile and the gall bladder?
causes contraction of the GB and the relaxation of the sphincter of Oddi, and therefore the entry of bile into the duodenum
name some organic anions
thyroid and steroid hormones prostaglandins, drugs (statins), toxins
organic anions : basolateral uptake method
by exchange with Cl- via OATP
organic anions : conjugation with ____ or _____
glucuronate or sulphate
organic anions : apical secretion via ______
MRP2
organic anions : sulphated sex steroids (St-Y) can enter via simple diffusion but once on cell get conjugated and then transported by what?
ABCG2
name some organic cations
cytotoxic drugs, local anaesthetic, antibiotics
how are small cations excreted?
facilitated diffusion via organic cation transporters (OCT1/3) and then by exchange with H+ (MATE1)
how are bulky organic cations excreted?
OATP and the MDR1
how are cholesterol and phospholipids excreted?
- cholesterol via ABCG5/8
- phospholipids via a flippase (MDR3)
what follows phagocytosis of RBCs?
breakdown of haem to bilirubin
bilirubin is carried by what to the liver and then taken up via what?
- carried by albumin to liver
- taken up via OATP
bilirubin is conjugated with what in the endoplasmic reticulum? what is it then secreted by?
- glucuronate
- MRP2
bacteria in the terminal ileum and colon do what to some of the bilirubin?
deconjugate some of it and convert it to urobilinogen (colourless)
most urobilinogen is further converted to what in the colon, giving faeces its brown colour?
stercobilin
some urobilingoen is reabsorbed and excreted as what via the kidney, making urine yellow?
urobilin
what is jaundice due to?
accumulation of bilirubin in body fluid and tissues
what is an accumulation of unconjugated bilirubin due to?
haemolysis or failure of liver to conjugate. normal urine and neurotoxicity (kernicterus)
what is kernicterus?
jaundice isn’t treated — bilirubin can become neurotoxic and in conjugated form it is quite lipid soluble so can cross the BBB and lead to neurotoxicity in newborn = kernicterus
what is an accumulation of conjugate bilirubin due to?
cholestasis (blockage in biliary system) — dark urine
what is an accumulation of a mixture of unconjugated and conjugated bilirubin due to?
acute liver disease eg. hepatitis — can’t conjugate and cant secrete bile very well due to massive inflammation in the liver
what is hepatic encephalopathy due to?
accumulation of ammonium in the blood
liver has a major role in removing NH3. where does the NH3 come from?
- 50% from kidneys and waste product of liver metabolism of amino acids
- 50% produced by gut bacteria
what is NH3 normally detoxified by?
urea synthesis
how does liver disease affect NH3 removal? effects?
disease of liver causes failure to produce urea —> increase NH3 conc in plasma —> NH3 crosses BBB —> neurotoxicity —> confusion —> changes in cognition —> coma
what are cholangiocytes in bile ducts responsible for?
secretion of fluid and HCO3 into the bile
the Cl- channels allowing Cl- to leave the cell in fluid secretion by cholangiocytes are activated by what?
Ca++
what do CFTR channels allow in fluid secretion by cholangiocytes?
allow Cl- and HCO3- to leave
in fluid secretion by cholangiocytes, you end up with what in the lumen? effect?
NaCl and HCO3- —> drives water movements via osmosis
in fluid secretion by cholangiocytes, what can some Cl- be recycled by?
Cl- / HCO3- exchanger
in fluid secretion by cholangiocytes, you get paracellular transport of Na+ throguh what?
junctional complexes between cells
what is normally closed between meals, so that when bile is produced between meals it cant get into the duodenum and therefore gets stored in the GB?
sphincter of Oddi
50% of bile secreted each day is diverted where between meals?
GB
what does the GB (volume 50ml) reabsorb?
electrolytes and water
other solutes are concentrated 10-20 fold
in reabsorption by gall bladder epithelium. NaH exchangers are to some extent functionally coupled to what?
Cl- HCO3- exchangers
what is Na+ reabsorbed by in the GB?
apical Na+ H+ exchangers and basolateral NaK ATPase
in reabsorption in GB epithelium, some Cl- reabsorbed in exchange for _______, but net ______ secretion
- HCO3-
- H+
summarise how hepatic bile is concentrated
by reabsoprtion of electrolyte and water by gall bladder epithelium
bile acids are synthesised, conjugated,m secreted and recycled to aid what?
fat digestion
what are secreted by hepatocytes and cholangiocytes as a vehicle?
fluid and electrolytes
