Biochemical aspects of liver metabolism Flashcards
What are the principle roles of the liver?
- First destination of most nutrients and xenobiotics absorbed by the GI tract
- Bile production
- Elimination of unwanted molecules (metabolism, or excretion into the biliary tree and faecal excretion)
- Secretion of plasma proteins (e.g. albumin)
- Storage of important molecules (e.g. fuels, iron, vitamins)
- Regulation of metabolism (carbohydrate and lipid metabolism, which leads to storage, and amino acid metabolism, which leads to the urea cycle).
What is the urea cycle?
This is the pathway which makes urea.
It occurs in the liver, and it is the way in which we get rid of excess nitrogen.
The kidneys excrete the urea.
What can be used to separate plasma proteins by size?
Electrophoresis
What are the main groups of plasma proteins?
Albumin, alpha globulins, beta globulins and gamma globulins (which include immunoglobulins).
What are the main functions of plasma proteins?
- Maintenance of oncotic or colloid osmotic pressure
- Transport of hydrophobic substances (steroid hormones, free fatty acids, bilirubin, cholesterol)
- pH buffering (amino acid side chains can carry net charges)
- Enzymatic (e.g. blood clotting)
- Immunity
What is the most abundant plasma protein?
What percentage of all plasma proteins does it make up?
How many grams per litre should be present in the blood?
Albumin.
It makes up 50% of all plasma proteins.
There should be 35-45 g/L
What is the main determinant of plasma osmotic pressure?
Albumin
Which hormone stimulates the production of albumin?
Insulin
What can cause low levels of albumin?
Liver disease
Starvation/ low protein diet
How does albumin bind to the substances which it transports?
It has hydrophobic clefts in globular domains where the substances it transports can bind.
Describe the affinity of albumin for the substances it transports
It has a low affinity, but a high capacity because of its high concentration
What sort of substances does albumin transport?
Give examples.
It transports important, endogenous lipophilic substances E.g: - Fatty acids - Bilirubin - thyroid hormones
It also transports exogenous substances e.g.
- drugs like aspirin
Why is iron important?
How is it transported?
How is it stored?
It is a component of heamoglobin, myoglobin and cytochromes.
It is transported as the ferric ion (Fe3+) bound to transferrin
It is stored in cells bound to ferritin
How is copper transported?
In what disease is there a deficiency of copper?
Bound to ceruloplasmin
Wilson’s disease
Which hormones are hydrophobic?
The steroid hormones (which are derived from cholesterol)
T3/T4 thyroid hormones
How is thyroxine transported in the blood?
Bound to thyroid-binding globulin
How is cortisol transported in the blood?
Bound to cortisol-binding globulin
What is the effect have transporters on hormones?
It extends the biological half life of the hormones and increases their plasma concentration.
If they were not bound to transporters they would rapidly be eliminated by the liver or the kidney.
What is the origin and function of chylomicrons?
They originate in the small intestine and transport exogenous fat to the liver
What is the origin and function of VLDL?
They originate in the liver and transport endogenous fat to peripheral cells
What is the origin and function of ILD?
The origin is VLDL and it is a precursor of LDL
What is the origin and function of LDL?
Originate from liver/VLDL/IDL. The function is to transport cholesterol to the peripheral tissues.
What is the origin and function of HDL?
Originate from the intestine and the liver.
The function is to transport cholesterol from peripheral tissues to the liver.
Which lipoprotein transports dietary fat?
Chylomicrons
Which lipoprotein transports endogenous/synthesised fat?
VLDL
Describe reverse cholesterol transport
This is the function of HDL.
Excess cholesterol is removed from cells and is esterified with fatty acids. It is then transported back to the liver and excreted as bile salts via the biliary system and faeces.
What is the only organ capable of metabolising and excreting cholesterol?
The liver
What is stored in the liver?
Vitamin A- stored as retinol palmitate
Vitamin D
Vitamin B12
Iron (from the breakdown of haemoglobin), stored bound to ferritin.
What is the function of cholesterol in mammalian cell membranes?
It increases rigidity
Cholesterol is the precursor for which 3 important classes of biologically active compounds?
Bile acids
Steroid hormones
Vitamin D
What sort of disease is linked to cholesterol metabolism?
Cardiovascular disease, and the formation of gallstones
What are the main dietary sources of cholesterol?
Meat, eggs and dairy
How much cholesterol do humans synthesise per day on average?
About 1 g
how much circulating cholesterol is in the free form?
About 30%
What form is the majority of cholesterol in?
What effect does this have on its solubility?
The majority is esterified to a wide range of long chain fatty acids
This makes it even less soluble than it is in its free form
how can cholesterol be solubilised?
By being incorporated into lipoproteins, where it is located in the core.
Which human cells can synthesise cholesterol?
Virtually all of them.
What is the main site of cholesterol synthesis?
The liver.
Less contributions come from the intestine, the adrenal cortex and the gonads
What is HMG-coA reductase?
A rate-limiting enzyme which catalyses the irreversible formation of mevalonic acid (an intermediate in the formation of cholesterol)
What stimulates the synthesis and activity of HMG-coA reductase?
Fasting
What reduces HMG-coA reductase activity?
Dietary cholesterol and high intra-hepatocyte cholesterol
Which drugs target HMG-coA reductase?
Statins
What else, apart from HMG-coA reductase, controls the synthesis of cholesterol?
Hormones
What is vitamin D?
What role does it have?
What is the most abundant form in the circulatory system?
It is a group of structurally related compounds which are derived from cholesterol.
It has a role in the regulation of calcium and phosphorous metabolism.
The most abundant form in the circulatory system is Vit D 3.
What are the three groups of steroid hormones, and where are they synthesised? How many carbon atoms does each have?
Corticosteroids- synthesised in the adrenal cortex. Has 21 carbon atoms.
Androgens- synthesised in the testes. These have 19 carbon atoms.
Estrogens- synthesised in the ovaries. These have 18 carbon atoms.
All three organs are capable of secreting small amounts of the other groups of steroid hormones
What is the main metabolic product of cholesterol?
Bile salts
Where are bile salts synthesised and secreted from?
The liver
Where, and how, are bile salts stored?
In the gallbladder, as a component of bile
What is the function of bile salts?
They act as detergents in the duodenum to emulsify ingested lipids
What system recycles bile salts?
The enterohepatic circulation
What happens to a portion of primary bile salts, due to the action of bacteria in the intestine?
They are converted into secondary bile salts
Which drugs bind bile salts and inhibit their reabsorption in the enterohepatic circulation?
What is the effect of this?
Anion exchange resins, e.g. cholestyramine.
There is increased bile salt excretion, therefore there is increased synthesis of bile salts to compensate for this.
The concentration of cholesterol in the liver is therefore decreased, so there is an increase in expression of LDL receptors on hepatocytes, and an increase in LDL removal from the plasma.
Name some molecules of endogenous and exogenous origin that are excreted by the liver in bile.
Molecules of endogenous origin:
steroid hormones
bilirubin
Molecules of exogenous origin:
environmental molecules ingested unconsciously
lipid-soluble substances ingested as drugs- conjugated in the liver and excreted via the biliary tree- appear in faeces
What happens to drugs which enter bile but are not excreted as faeces?
They enter the bile but are reabsorbed in the small intestine via the enterohepatic circulation.
This can act as a reservoir of circulating drugs.
It prolongs drug action.
It can lead to overdose when renal function becomes impaired.
Do liver enzymes have a high or a low specificity?
low
What is the strategy for excreting molecules from the liver?
Two phases.
In phase one, the unwanted molecule undergoes oxidation, hydrolysis or reduction to form a derivative. This is catalysed by microsomal cytochrome P-450 oxidases.
The derivative is conjugated with an endogenous compound e.g. glucuronic acid or sulphate, to form a conjugate.
What group do cytochrome P-450 enzymes contain?
Haem
Where are cytochrome P-450 enzymes found?
Mostly in the liver
What can induce the synthesis of cytochrome P-450 enzymes?
Certain drugs
What determines the response of cytochrome P-450 enzymes to drugs?
Genetic polymorphisms
What can inhibit cytochrome P-450 enzymes?
Drugs that form a stable complex
What is drug hepatotoxicity?
Give an example.
Toxic effects on the liver through production of a toxic metabolite.
E.g. Paracetamol
In overdose, the conjugation pathway is overwhelmed.
There is hepatocellular damage.
Where is bilirubin derived from?
It is a catabolic product of haem which is derived from haemoglobin from senescent red blood cells. This is then converted to bilirubin in the spleen.
How is bilirubin transported to the liver from the spleen?
It is transported by plasma albumin
What happens to bilirubin in the liver?
It is conjugated with glucuronic acid to increase its water solubility.
What happens to conjugated bilirubin in the intestine?
It is catabolised to colourless stercobilinogen by gut bacteria.
This is then oxidised to coloured stercobilin, of which some may be reabsorbed.
The rest is excreted in faeces.
What causes Jaundice?
A failure to excrete bilirubin
What concentration of bilirubin in the plasma is normal?
What concentrations are seen in jaundice?
About 17 micromol per litre is normal.
In jaundice, levels are high, >50 micromol per litre
What causes prehepatic jaundice?
Excess production of bilirubin after haemolysis
What can cause post hepatic jaundice?
One example is a blocked bile duct from a gallstone.
There is increased conjugated (hydrophilic) bilirubin in the plasma.
There are pale coloured stools due to a reduction in faecal bile pigments.
There is dark coloured urine due to excretion of water soluble bilirubin conjugates.
What causes intrahepatic jaundice?
generalised hepatocyte dysfunction
Which patients is intrahepatic jaundice common in?
common in neonates, particularly in premature babies
due to immaturity of enzymes involved in bilirubin conjugation
occurs within 48 hours after birth, recovers usually within 10 days
Why is intrahepatic jaundice in neonates dangerous?
How is it treated?
unconjugated bilirubin is toxic to the immature brain
treated by phototherapy with blue-white light
isomerises bilirubin to more soluble form which can be excreted with bile
in extreme cases: exchange blood transfusion
What happens to excess glucose in postprandial metabolism?
Excess glucose is diverted to the pentose phosphate pathway
makes NADPH for biosynthetic processes
What percentage of glucose is taken up by insulin-independent tissues?
80%
50% to the brain, and 30% to erythrocytes
What are the insulin-dependent tissues that takes up the remaining 20% of glucose?
Muscle tissue and adipose tissue
What provides amino acids for gluconeogenesis?
Muscle protein which is degraded
Which hormone stimulates lipolysis by hormone-sensitive lipase?
What are the products of this used for?
Glucagon
Glycerol is used for gluconeogenesis
Fatty acids are metabolised, which increases ketone body formation, and these are used as energy sources by the heart and skeletal muscle.
What are the hormone levels like in prolonged starvation?
There is a chronic low insulin and high glucagon state.
Thyroid hormone decreases which slows down metabolic rate.
What are the main energy substrates in prolonged starvation?
Fatty acids
Why is there an increase in ketogenesis in prolonged starvation?
Gluconeogenesis requires substrates
Muscle proteolysis increases
Almost total reliance on fatty acids as energy source
Glucose import into muscle and adipose tissue decreases
‘saves’ glucose
Brain adapts to using ketone bodies as fuel
