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PBL SEM 4 > secretion and exretion in the liver > Flashcards

secretion and exretion in the liver Flashcards

1
Q

summarise the functions of the liver

A
  • 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
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2
Q

where are Kupffer cells found?

A

lining the walls of the liver sinusoids

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3
Q

what vitamin is hydroxylated in the liver and kidney to produce the active form?

A

vitamin D

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4
Q

where does the liver get its blood from?

A
  • 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)

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5
Q

what is the single venous drainage pathway from the liver?

A

central vein —> hepatic vein —> IVC

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6
Q

what do portal triads contain?

A

hepatic artery, portal vein, bile duct

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7
Q

what is the name given to an area of the liver served y a single portal triad?

A

acinar

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8
Q

sinusoids run between plates towards what?

A

central vein

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9
Q

what run into the bile duct?

A

bile canaliculi

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10
Q

describe zone 1 and what happens here

A
  • periportal = most oxygen here = things that require most oxygen happen here
  • amino acid catabolism
  • gluconeogenesis
  • cholesterol synthesis
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11
Q

describe zone III and what happens here

A
  • pericentral - things happening here require less O2
  • lipid synthesis
  • ketogenesis
  • glutamine synthesis
  • drug metabolism
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12
Q

fibrosis first occurs aroudn what?

A

central vein - where there is less O2, cells here least able to regernate

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13
Q
A
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14
Q

what are hepatocytes?

A

polarised epithelial cells

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15
Q

what does a fenestrated epithelium mean?

A

has holes in the cells allowing quite large substances to pass from the intestitial fluid which fills then Space of Disse in the liver

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16
Q

what are the basolateral and apical membranes also called in hepatocytes?

A

basolateral = sinusoidal membrane

apical = canalicular membrane

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17
Q

what separates the canalicualr membrnae from the basolateral membrane?

A

zona occludens

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18
Q

where are junctional complexes?

A

at the ends of a bile canaliculus

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19
Q

what is secreted into the canalicualr space?

A

bile

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20
Q

how much bile is secreted by the liver each day and how much of it reaches the duodenum?

A

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

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21
Q

what does bile contain?

A
  • 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)
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22
Q

what are bile acids produced from?

A

cholesterol

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23
Q

primary vs secondary bile acid synthesis

A
  • ‘primary’ bile acids synthesised in liver. they are weakly ionised (BAH = undissociated)
  • secondary = bacterial modification in terminal ileum and colon
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24
Q

most bile acids exist in what form?

A

undissociated form with a proton attached (very little bile acid will exist in dissociated form at a neural pH)

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25
Q

how are bile acids converted to a bile salt? what is the effect on the dissociation constant?

A

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)

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26
Q

what 2 ways are unconjugated (BA-) and conjugated bile salts (BA-X) apically secreted?

A
  • bile salt export pump (BSEP)
  • multi drug resistant associated protein 2 (MRP2)

—> these are both ABC transproters with wide substrate specificities

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27
Q

what are ABC transproters?

A

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)

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28
Q

describe MRD1

A
  • 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
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29
Q

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?

A

3g in body but >15g needed to digest a fat-rich meal

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30
Q

enterohepatic circulation of bile acids: what are passively reabsorbed across the proximal intestinal wall and why?

A

some unconjugated bile acids are passively absorbed because they are lipid soluble and so can pass through the lipid cell membranes of intestinal cells

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31
Q

enterohepatic circulation of bile acids: where and how does active uptake of conjugated bile salts occur?

A

occurs in the terminal ileum via Na+ bile salt cotransporter ASBT and organic solute transporter (OST)

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32
Q

most bile produced is stored in between meals in the gall bladder in what form?

A

conjugated bile salt form

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33
Q

how does bile salt leave the enterocyte in terminal ileum?

A

via facilitated diffusion on an organic solute transporter (after entering enterocyte in terminal ileum via ASBT)

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34
Q

what happens to hte bulk of bile salts and acids?

A

get back into portal blood and can be transported back to the liver and are resecreted

35
Q

how is the loss of bile acids in faeces compensated for?

A

synthesis of new primary bile acids in the liver (from cholesterol)

36
Q

what do enterocytes in the terminal ileum express?

A

ASBT = Na+ coupled bile acid transporter

37
Q

undissociated bile acid can be absorbed how?

A

by passive absorption - simple diffusion

38
Q

bile arrives back at the liver in ______ blood and needs transporters on the _______ side to bring bile into the hepatocyte

A
  • portal
  • sinusoidal
39
Q

uptake of recycled bile salts is via what? (basolateral uptake of bile acids/salts in the liver)

A
  • 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!!

40
Q

the biliary tree is lined with epithelial cells called what?

A

cholangiocytes

41
Q

30-50% of hepatic bile is secreted by what? describe the bile

A
  • cholangiocytes lining the bile duct
  • HCO3- rich
  • isosmotic fluid
42
Q

mechanism of secretion of bile in the biliary tree

A
  • secondary active transport of Cl- and HCO3-
  • paracellular Na+ transport with isosmotic water flow
43
Q

what is bile secretion stimulated by?

A

secretin, VIP, glucagon

44
Q

what is bile secretion inhibited by?

A

somatostatin

45
Q

what is the effect of ACh on bile and the gall bladder?

A

causes contraction of the GB and the relaxation of the sphincter of Oddi, and therefore the entry of bile into the duodenum

46
Q

name some organic anions

A

thyroid and steroid hormones prostaglandins, drugs (statins), toxins

47
Q

organic anions : basolateral uptake method

A

by exchange with Cl- via OATP

48
Q

organic anions : conjugation with ____ or _____

A

glucuronate or sulphate

49
Q

organic anions : apical secretion via ______

A

MRP2

50
Q

organic anions : sulphated sex steroids (St-Y) can enter via simple diffusion but once on cell get conjugated and then transported by what?

A

ABCG2

51
Q

name some organic cations

A

cytotoxic drugs, local anaesthetic, antibiotics

52
Q

how are small cations excreted?

A

facilitated diffusion via organic cation transporters (OCT1/3) and then by exchange with H+ (MATE1)

53
Q

how are bulky organic cations excreted?

A

OATP and the MDR1

54
Q

how are cholesterol and phospholipids excreted?

A
  • cholesterol via ABCG5/8
  • phospholipids via a flippase (MDR3)
55
Q

what follows phagocytosis of RBCs?

A

breakdown of haem to bilirubin

56
Q

bilirubin is carried by what to the liver and then taken up via what?

A
  • carried by albumin to liver
  • taken up via OATP
57
Q

bilirubin is conjugated with what in the endoplasmic reticulum? what is it then secreted by?

A
  • glucuronate
  • MRP2
58
Q

bacteria in the terminal ileum and colon do what to some of the bilirubin?

A

deconjugate some of it and convert it to urobilinogen (colourless)

59
Q

most urobilinogen is further converted to what in the colon, giving faeces its brown colour?

A

stercobilin

60
Q

some urobilingoen is reabsorbed and excreted as what via the kidney, making urine yellow?

A

urobilin

61
Q

what is jaundice due to?

A

accumulation of bilirubin in body fluid and tissues

62
Q

what is an accumulation of unconjugated bilirubin due to?

A

haemolysis or failure of liver to conjugate. normal urine and neurotoxicity (kernicterus)

63
Q

what is kernicterus?

A

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

64
Q

what is an accumulation of conjugate bilirubin due to?

A

cholestasis (blockage in biliary system) — dark urine

65
Q

what is an accumulation of a mixture of unconjugated and conjugated bilirubin due to?

A

acute liver disease eg. hepatitis — can’t conjugate and cant secrete bile very well due to massive inflammation in the liver

66
Q

what is hepatic encephalopathy due to?

A

accumulation of ammonium in the blood

67
Q

liver has a major role in removing NH3. where does the NH3 come from?

A
  • 50% from kidneys and waste product of liver metabolism of amino acids
  • 50% produced by gut bacteria
68
Q

what is NH3 normally detoxified by?

A

urea synthesis

69
Q

how does liver disease affect NH3 removal? effects?

A

disease of liver causes failure to produce urea —> increase NH3 conc in plasma —> NH3 crosses BBB —> neurotoxicity —> confusion —> changes in cognition —> coma

70
Q

what are cholangiocytes in bile ducts responsible for?

A

secretion of fluid and HCO3 into the bile

71
Q

the Cl- channels allowing Cl- to leave the cell in fluid secretion by cholangiocytes are activated by what?

A

Ca++

72
Q

what do CFTR channels allow in fluid secretion by cholangiocytes?

A

allow Cl- and HCO3- to leave

73
Q

in fluid secretion by cholangiocytes, you end up with what in the lumen? effect?

A

NaCl and HCO3- —> drives water movements via osmosis

74
Q

in fluid secretion by cholangiocytes, what can some Cl- be recycled by?

A

Cl- / HCO3- exchanger

75
Q

in fluid secretion by cholangiocytes, you get paracellular transport of Na+ throguh what?

A

junctional complexes between cells

76
Q

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?

A

sphincter of Oddi

77
Q

50% of bile secreted each day is diverted where between meals?

A

GB

78
Q

what does the GB (volume 50ml) reabsorb?

A

electrolytes and water

other solutes are concentrated 10-20 fold

79
Q

in reabsorption by gall bladder epithelium. NaH exchangers are to some extent functionally coupled to what?

A

Cl- HCO3- exchangers

80
Q

what is Na+ reabsorbed by in the GB?

A

apical Na+ H+ exchangers and basolateral NaK ATPase

81
Q

in reabsorption in GB epithelium, some Cl- reabsorbed in exchange for _______, but net ______ secretion

A
  • HCO3-
  • H+
82
Q

summarise how hepatic bile is concentrated

A

by reabsoprtion of electrolyte and water by gall bladder epithelium

83
Q

bile acids are synthesised, conjugated,m secreted and recycled to aid what?

A

fat digestion

84
Q

what are secreted by hepatocytes and cholangiocytes as a vehicle?

A

fluid and electrolytes

PBL SEM 4 (50 decks)

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