Liver function Flashcards
Why is cholesterol important?
It is a key component in the synthesis of cell membranes and contributes to the fluidity of membranes (lipid rafts) and is the precursor for the synthesis of several molecules including vitamin D, cortisol, aldoesterone, progesterone, estrogen, testosterone and bile salts.
What are lipid rafts?
Patches of different fluidity in the membrane due to clustering proteins.
How and where is cholesterol synthesised?
80% of the total daily production is in the liver and it is synthesized from Acetyl Co-A.
What are the first main step in cholesterol synthesis?
3-isopentenyl pyrophosphate is formed from mevalonate.
What are the following steps in cholesterol synthesis?
Squalene is synthesised from isopentenyl pyrophosphate and there is cyclization to form lanosterol. Lanosterol eventually then forms cholesterol.
How is cholesterol transported around the body?
As it is a lipophilic molecule and does not dissolve well in aqueous environments, it is packaged with phospholipids and apolipoproteins to form a series of different lipoproteins.
What is the structure of lipoproteins?
They have a lipid core (cholesterol esters and triglycerides) and a hydrophilic outer surface containing phospholipids, free cholesterol and apolipoproteins.
What are the two main different types of lipoproteins?
Low density and high density (LDL and HDLs).
What are the differences in terms of health of these two different lipoproteins?
LDLs are a risk factor for cardiovascular disease wheres HDLs are protective and are seen as healthy.
What is atherosclerosis?
A progressive disease of large arteries and a leading cause of cardiovascular diseases and stroke.
What is associated with the development of atherosclerosis?
Increasing levels of LDL.
How can atherosclerosis be treated?
Inhibitors of cholesterol synthesis such as statins that inhibit HMG CoA reductase in the cholesterol synthesis pathway.
What is the difference between statins and drugs that target the enzyme PCSK9?
Statins regulate the production of cholesterol whereas these other drugs regulate cholesterol directly in the circulation.
Recap: what is the process for bile sale production?
The sphincter of oddi releases bile, bacterial flora modify the primary bile acids which are then released into the GI tract where they are modified by the bacteria.
What does bile contain?
Bile salts, lecithin, HCO3, cholesterol, bile pigments and trace metals.
How is the volume of bile increased?
Epithelial cells lining bile ducts secrete a bicarbonate rich fluid into the bile.
What are the primary bile acids?
Cholic acid and chenodeoxycholic acid.
What are the secondary bile acids?
Deoxycholic and lithocholic.
How are bile salts generated?
Bile acids are conjugated to amino acids to generate water soluble bile salts.
Give an example of a bile salt and how it is formed.
Glycocholate from cholic acid and glycine.
What are bile salts important for?
For the emulsification of fats.
What happens to bile salts once they have entered the liver?
They are recycled back to the liver via the portal vein.
What is enterohepatic circulation?
Recycling of bile salts from the GI tract to the liver.
How are the bile salts recycled?
When they reach the ileum (last segment of the small intestine) they are re-absorbed by a sodium-dependent pathway.
What happens to the bile salts that are not recycled?
They are lost in the faeces.
What is the sphincter of oddi?
A ring of smooth muscle where the common bile enters the small intestine.
What happens when a fatty meal is ingested?
There is a release of hormones that relax the sphincter of oddi and contract the gall bladder to release bile acid.
What hormone causes the release of bile?
Cholecystokinin (CCK) which is a peptide hormone produced by the small intestine.
How does the gall bladder concentrate bile?
It removes salt and water.
What are bile pigments?
Breakdown products of the heme portion of haemoglobin from erythrocytes broken down in the liver and spleen.
What is the major pigment in bile pigments?
Bilirubin.
What are the main plasma proteins?
Albumin, globulins and clotting factors.
What are the roles of albumin?
It transports lipids and steroid hormones.
What are the roles of globulins?
They transport lipids and steroid hormones.
What are examples of clotting factors?
Fibrinogen and prothrombin.
What is IGF and what is its function?
Insulin-like growth factor (IGF) and it is an important mediator of growth hormone (GH) action. It is structurally similar to pro-insulin.
When does the liver produce IGF?
It produces IGF-1 and IGF-2 in response to growth hormone.
How do levels of IGF-1 and IGF-2 vary throughout growth?
IGF-1 is low in infancy, peaks during puberty and declines in adults whereas IGF-2 is more important in fetal and neonatal growth.
What role does the liver play in drug metabolism?
It is important in activating drugs and also in removing drugs and toxic by-products.
What does activation of drugs do?
It changes the drug into something else.
What happens in phase 1 drug metabolism?
The drug undergoes different reactions that usually involves cytochrome P450 enzymes.
What dietary substances can alter drug metabolism?
Grapefruit juice can inhibit P450 enzymes and brussel sprouts can induce P450 enzymes.
What is clopidogrel?
An anti-thrombotic agent that inhibits platelet activation.
What is the action of clopidogrel?
Hepatic P450 enzymes generate the active thiol metabolite that reacts with platelets and binds selectively and irreversibly to the P2Y12 receptor on platelet membranes.
How does clopidogrel work to inhibit platelet activation?
It binds to the P2Y12 receptor which) prevents ADP from binding, so platelet aggregation cannot occur.
Why is not much of clopidogrel activated?
Most is inactivated by blood esterases so only around 15% can be metabolised by hepatic P450 enzymes.
What else can cause a reduced response to clipidogrel?
Genetic mutations in P450 enzymes.
What is phase 2 of drug metabolism?
This is a conjugation step that usually leads to a pharmacologically inactive or less lipid soluble product that is eliminated in urine or bile.
What groups may be added in phase 2 of drug metabolism?
Glucuronyl, sulphate, methyl, acetyl, glycyl and glutathione.
What is paracetamol?
A commonly used non-narcotic analgesic-antipyretic agent (non-addictive, pain relieving fever-reducing drug).
How is paracetamol inactivated?
By the liver by conugation with glucuronide or sulphate.
What does an overdose of paracetamol cause?
Hepatotoxicity - chemical driven liver damage.
What are Kupffer cells?
Resident macrophages of the liver found in hepatic blood sinusoids.
