Cardio Flashcards
What do HDL particles contain?
contain apoA1 and apoA2
What do LDL particles contain?
contain apoB-100
What do VLDL particles contain?
contain apoB-100
What do chylomicrons contain?
contain apoB-48
Summarise the life cycle of ApoB containing liposomes?
Assembly [with apoB100 in the liver and apoB48 (a truncated variant) in the intestine]
Intravascular metabolism (involving hydrolysis of the triglyceride core)
Receptor mediated clearance
Which protein is responsible for the uptake of cholesterol?
Niemann-Pick C1 like protein
What activates chylomicrons and VLDL?
Transfer of apoCII from HDL
Where is LPL found?
associated with the endothelium of capillaries
What apoCII do?
facilitates binding on chylomicron and VLDL to LPL
What does LPL do?
Hydrolyses core triglycerides to free fatty acids and glycerol which enter tissues
How is LDL cleared?
Cellular uptake of LDL particles occurs via receptor-mediated endocytosis
Within the cell at the lysosome, cholesterol (C) is released from cholesteryl ester (CE) by hydrolysis
Released cholesterol causes:
inhibition of HMG-CoA reductase which is the rate limiting enzyme in de novo cholesterol synthesis
down regulation of LDL receptor expression
storage of cholesterol as cholesterol ester
Why is LDL bad cholesterol
oxidised to athrogenic OXLDL
Migration of monocytes (white blood cell) across the endothelium into the 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 (an early event in atherogenesis)
Release of inflammatory substances from various cell types causes division and proliferation of smooth muscle cells into the intima and the deposition of collagen
The 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)
Why is HDL the ‘Good’ Cholesterol?
accepts excess cholesterol from the plasma membrane of cells (e.g. macrophages) and delivers cholesterol to the liver, known as reverse cholesterol transport, by several mechanisms;
>HDL reaching the liver interacts with a receptor (scavenger receptor-B1, SR-B1) that allows transfer of cholesterol and cholesteryl esters into hepatocytes
>In the plasma, cholesterol ester transfer protein (CETP) mediates transfer of cholesteryl esters from HDL to VLDL and LDL, indirectly returning cholesterol to the liver
What is the drug treatment for elevated LDL?
Statin and ezetimibe
What is the drug treatment for elevated LDL and VLDL?
Fibrates, statin, nicotinic acid
What is the drug treatment for elevated BVLDL?
Fibrates
What is the drug treatment for elevated VLDL?
Fibrates
What is the drug treatment for elevated Chylomicrons and VLDL?
Fibrate, niacin, fish oil and statin combination
Describe the action of statins?
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 (note: statins are ineffective in homozygous familial hypercholesterolaemia where LDL receptors are lacking
Other beneficial effects of statins?
Decreased inflammation
Reversal of endothelial dysfunction
Decreased thrombosis
Stabilization of atherosclerotic plaques
How are statins administered?
Administered orally at night
Adverse effects of statins?
include myositis and rarely rhabdomyolosis incidence of which is increased if statin is combined with a fibrate
How do fibrates work?
First line drugs in patients with very high triglyceride levels
agonists of a nuclear receptor (PPARa) to enhance the transcription of several genes, including that encoding LPL
Which drugs inhibit cholesterol synthesis?
Bile acid binding resins (colestyramine, colestipol, colsevelam) cause the excretion of bile salts resulting in more cholesterol to be converted to bile salts by interrupting enterohepatic recycling
How are bile acid binding resins absorbed?
not absorbed from GI tract
How does ezetimbe work?
Relative new agent, acts to inhibit Niemann-Pick C1 like-1 (NPC1L1) transport protein in enterocytes of the duodenum, reducing the absorption of cholesterol
When is ezetimbe used?
in combination with statins when the latter alone does not achieve a sufficient response
