Lipid Metabolism Flashcards
What is the ratio of lipoproteins which is associated with atherosclerosis?
elevated LDL and decreased HDL
How are non-polar lipids transported within the blood?
within lipoproteins either high density - HDL or low density - LDL
What are apoproteins?
Specialised proteins within the outer monolayer of the hydrophilic coat
they are recognised by receptors in liver and other tissues allowing them to bind to cells
What is a lipoprotein comprised of?
a hydrphobic core - containing esterified cholesterol and triacylglycerols
a hydophilic coat - compromising of a monolayer of amphipathic cholesterol, phospholipids and apoproteins
What are the 4 main classes of lipoproteins?
HDL particles (contain apoA-I and apoA-II)
LDL particles (contain apoB-100)
Very-low density lipoprotein (VLDL) particles (contain apoB-100)
Chylomicrons (contain apoB-48)
What is the function of ApoB-Containing Lipoproteins?
deliver TAGs to muscle for ATP biogenesis and adipocytes for storage
Chylomicrons function
they are formed in the intestinal cells and transport dietary triglycerides - the exogenous pathway
Very low density lipoproteins function
they are formed in liver cells and transport TAGs synthesised by that organ - the endogenous pathway
The stages of the existence of ApoB-containing liposomes
Assembly - (apoB-100 in liver and apoB-48 in the intestine) Intravascular metabolism (involving hydrolysis of the TAG core) Receptor mediated clearance
How are TAGs (triacylglycerols) formed?
the monoglycerides and free fatty acid from dietary fat diffuse into the enterocytes and are synthesised into TAGs
What happens to cholesterol in the enterocytes?
It enters through the NPC1L1 and then undergoes esterification
Where does cholesterol used in the body come from?
25% from diet
75% from bile
Once assembled how does the chylomicron exit the enterocyte?
exocytosis
What is the class of drugs best for reducing total and LDL cholesterol?
Statins e.g. sinvaststin and atrovastatin
When are statins normally given?
At night because the majority of cholesterol seems to be made in the morning hence they are given before the peak
What are the main adverse effects of statins?
muscle pain and rhabdomylosis (skeletal muscle breakdown) made worse when taken with fibrates
What are fibrates used to treat?
they reduce TGA levels to be reduced
Why do you not give fibrates to alcoholics?
they are more prone to muscle damage and breakdown therefore despite their high triglyceride levels these drugs are not recommended
What is the role of chylomicrons and VLDL particles?
To target TAG delivery to adipose and muscle tissue - activated by transfer of apoC-II from HDL particles
What is the intravascular metabolism of ApoB-containing lipoproteins?
ApoC-II facilitates chylomicron and VLDL particles binding to Lipoprotein lipase (LPL) - (lipolytic enzyme associated with the capillary endothelium)
LPL hydrolyses core TAGs to free fatty acids and glycerol which enter tissues
What is a MTP?
a microsomal triglyceride transfer protein
MTP lipidates apoB-100 form what?
nascent VLDL which coalesces with TAG droplets
What is the process of clearing ApoB-containing lipoproteins?
- LPL, due to TAG metabolism causes chylomicrons and VLDL particles to become enriched with cholestryl esters
- chylomicrons and VLDL dissociate from LPL
- ApoC-II is transferred back to HDL particles in exchange for apoE a high affinity ligand for receptor mediated clearance - particles are now remnants
- The remnants are returned to the liver and metabolised by hepatic lipase
- all chylomicron remnants and 50% of VLDL remnants are cleared by receptor-mediated endocytosis into hepatocytes
- the remaining VLDL remnants lose further TAG through hepatic lipase and become smaller and enriched in cholesteryl ester and via intermediate density lipoproteins thry become LDL particles lacking apoE and solely retaining apoB-100
How LDL particles are cleared?
- dependent on LDL receptor expressed by the liver and other tissues
- clearance by the liver is most important
- LDL uptake by particles occurs via receptor-mediated endocytosis
- in the cell at the lysosome cholesterol is released from cholesteryl ester via hydrolysis
What does released cholesterol do?
inhibits HMG-CoA reductase which is the rate limiting enzyme in de novo cholesterol synthesis
down regulates LDL receptor expression
may be stored as cholesterol ester or used as a precursor for bile salt synthesis
Why is LDL ‘bad’ cholesterol?
It is very involved in the disease progression of atherosclerosis
- LDL is taken up from the blood into the intima of the artery and subsequently it’s oxidised to atherogenic oxidised LDL (OXLDL)
- Monocytes migrate across the endothelium into the intima where they become macrophages
- OXLDL is taken up by the macrophages and converts them to cholesterol-laden foam cells which form a fatty streak
- Release of inflammatory substances from various cell types causes division and proliferation of smooth muscle cells into the intima and the deposition of collagen
- Atheromatous plaque forms consisting of a lipid core and a fibrous cap
Why is HDL the ‘good’ cholesterol?
- Removes excess cholesterol from cells by transporting it in the plasma to the liver
- HDL is mainly in the liver in its component parts
- Mature HDL accepts excess cholesterol from plasma membrane of cells
How do statins reduce total and LDL cholesterol?
- 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 means there is a compensatory increase in LDL receptor expression and enhanced clearance of LDL
What effect do fibrates have on blood lipids?
- cause a pronounced decrease in TGAs and modestly decrease LDL and increase HDL
- 1st line in patients with high TGA
How do fibrates decrease TGA levels?
act as agonists of a nuclear receptor to enhance transcription of several genes including those which encode LPL
Adverse effects of fibrates?
- myositis (rarely) shouldn’t be used with statins
- GI symptoms
- Pruritus
- rash
How do bile acid binding resind (colestyramine, colestipol, colsevelam) reduce cholesterol?
- more bile salts are excreted so the cholestrol is converted to bile salts
- oral and can have adverse effects on the GI tract
- cause decreased absorption of TGAs and increased LDL receptor expression
How does Ezetimibe reduce cholesterol?
to inhibit Niemann-Pick C1 like-1 (NPC1L1) transport protein in enterocytes of the duodenum, reducing the absorption of cholesterol
How is ezetimibe used?
in combination with statins and causes LDL decrease
oral administration - half life 22 hours
Adverse effects of ezetimibe
diarrhoea
abdominal pain
headache
contraindicated in breastfeeding
