Liver Flashcards
where does the liver develop from, embryologically
the foregut
what is the bare area and where is it
the area of the liver that is not covered with peritoneum as it is in direct contact with the diaphragm
found in the top right of the right lobe anterior surface
what are the tributaries to the common bile duct
common hepatic duct
cystic duct
what lies immediately behind the lesser sac
the abdominal aorta on the left and the inferior IVC on the right
which structures leave impressions on the liver
the right kidney
the hepatic flexure of the colon
the stomach
the gall bladder
describe the mucosa of the gall bladder
honeycomb
label
where is gall bladder pain felt and why
in the skin of the right shoulder
because the gall bladder is close to the diaphragm, any disease may cause the gall bladder to rub against the diaphragm, which is supplied by C3,4,5.
- C3,4,5 cervical roots also supply the the dermatomes of the right shoulder
which artery does the cystic artery branch off
the right hepatic artery
what structure degenerates to form the ligamentum venosum and where is it found
the ductus venosum
found between the caudate lobe and the left lobe
where does the portal triad enter the liver
the porta hepatis
where do the hepatic veins drain
the inferior ivc
Borders and contents of Calot’s triangle
- borders:
- superior: inferior border of the liver
- medial = common hepatic duct
- inferior = cystic duct
- contents
- cystic artery
- right hepatic artery
- lymphatics
structure and location of the gall bladder
- made of a body, fundus and neck
- located
- inferiorly and posterior to the liver
- anterior to the first part of the duodenum and transverse colon
components of biliary tree
- common hepatic duct
- cystic duct
- common bile duct
- pancreatic duct
- hepatopancreatic ampulla of vater
arterial and venous drainage of gall bladder
- cystic artery - branch of right hepatic artery
- cystic vein, drains into the hepatic portal vein
describe the microanatomy of the liver
- The liver is organised in hexagonal lobules with a central hepatic vein portal triads in the corners.
what is a triglyceride made up of
- 3 fatty acid chains
- 1 glycerol
- joined together at carboxyl heads
where are fats stored in the body
- adipocytes
- liver
- elsewhere
what role do fats play within the body?
- energy production
- hormonal metabolism
- many hormones are derived from cholesterol
- active vitamin D derived from 7-dehydroxycholesterol
- structure and other functions
- form part of the cell membrane
- integral part of cell function
- inflammatory cascades
where and why is cholesterol esterified
which enzymes do this
- esterified intracellularly to improve transport:
- acyl-CoA: cholesterol acyltransferase
- lecithin: cholesterol acyltransferase in lipoproteins
where is cholesterol mainly processed
the liver
how is cholesterol excreted
through bile
this is the only mechanism of export
how much cholesterol is endogenous and how much comes from diet
•90 % of Cholesterol is endogenous
10% from diet
how is cholesterol transported in the blood
by lipoproteins
which macronutrient provides most energy in the body
lipids > carbs> proteins
what is the main storage place of glycogen
the liver
what is a lipoprotein made up of
- a core containing triglycerides and cholesterol esters
- a monolayer of:
- phospholipids
- cholesterol
- proteins
what types of lipoprotiens are there
HDL
LDL
VLDL
chylomicrons
what determines the density of a lipoprotein
the protein: lipid ratio
what is “good cholesterol”
HDL
functions of HDL
where is it formed
- removes excess cholesterol from the blood and tissues and delivers it to the liver to be secreted in bile
- formed in the liver
functions of LDL
where is it formed
- main cholesterol carrier.
- deliveres cholesterol to all the cells in the body
- essntail for cell membrane and steroid hormone production
- deliveres cholesterol to all the cells in the body
- formed in the plasma
function of VLDL
where is it formed
- delivers TGs from the liver → adipocytes
- formed in hepatocytes
how are fatty acids exported
- using apoproteinB - a type of lipoprotein
- the lipids are made in the SER and added to the ApoB
- the ApoB is then transferred to the golgi apparatues for glycosylation
- the glycosylated ApoB is released in a vesicle and fuses with the membrane → VLDL release
- TGs and FAs can diffuse through cell membranes
- T/F
- false
- TGs can’t diffuse through cell membranes but FAs can
how are lipid transported to the liver
- portal vein
- hepatic artery
- lyphatics
which nerves innervate the liver
Parasympathetic and sympathetic stimulation comes from the celiac plexus. The anterior vagal trunk also gives rise to a hepatic branch.
how are fats taken up into hepatic adipocytes
- TGs can’t diffuse through the cell membrane
- lipoprotein lipase breaks TGs → FAs
- FAs are lipophilic so pass through by passive diffusion and are taken up by facilitated transport
- once inside they are converted back to TGs
how are lipids transported from hepatic adipocytes to hepatocytes
- Hormone sensitive lipase breaks down the TG storage into FFA allowing it to pass out the adipose cells.
- At the hepatocyte, the FFA will be further broken down by hepatic lipase before passing into the hepatocyte.
- In the hepatocyte, the FFA is either oxidised or stored as TG.
how do fatty acids produce energy?
vis beta-oxidation -→ formation of acetyl CoA + FADH2 + NADH → krebs cycle and ETC respectively
key enzyme in beta oxidation
thiolase
carries out the final step → acetyl CoA formation
what are the effects of insulin on adipocytes
- promotes fat storage in adipocytes by stimulating lipoprotein lipase
- inhibits the activity of hormone sensitive lipoprotein → reduced FA export from adipocytes.
how does insulin resistance affect the adipocytes
- increases lipolysis → more circulating triglycerides
- more Free fatty acids available to hepatocytes → increased uptake, so more fat stores in liver rather than adipocytes.
- increase in glucose levels in the blood → less demand for lipids to be used as an energy source.
function of the gall bladder
production AND concentration of bile
Bilirubin and enterohepatic secretion of bile salts
what causes increased peripheral mobilisation of fatty acids
increased glucagon secretion
decreased insulin secretion
what are the 3 locations of fatty acid beta oxidation in the liver
- Peroxysomal β-oxidation in ribosomes
- Main role = detoxification
- mitochondrial β-oxidation
- Main role = oxidation of FAs with diff. lengths via a multistep process.
- ER Ω-oxidation (CYP4a catalysed)
- Normally a minor metabolic pathway but role increases in fat overload
what makes up an amino acid
- All amino acids have an amino group, a carboxyl group and a carbon backbone
- they also all have a variable R-side chain that changes the AA
what is the main source and loss of nitrogen in the body
main source = protein in diet
main loss via kidneys and gut as urea
what are the 3 main groups of amino acids and what is the difference between tehm
- essential
- body cannot produce so must come from diet
- non-essential
- simpler AAs
- the body can produce de novo
- conditionally essential
- under certain circumstances, these AAs can be produced and other times they may have to come from the diet
define anabolism and catabolsim in relation to nitrogen
- anabolism = +ve nitrogen balance = net gain of nitrogen
- catabolism = -ve nitrogen balance = net loss of nitrogen
Amino acids can either be glucogenic or ketogenic what does this mean
- glucogenic = the carbon backbone of the AA can be used in gluconeogenesis
- ketogenic = the carbon backbone of the AA can be used in ketogenesis by forming acetyl CoA
which AAs are ONLY ketogenic
leucine and lycine
which AAs are glucogenic and ketogenic?
tryptophan
isoleucine
phenyl-alanine
tyrosine
how many AAs must be present to classify as a protein
>50
how are AAs joined together
peptide bonds
AAs can be stored
T/F
False
what is transamination
why does it occur
- removal of the amino group from an amino acid → amine + keto-acid
- the amino group is then added to an acceptor keto-acid → amino acid of the keto-acid
- basically swapping the amino group over to make a new AA
happens because AAs cannot be stored
what is anabolism
the synthesis of complex molecules from simpler ones together with the storage of energy
where does anabolism take place
and what are the products
- occurs in the liver
- results in
- proteins
- glucose → glycogen
- Triglycerides - produced from excess AAs
what stimulates anabolism
a surplus of AAs
what is catabolism
- the breakdown of complex molecules to form simpler ones, together with the release of energy.
where does catabolism take place
what does it result in
- in the muscles - protein is broken down into AAs
- The AAs can enter the TCA cycle or enter peripheral circulation to the liver for gluconeogenesis
- Alanine is the most important one as it returns to the liver where it can be converted back into pyruvate
what stimulates catabolism - physiological factors AND hormonal
- a drop in the level of glucose in the blood AND depletion of the glycogen stores
- stimulated by glucagon and cortisol
which enzyme facilitates the glucose alanine cycle
where is the enzyme found
what substrates are needed for this cycle
- ALT - alanine aminotransferase
- found in muscle and hepatocytes
- alanine and alpha-ketoglutarate
which enzyme converts glutamate → α-ketoglutarate
Glutamate dehydrogenase (GDH)
converts glutamate to α-ketoglutarate and ammonia
summarise the glucose-alanine cycle
- Excess alanine is transported to the liver
- ALT breaks down alanine → pyruvate + glutamate
- amino group swapped from alanine to α-ketoglutarate
- pyruvate → glucose via gluconeogenesis
- glucose travels to muscle where it undergoes glycolysis → pyruvate + lactate
- the pyruvate undergoes transamination with glutamate → alanine + α-Ketoglutarate
- Alanine travels back to the liver and the cycle continues
- the glutamate formed in the liver from transamination of alanine can → NH4+ → urea via urea cycle
what is a function of alpha-ketoacids
they are metabolic intermediates
what are the products of protein breakdown
- alpha-ketoacids → ATP via krebs cycle as they can be metabolic intermediates
- glucose via gluconeogenesis e.g.alanine
- Urea. The ammonia group forms carbamyl phosphate [NH2+PO4] and enters the urea cycle.
give examples of +ve nitrogen balance and -ve N balance
- positive
- pregnancy
- lactation
- body builders on steroids
- recovery phase
- negative
- protein malnutrition -Kwashiokor
- severe illness, trauma or sepsis
- Cx Tx
- essental AA deficiency
what is the universal acceptor of amine groups
alpha-ketoglutarate
why does protein degradation occur?
- Faulty, old or obsolete proteins
- Signal transduction
- A flexible system to meet protein or energy requirements if environment.
what are the main methods of protein degradation
- proteasomes - ubiquitin dependent
- Lysosomes.
summarise proteasome degradation
- ubiquitin is a Small protein that binds to proteins
- The Carboxyl group of ubiquitin forms isopeptide bond with multiple Lysine residues
- this signals to proteasomes that the protein needs to be destroyed
- Three enzymes involved:
- E1 Ubiquitin-activating enzyme
- E2 Ubiquitin-conjugating enzyme
- E3 Ubiquitin-protein ligase
- Polyubiquitination amplifies the signal for death.
- Multiple ubiquitins join on, further increasing the strength of the signal
how is protein half-life determined
- The N-terminal rule determines the protein half-life as certain sequences easily accept ubiquitin \ shorter half life.
describe lysosomal protein degradation
-
MACROAUTOPHAGY – non-selective
- ER derived autophagisomes engulf cytosolic proteins/aggregates organelles. Lysosome fuses with this to initiate proteolysis.
-
MICROAUTOPHAGY - non-selective
- Invaginations of lysosomal membrane engulf proteins/organelles.
-
CHAPERONE-MEDIATED AUTOPHAGY – selective
- Chaperone protein hsc70, in cytosol and intralysosomal, accompany specific cytosolic proteins in response to stressors (fasting/ oxidative stress etc).
- ENDOCYTOSIS/PHAGOCYTOSIS - Extracellular substances
where is albumin produced
in the liver
how does albumin leave circulation
leave via interstitium
collected by lymphatics
and return to circulation via thoracic duct
what are the functions of albumin
- maintains oncotic pressure
- binding and transport or hydrophobic compounds - e.g. bilirubin, hormones and FAs
- neutralisation of free radicals
- anticoagulant effects
Why might liver failure result in oedema?
Liver failure may mean less albumin is produced and so you get hypoalbuminaemia. This means the capillary oncotic pressure is reduced and H2O accumulates in the interstitial space - oedema.
where is vitamin K absorbed
the intestine
why is vitamin K needed
production of clotting factors
what are the 2 essential proteins made by the liver
- albumin
- clotting factors
what are the pathways of the clotting cascade
- intrinsic
- extrinsic
- common pathway
how is the intrinsic pathway triggered
exposure of endothelial collagen
how is the extrinsic pathway triggered
clotting factor 12 coming into contact with tissue factor
where does the urea cycle take place
partly in the cytosol
partly in the mitochondria - STARTS here
what is the purpose of the urea cycle
- to convert free ammonia into urea
- ammonia is toxic and connot be easily excreted
- urea isn’t toxic and can easily be excreted
where are the enzymes involved in the urea cycle found
in the hepatocytes
- either in the cytoplasm or mitochondria
how is ammonia produced in the body
from AA breakdown
summarise the steps of the urea cycle linked to the TCA cycle
-
HCO3- + ammonia → carbamoyl phosphate: in the mitochondria.
- carbamoyl phosphate synthase
-
Carbamoyl phophate + ornithine → citrulline
- ornithine carbamoyl transferase
-
Citrulline +aspartate → argino-succinate
- argino-succinate synthase
-
argino-succinate → Arginine + fumarate
- argino-succinate lyase
- fumarate joins shunt of citric acid cyle → oxaloacetate.
- argino-succinate lyase
-
Arginine → urea + ornithine
- arginase
summarise the urea cycle
- ammonia and CO2 are added to ornithine → citrulline
- citrulline recieves another ammonia → arginine
- arginine is cleaved by arginase → ornithine and urea
- ornithine is recycled back into the cycle
how is the urea cycle regulated
via up or down regulation of the enzymes involved
what does deficiency of urea cycle enzymes cause
raised blood ammonia levels
what are the energy requirements of the urea cycle
where does the enrgy required come from
- 1 cycle:
- consumes 3 ATP
- consumes 4 high energy nucleotide PO4-
- The energy consumed by urea production is generated in the production of the cycle intermediates.
what is the most common plasma protein
albumin
what is a xenobiotic
- a foreign chemical substance that the body cannot produce and has no nutritional value
how do xenobiotics enter the body
- ingested
- inhaled in lungs
- absorbed through the skin
how are metabolic reactions carried out
by microsomal or non-microsomal enzymes
where are microsomal enzymes found
in smooth ER of liver, kidney and small intestine cells
give an example of microsomal enzymes
- mono-oxygenases
- CYP and UGTs
what type of reactions are microsomal enzymes involved in
- drug biotransformation
microsomal enzymes are not inducible
T/F
False
they are by drugs, diet and lifestyle
where are non-microsomal enzymes found
the mitochondria and cytoplasm of hepatocytes
give examples of non-microsomal enzymes
esterases
protein oxidases
what is the purpose of biotransformation reactions
to make molecules more polar thus hydrophilic for elimination in urine
how is urea excreted
in the urine
what is the aim of a phase 1 reaction
to add or expose a functional group to increase the hydrophilicity of the molecule
what are the types of phase 1 reactions
summarise each one
- oxidation
- hydroxylation - adding -OH groups
- deamination - removing amines
- nitrogen and oxygen dealkylation
- reduction
- hydrogen addition = saturation of bonds
- H donated from NADH, FADH2
- hydrogen addition = saturation of bonds
- hydrolysis
- splitting of amides and ester bonds (C-N-C and C-O-C)
what is the overall aim of phase 2 reactions
conjugation to produce hydrophilic molecules
give examples of phase 2 reactions
- glucuronidation
- sulphation
- acylation
- methylation
- Glutathione -GSH
summarise what happens in phase 2 reactions
hydrophilic molecules are added to molecules by forming covalent bonds → increased hydrophilicity
what is the most common phase 2 reaction
explain what happens
- glucuronidation
- glucuronic acid is added to the molecule via UGT enzymes
which group of enzymes is responsible for most phase 2 reactions
transferases
define ADME
- Absorption
- Distribution
- metabolism
- excretion / elimination
all molecules have to go through phase 1 and 2 of detoxification
T/F
False
e.g. morphine can go straight through phase 2
how does age affect phase 1 and 2 reactions
- with age
- Rate of Phase 1 reactions fall
- Rate of phase 2 reactions remains constant
*
how many genes encode CYP p450
>55
how many groups of CYP450s
10
where are cytochrome-P450 enzymes found
in the SER hence they are microsomal
what is the primary role of Cytochromes P450 enzymes
they oxidise molecules and reduce oxygen
what are the outcomes of metabolism
- Complete inactivation and elimination
- formation of an active metabolite from an active drug
- codeine → morphine
- activation of prodrugs
- Active drug to reactive intermediates
- toxification of xenopbiotics [paracetamol]
why is bile important
- lipid digestion and absorption
- cholesterol homeostasis
- excretion of lipid-soluble xenobiotics, heavy metals and drug metabolites
where is bile produced
in liver hepatocytes
then secreted and passed through the hepatic ducts
what is bile
- Bile is a lipid-rich micellar solution made of 6 main components:
- Water
- bile acid/salt
- cholesterol
- bile pigments
- phospholipids
- HCO3- and other salts.
bile is hypotonic to plasma
T/F
false
bile is isosmotic
how much bile is made daily on average
500-600ml
bile is hydrophobic
T/F
false
it is amphiphilic
what is formation of bile dependent on
- Formation depends on hepatic synthesis and canalicular secretion of bile acids
what are bile acids
- acids synthesised from cholesterol in the pericentral hepatocytes of the acini
how are bile acids produced
- Cholesterol → primary bile acids - they are then conjugated before secretion into the canaliculi and SI → secondary bile acids.
- Step 1: CYP7A1
- Step 2: intestinal bacteria
- primary bile acids=
- cholic acid (CA) and
- chenodeoxycholic acid (CDCA)
- secondary bile acids=
- deoxycholic acid
- lithicolic acid
summarise breakdown of lipids in the SI
- bile emulsifies fats in the SI into small droplets as it is amphiphilic,
- this increases the surface area available for lipases to breakdown
- co-lipase binds to the emuslified fat droplets which allows lipase to get closer to the droplet for breakdown
- Lipases cause lipolysis on the surface of the emulsified droplet: TGs →FAs
- once broken down, the bile surrounds the monoglycerides and FAs to form micelles containing cholesterol, FAs and fat soluble vitamins
- the micelles are then able to diffuse into the enerocyte
- in the enterocyte they are put back together by the SER to form TGs.
- the TGs, cholesterol and fat soluble vitamins are packaged into a chylomicron and enter the blood stream
what stimulates release of bile into the SI
cholecystokinin
what are the functions of bile acids
- Induce bile flow (osmotic effect) & secretion of biliary lipids (PL and cholesterol)
- Digestion of fats
- Facilitating protein absorption by accelerating hydrolysis by pancreatic proteases
- Cholesterol homeostasis
- Antimicrobial – induces anti-microbial genes
- Prevents calcium gallstones and oxalate renal stones.
what effect does CCK have
- Liver and gall bladder:
- relaxes the sphincter of Oddi
- causes contraction of the gall bladder
- pancreatic effects:
- Accelerates release of enzymes
- Increases HCO3- secretions
how does the gall bladder concentrate bile
it absorbs water out of the bile
summarise enterohepatic circulation
- The conjugated bile acids remain intraluminal - due to conjugation
- They are actively transported via the apical sodium bile acid transporter (ASBT) in the ileum.
- They re-enter the liver via portal circulation
- Bile acids taken up by hepatocyte and (re-conjugated) secreted into biliary canaliculi.
describe the feedback mechanism of bile acids
- In the liver CYP7A1 catabolises cholesterol → primary bile acids which enter the SI and are converted to 2° bile acids
- Bile acids bind to Farnesoid X receptor in the ileum → activation of FGF19 polypeptide hormone.
- FGF19 in inhibits CYP7A1 to reduce bile acid reduction.
- Depending on the amount of bile acids in the SI will affect the rate of production of FGF19, thus affecting the amount of inhibition on the CYP7a1.
