Liver Flashcards
How much of the blood supply to the liver is from the hepatic portal vein?
75%
Why can the liver be described as a factory?
metabolism: CHO, proteins, lipids
synthesis: bile, proteins, nucleotides, cholesterol
what waste management does the liver carry out?
internal waste products e.g. bilirubin, ammonia, hormones (insulin, growth hormones, oestogen)
treats hazardous material e.g. food toxins, drugs
what 2 components are found in the space of disse?
collagen, stellate cells
what is the function of stellate cells
contractile
control connective tissue turnover and collagen synthesis
what percentage of liver cells do hepatocytes contribute to and what is their function?
60%
most metabolic functions
where are kupffer cells found and what do they do?
in sinusoidal lining
remove antigens, produce cytokines, immune ‘sieving’ system
what are pit cells?
liver associated lymphocytes
NKCs –> protect from viruses/ tumours
what is the immunological function of the liver?
degrades bacteria and antigens
kupffer cells –> immunoglobulins, TNF, collagenase, lysosomal hydrolases
what are the 3 internal waste products that the liver disposes of?
bilirubin, ammonia –> urea, hormones
What are xenobiotics?
potentially toxic compounds such as food toxins, drugs, food addictives
how many phases are involved in the metabolism of xenobiotics?
2
what occurs in the 1st stage of xenobiotic metabolism?
Cytochrome P450 enzyme
oxidation (oxygen donor), reduction (required NADH), hydrolysis, hydroxylation
–> MORE REACTIVE COMPOUND
in ER
what happens during the 2nd phase of xenobiotic metabolism?
conjugation - glucuronyl, acetyl, sulphate, glycyl, methyl groups added
occurs in liver, lungs, kidney
INACTIVE PRODUCTS MORE WATER SOLUBLE
how are xenobiotics eventually excreted from the body?
in urine or bile
how does the alcohol metabolism pathway change with chronic alcohol consumption?
induced CP450 production so more metabolised by this pathway
which enzyme is involved in the 1st stage of alcohol metabolism and where does this occur?
alcohol dehydrogenase in the cytosol of hepatocytes –> acetaldehyde
What happens to NAD during alcohol metabolism?
reduced to NADH
What happens during the 2nd stage of alcohol metabolism and where does this take place?
acetaldehyde dehydrogenase:
acetaldehyde –> acetate
what is the product of alcohol metabolism and what happens to it?
acetate –> acetyl coA –> krebs cycle –> ATP
Which cofactor is required for phase 1 xenobiotic metabolism?
NADPH
where do phase 2 xenobiotic metabolism reactions occur?
liver, kidney, lungs
Why is xenobiotic metabolism a problem with pharmacology?
ist pass metabolism –> inactives srug if taken orally –> poor bioavailability
where are RBCs disposed of?
spleen, liver, bone marrow by kupffer cells
where is haem degraded to bilirubin?
kupffer cells
how is haem degraded to bilirubin?
haem –> biliverdin –> bilirubin
NADPH required at each step
what colour is biliverdin?
green
what colour is bilirubin?
yellow
how is bilirubin transported to the liver hepatocytes?
attached to albumin
what happens to bilirubin in the liver hepatocytes?
conjugated mainly with glucuronic acid
is conjugated bilirubin secretion active or passive?
active
where is conjugated bilirubin secreted into?
bile canaliculi –> bile –> intestines
how is urobilinogen formed?
bacteria in the gut convert bilirubin to urobilinogen
why is urine yellow?
contains urobilin = derivative of bilirubin
why is faeces brown?
contains stercobilin
bilirubin –> stercobilinogen –> oxidised to stercobilin
why does jaundice occur?
problem with haem degredation
why might pre-hepatic jaundice occur?
overload of haem
haemolytic anaemia breaking down RBCs
why might intra-hepatic jaundice occur?
liver damage
Gilbert’s syndrome
which forms of jaundice result in raised unconjugated bilirubin levels?
pre-hepatic and intra-hepatic
why might extra-hepatic jaundice occur?
obstruction to bile duct e.g. blockage from gallstones, pancreatic carcinoma
what is globin degraded to?
amino acids
What are the 2 things that dietary amino acids can be use for?
synthesis of new compounds
breakdown for energy
Name 6 types of N containing metabolites
haem, NTs (dopamine, noradrenaline, adrenaline)
serotonin, histamine, creatinine, purine bases
which amino acid forms histamine?
histidine
which 3 AAs form purine bases?
glycine, aspartate, glutamine
why must the amino group be removed from AAs before they are used for energy?
ammonia is very toxic so blood levels must be kept very low
what are the symptoms of hyperammonia?
tremor vomiting cerebral oedema death
why might hyperammonia arise?
genetic defect - urea cycle enzyme deficiencies
liver disease
what is kwashiorkor?
protein deficiency disease
what are the symptoms of kwashiorkor?
abdominal bloating, lower leg oedema, poor nutrient absorption, poor skin condition, hair/skin colour changes, susceptible to infection
why does kwashiorkor result in hair and skin colour changes?
melanin = nitrogen containing (from amino acids)
which 3 ways can the carbon skeleton of AAs be used?
ketogenic pathways –> fatty acids and ketone bodies
glucogenic pathways –> glucose precursors, gluconeogenesis –> glucose
krebs cycle –> ATP (All AAs)
which 2 amino acids cannot be used in gluconeogenesis and why?
leucine, lycine because they only form acteyl coA –> carbon atoms released as CO2
when are AAs used for fatty acid synthesis?
storage
when are ketone bodies formed from AAs?
fasting
When are AAs used for gluconeogenesis?
fasting, exercise
where does gluconeogenesis occur?
liver and kidney mainly in cytosol
what 3 compounds can be used in gluconeogenesis to produce glucose?
anaerobic respiration –> lactate
AAs –> keto acids
triacylglycerol –> glycerol
which AA in particular can be used in gluconeogenesis?
alanine
what is the Cori cycle?
helps to maintain muscle metabolism by removing lactate from anaerobic respiration –> used in liver to produce glucose
what are the 3 stages of amino group removal?
transamination, deamination, urea cycle
where does transamination occur and what happens?
peripheral tissues
amino group from AAs attached to a-ketoglutarate to form glutamate
extra amino group –> glutamine
which enzyme is involved in transamination?
transaminase
which cofactor is required for transamination?
Pyroxidal phosphate (active form of vit. B6)
what symptoms arise from a lack of B6 (pyroxidal phosphate)
poor growth, skin lesions, poor immune response (synthesis of AAs)
neurological symptoms (required for energy metabolism and NT synthesis)
anaemia (required for haem synthesis)
where does deammination occur?
liver hepatocytes
which enzyme is required for deamination?
glutamate dehydrogenase
why must transamination occur?
to transport toxic ammonia in the blood to the liver
where does the urea cycle occur?
in mitochondria and cytosol of liver hepatocytes
which 2 compounds enter the urea cycle?
CO2 and NH3
what is the control step of the urea cycle?
formation of carbamoyl phosphate
which enzyme is responsible for carbamoyl phosphate synthesis?
carbamoyl phosphate synthetase 1
what role does N-acetyl glutamate play in the control step of the urea cycle?
N-actyl glutamate allosterically activates carbamoyl phosphate synthetase 1, which is required for the synthesis of carbamoyl phosphate
high levels of glutamate forms N-acetyl glutamate
high levels of AAs activate the urea cycle
what is uric acid?
formed from purine nucleotides
what are the symptoms of hyperuricaemia?
kidney stones (sodium urate crystals in kidneys) gout (sodium urate crystals in joints)
why might hyperuricaemia occur?
too much high purine foods (red meat seafood)
poor excretion from kidneys
over-production of urate
which protein is not synthesised in the liver?
gamma globulins
what are the 3 control steps in glycolysis?
glucose –> glucose -6-phosphate
fructose-6-phosphate –> fructose 1,6-bisphosphate
phosphoenolpyruvate –> pyruvate
which enzyme converts glucose to glucose-6-phosphate?
hexokinase/ glucokinase
which enzyme converts fructose 6 phosphate to fructose 1,6 bisphosphate?
phosphofructokinase
which enzyme converts phosphoenolpyruvate to pyruvate?
pyruvate kinase
which enzyme is the main control point for glycolysis?
phosphofructokinase
where does glycolysis take place?
in the cytoplasm
what are the 3 main factors that activate phospho-fructokinase?
high AMP (allosteric activation), insulin (alters transcription to increase gene expression), F2,6-bisP
what effect does glucagon have on glycolysis and where does it affect the pathway?
inhibits production of F2,6-bisP therefore inhibits phosphofructokinase
glucagon dephosphorylates an enzyme which inhibits F2,6 bisP
what are high levels of AMP indicative of and why?
low energy levels because 2 ADP join together to form ATP and AMP (enzyme = adenylate kinase)
AMP-activated protein kinases activate key enzymes
how many pyruvate molecules are formed from one molecule of glucose?
2
how many NAD coenzymes are required in glycolysis?
2 (to produce 2 pyruvate)
how many ATP are directly made from glycolysis?
2
overall including oxidative phosphorylation how many ATP can be make from aerobic glycolysis?
5-7 (2 directly and a further 3-5 from oxidative phosphorylation of 2 NADH)
how does glucagon inhibit glycolysis?
phosphorylates an enzyme that inactivate F2,6BisP
what inhibits hexokinase/glucokinase and what is this an example of?
product inhibition from glucose 6 phosphate
which 2 enzymes are key to guconeogenesis?`
fructose 1,6 bisphophatase
glucose 6 phosphatase
where do alanine and lactate enter gluconeogenesis?
converted into pyruvate
does ATP inhibit gluconeogenesis or glycolysis?
glycolysis (because signals high energy state)
inhibits phosphofructokinase and pyruvate kinase
what 4 factors regulate the activity of fructose1,6 bisphosphatase in gluconeogenesis?
AMP, insulin –> inhibit
citrate, glucagon –> activate
which enzyme is involved in breaking down glucagon into glucose 1 phosphate?
glycogen phosphorylase
in which organs can glycolysis produce glucose?
liver and kidneys
why can’t glucose be released from muscle tissue?
glucose 1 phosphate can’t be broken down into glucose as lacking the enzyme for conversion (glucose 6 phosphatase)
how many ATP/ GTP are required for gluconeogenesis to take place?
6
why does alcohol inhibit gluconeogenesis and make you feel hungry?
alcohol metabolism produces NADH which favours the conversion of alanine to pyruvate then to lactate not lactate to pyruvate. glyceraldehyde is also converted back to glycerol. Gluconeogenesis is therefore inhibited
what are the 2 phases of glycolysis?
preparative phase
generating phase
what is produced in the preparative phase?
fructose 1,6-bisphosphate
why is ATP needed for the first step of glycolysis?
to activate glucose by phosphorylating it
