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Flashcards in Cardio Deck (27):
1

What do HDL particles contain?

contain apoA1 and apoA2

2

What do LDL particles contain?

contain apoB-100

3

What do VLDL particles contain?

contain apoB-100

4

What do chylomicrons contain?

contain apoB-48

5

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

6

Which protein is responsible for the uptake of cholesterol?

Niemann-Pick C1 like protein

7

What activates chylomicrons and VLDL?

Transfer of apoCII from HDL

8

Where is LPL found?

associated with the endothelium of capillaries

9

What apoCII do?

facilitates binding on chylomicron and VLDL to LPL

10

What does LPL do?

Hydrolyses core triglycerides to free fatty acids and glycerol which enter tissues

11

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

12

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)

13

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

14

What is the drug treatment for elevated LDL?

Statin and ezetimibe

15

What is the drug treatment for elevated LDL and VLDL?

Fibrates, statin, nicotinic acid

16

What is the drug treatment for elevated BVLDL?

Fibrates

17

What is the drug treatment for elevated VLDL?

Fibrates

18

What is the drug treatment for elevated Chylomicrons and VLDL?

Fibrate, niacin, fish oil and statin combination

19

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

20

Other beneficial effects of statins?

Decreased inflammation
Reversal of endothelial dysfunction
Decreased thrombosis
Stabilization of atherosclerotic plaques

21

How are statins administered?

Administered orally at night

22

Adverse effects of statins?

include myositis and rarely rhabdomyolosis incidence of which is increased if statin is combined with a fibrate

23

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

24

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

25

How are bile acid binding resins absorbed?

not absorbed from GI tract

26

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

27

When is ezetimbe used?

in combination with statins when the latter alone does not achieve a sufficient response