Pharmacology 4 Flashcards
What are features of lipids? What are their functions? (4)
- Insoluble in water
- Component of membranes
- Maintain membrane integrity
- Energy sources
- Pre-cursors for hormones and signalling molecules
How are non-polar lipids transported in blood? Examples of non-polar lipids? (2)
- Within lipoproteins like HDL and LDL
* Cholesterol esters and triglycerides
What is cardiovascular disease (atherosclerosis) associated with? (2) Causes? (2)
- Elevated LDL or particles rich in triglycerides
- Decreased HDL
- Diet and lifestyle (particularly Western)
- Genetic factors (e.g. familial hypercholesterolaemia)
What are lipoproteins? What are their components? (2)
- Microscopic spherical particles 7-1000 nM diameter
- Inner hydrophobic core containing esterified cholesterol and triglycerides
- Outer hydrophilic coat containing monolayer of amphipathic cholesterol, phospholipids and apoproteins (apo)
What are examples of lipoproteins? (4) What apoproteins does each contain? Rank from smallest to largest
- HDL particles (contain apoA1 and apoA2), smallest
- LDL particles (contain apoB-100)
- Very-low density lipoprotein (VLDL) particles (contain apoB-100)
- Chylomicrons (contain apoB-48), largest
What do apoB-containing lipoproteins do? Examples of apoB-containing lipoproteins? (3)
- Deliver triglycerides (i) to muscle for ATP biogenesis and (ii) adipocytes for storage
- LDL, LVDL and chylomicrons
What are the 2 pathways by which lipids are delivered to tissues?
- Exogenous and endogenous
What are chylomicrons?
Lipoproteins formed in intestinal cells that transport dietary triglycerides – the EXOGENOUS pathway
What are VLDL particles?
Lipoproteins formed in liver cells that transport triglycerides synthesised in liver (non-dietary) – the ENDOGENOUS pathway
Explain the “life-cycle” of apoB-containing liposomes? (3)
- Assembly (with apoB100 in the liver and apoB48 in intestine)
- Intravascular metabolism (involving hydrolysis of triglyceride core of lipoprotein)
- Following hydrolysis of core, end up with particle called REMNANT which is cleared form liver by receptor mediated clearance
What is the difference between apoB100 and apoB48?
ApoB48 is truncated version of apoB100
Explain the assembly of apoB-containing chylomicrons (8)
- Digestion of fat produces monoglycerides and free fatty acid chains
- These enter into cells lining intestine (enterocytes)
- Once inside, monoglyceride and fatty acid molecules resynthesised into triglyceride molecule
- Cholesterol is transported into cell by Niemann-Pick C1-like 1 Protein (NPC1L1)
- Cholesterol is then esterified to form cholesterol ester
- ApoB48 is synthesised by ribosomes and attached to developing lipoprotein in endoplasmic reticulum (lipidation by MTP) to form outer shell
- Triglyceride incorporated into lipoprotein by MTP (microsomal triglyceride transfer protein)
- Cholesteryl ester also incorporated, which together with ApoB48 and triglycerides forms chylomicron
Explain how chylomicron exits enterocyte (2)
- Exocytosis following addition of second apoprotein apoA1
* Enters lymphatics and is carried in lymph to systemic circulation via thoracic duct into subclavian vein
Where are VLDL particles containing triglycerides assembled? What are they assembled from? Explain the assembly of apoB-contaiing lipoproteins? (3)
- In liver hepatocytes
- Triglyceride core formed from free fatty acids from (i) adipose tissue - particularly during fasting - and (ii) de novo synthesis
- MTP lipidates apoB100 forming VLDL that coalesces with triglyceride droplets
How are chylomicrons and VLDL particles activated?
By transfer of apoCII from HDL particles
What is lipoprotein lipase?
Lipolytic enzyme associated with endothelium of capillaries in adipose and muscle tissue
What is the function of apoCII? What does this lead to? What are the particles that are depleted of triglycerides (but STILL contain cholesterol esters) called?
- ApoCII facilitates binding of chylomicrons and VLDL particles to LPL
- LPL hydrolyses core triglycerides to free fatty acids and glycerol WHICH ENTER TISSUES
- Chylomicron and VLDL remnants
Explain the process of clearance of apoB-containing lipoproteins (5)
- LPL causes chylomicrons and VLDL particles to become enriched with cholesterol due to triglyceride metabolism
- Chylomicrons and VLDL dissociate from LPL
- ApoCII transferred back to HDL particles in exchange for apoE - a high affinity ligand for receptor mediated clearance (particles now called remnants)
- Remnants return to liver and further metabolised by hepatic lipase
- All apoB48-containing remnants and 50% of apoB100-containing remnants are cleared by receptor-mediated endocytosis into hepatocytes
If only 50% of apoB100-containing remnants are cleared, what happens to the other 50%? (2)
- Lose further triglyceride through hepatic lipase - become smaller and enriched in cholesteryl ester
- Intermediate density lipoprotein (IDL) converts them into LDL particles lacking apoE and retaining solely apoB100
What is clearance of LDL particles crucially dependent on? What happens once endocytosis has occurred?
- Expression of LDL receptor by the liver
- After internalisation of receptor and LDL by endocytosis and subsequent hydrolysis, LDL receptor is recycled to pick up more LDL
How does cellular uptake of LDL particles occur in the liver? What happens to LDL particles within the hepatocyte? What does release cholesterol cause? (3)
- Occurs via receptor-mediated endocytosis
- Within the cell at the LYSOSOME, cholesterol (C) is released from cholesteryl ester (CE) by hydrolysis
- inhibits synthesis of cholesterol by hepatocyte via inhibiting HMG-CoA reductase
- down regulation of LDL receptor expression
- storage of cholesterol as cholesterol ester
How do statins work?
Blocks synthesis of cholesterol so leads to increased expression of LDL recpetor on surface of hepatocyte, meaning LDL particles more readily cleared from plasma
What is atherosclerosis?
Focal disease of large and medium sized arteries
What causes atherosclerosis? What are risk factors?
- Dysfunction and injury of the lining (endothelium) of blood vessels
- Risk factors include diabetes, high BP, smoking)
Explain the disease progression of atherosclerosis (6)
- Uptake of LDL from blood into intima of the artery
- LDL oxidized to atherogenic oxidised LDL (OXLDL) - it is the oxidised form that causes the plaques
- Migration of monocytes across endothelium into intima where they become macrophages
- Uptake of OXLDL by macrophages (using scavenger receptors) converts them to cholesterol-laden foam cells that form a FATTY STREAK
- Release of inflammatory substances causes division and proliferation of smooth muscle cells into intima and deposition of collagen
- Formation of an atheromatous plaque consisting of a lipid core (product of dead foam cells) and a fibrous cap (smooth muscle cells and connective tissue)
What does the lipid core of atheromatous plaque consist of? Fibrous cap?
- Dead foam cells
* Smooth muscle cells and connective tissue
What is the function of HDL? Why the liver?
- Removing excess cholesterol from cells by transporting it in plasma to the liver
- Liver is only organ that has capacity to eliminate cholesterol from the body (as cholesterol secreted into bile, or used to synthesize bile salts)
Explain the formation of HDL (3)
- HDL is formed in the liver, initially as ApoA1 in association with a small amount of surface phospholipid and unesterified cholesterol (pre-B-HDL)
- Pre-B-HDL matures in plasma to spherical -HDL
- Surface cholesterol is enzymatically converted to hydrophobic cholesterol ester that migrates to the core of the particle
What is the purpose of mature HDL? What is this process known as?
- Accepts excess cholesterol from the plasma membrane of cells (e.g. macrophages) and delivers cholesterol to the liver
- Reverse cholesterol transport
What are the mechanisms by which HDL delivers excess cholesterol to the liver? (2)
Direct and indirect
- Direct - HDL interacts with receptor (scavenger receptor-B1, SR-B1) allowing transfer of cholesterol and cholesteryl esters into hepatocytes
- In plasma, cholesterol ester transfer protein (CETP) allows transfer of cholesteryl esters from HDL to VLDL/LDL, indirectly returning cholesterol to the liver
What is dyslipidaemia? What are the different types? (2)
- Excess lipids i.e. cholesterol in the blood
* Primary and secondary dyslipidaemia
What causes primary dyslipidemia?
- Primary - combination of diet and genetic factors
* Secondary - other diseases (e.g. type II diabetes, hypothyroidism, alcoholism, liver disease)
What is type IIa IIa hyperlipoproteinaemia caused by? What condition does this cause? What is a risk associated with this condition?
- Gene defect in LDL receptor
- Familial hypercholesterolaemia
- Ischaemic heart disease
What are statins? Examples?
- Drugs of choice to reduce LDL – very effective in reducing total and LDL cholesterol (up to 60%), decrease triglycerides (up to 40%) and increase HDL (about 10%)
- Simvastatin and atorvastatin
What is the mechanism of statins? What is the effect of this?
- Act as competitive inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase - rate limiting step in cholesterol synthesis in hepatocytes
- Decrease in hepatocyte cholesterol synthesis causes a compensatory increase in LDL receptor expression and enhanced clearance of LDL
When are statins not of use in treating high cholesterol?
Statins are ineffective in homozygous familial hypercholesterolaemia where LDL receptors are lacking (but work in heterozygous)
Other than enhanced LDL clearance, what are other beneficial effects of statins? (4)
- Decreased inflammation in vasculature
- Reversal of endothelial dysfunction (damage)
- Decreased thrombosis
- Stabilization of atherosclerotic plaques
How/when are statins administered? What are adverse effects of statins? (2)
- Orally at night
- Myositis (inflammation of skeletal muscle)
- Rhabdomyolosis (damage to skeletal muscle e.g. plaque distribution)
What are 2 classes of lipid-lowering drugs?
Statins and fibrates
What are the effects of fibrates? Examples?
- Decrease in triglycerides (up to 50%) and decrease in LDL (up to 15%) and increase (up to 20%) in HDL
- Bezafibrate and gemfibrozil
What are fibrates? What is their mechanism?
- First line drugs in patients with very high triglyceride levels
- Act as agonists of a nuclear receptor (PPAR) to enhance the transcription of several genes, including LPL
What are adverse side effects of fibrates? (5)
- Rare but can cause myositis
- Rhabdomyolosis
- GI upset
- Pruritus
- Rash
When should administration of fibrates be avoided?
Avoided in alcoholics who are predisposed to hypertriglyceridaemias
