Atherosclerosis and Dyslipidemias

Question 1

what 3 lipoprotein complexes transport lipid throughout the body?

Answer 1

HDL, LDL, VLDL

Question 2

what are lipoproteins?

Answer 2

packages of lipids (triglycerides, cholesterol) surrounded by apolipoproteins and phospholipids

Question 3

what are lipoproteins categorized by?

Answer 3

size and presence of apolipoproteins (B-100 in LDL and VLDL, A-1 in HDL)

Question 4

high levels of what lipoprotein is linked to adverse cardiovascular effects?

Answer 4

LDL-C (or generally, TC: total cholesterol)

Question 5

what is the leading cause of death in North America?

Answer 5

formation and rupture of atherosclerotic plaques followed by cardiac or neuronal occlusion

Question 6

what is the good and bad lipoprotein?

Answer 6

good: HDL
bad: LDL

Question 7

what is atherosclerosis?

Answer 7

fatty deposits of cholesterol in foam cells (transformed macrophages) that occlude blood vessels

Question 8

what mechanisms do macrophages (foam cells) have for uptake and efflux of cholesterol?

Answer 8

uptake: ApoE receptor, LRP1 (of LDL)
efflux: mature HDL

Question 9

what makes a plaque inert/stable?

Answer 9

occludes blood vessels but is isolated by fibrous cap (smooth muscle and connective tissue)

Question 10

what makes a plaque vulnerable?

Answer 10

thinning/rupture of fibrous cap exposes prothrombotic factors, causing thrombosis and total vessel occlusion

Question 11

what are the effects of statins?

Answer 11

decr TC, LDL-C and incr in HDL-C (decr cardiovascular events and all-cause mortality)

Question 12

where is VLDL and LDL formation primarily regulated?

Answer 12

liver

Question 13

what does the liver package into VLDLs?

Answer 13

apolipoproteins (eg. B-100), cholesterol, triglycerides, etc.

Question 14

where does cholesterol that liver uses to package in VLDLs come from? (2)

Answer 14

1. dietary/extrinsic (taken up via LDL receptor)

2. synthesized in hepatocyte (HMG-CoA)

Question 15

what pathway synthesizes cholesterol in the liver?

Answer 15

Mevalonate

Question 16

what is the rate limiting enzyme in the Mevalonate pathway?

Answer 16

HMG-CoA reductase

Question 17

what are statins? ex?

Answer 17

competitive inhibitors of HMG-CoA reductase; atorvastatin (Lipitor)

Question 18

what does HMG-CoA catalyze?

Answer 18

conversion of HMG-CoA to mevalonic acid

Question 19

where is HMG-CoA?

Answer 19

ER membrane (transmemb protein)

Question 20

how do statins reduce circulating LDL-C?

Answer 20

decr production of cholesterol via mevalonate pathway by inhibiting HMG-CoA step

Question 21

what is the compensatory response in the hepatocyte when HMG-CoA is inhibited?

Answer 21

low [chol] detected by sterol receptor in hepatocyte causes incr expression of LDL receptors to incr uptake of LDL from blood (decr circulating [chol])

Question 22

why is having high extraction good for statins?

Answer 22

primary target is liver

Question 23

are statins only administered as prodrugs?

Answer 23

no, can be given in active form (atorvastatin)

Question 24

when are statins taken? why?

Answer 24

before bed; most cholesterol synthesis occurs during sleep

Question 25

what are fibrates? ex?

Answer 25

agonists for intracellular receptor PPAR (act like steroids); fenofibrate

Question 26

what does binding of fibrates to PPARa cause?

Answer 26

receptor acts as a TF and migrates to nucleus, heterodimerizes w/ RXR (retinoic acid receptors), binds to DNA and incr transcription of lipoprotein lipase

Question 27

what is the main outcome of fibrates?

Answer 27

incr expression lipoprotein lipase leads to incr breakdown of triglycerides in VLDL and uptake of fa as E source in peripheral tissues

Question 28

what are 2 other reported effects of fibrates?

Answer 28

incr uptake of LDLs (incr LDLR) and decr production of VLDLs in liver (not as effective as statins)