Atherosclerosis and Dyslipidemias Flashcards
what 3 lipoprotein complexes transport lipid throughout the body?
HDL, LDL, VLDL
what are lipoproteins?
packages of lipids (triglycerides, cholesterol) surrounded by apolipoproteins and phospholipids
what are lipoproteins categorized by?
size and presence of apolipoproteins (B-100 in LDL and VLDL, A-1 in HDL)
high levels of what lipoprotein is linked to adverse cardiovascular effects?
LDL-C (or generally, TC: total cholesterol)
what is the leading cause of death in North America?
formation and rupture of atherosclerotic plaques followed by cardiac or neuronal occlusion
what is the good and bad lipoprotein?
good: HDL
bad: LDL
what is atherosclerosis?
fatty deposits of cholesterol in foam cells (transformed macrophages) that occlude blood vessels
what mechanisms do macrophages (foam cells) have for uptake and efflux of cholesterol?
uptake: ApoE receptor, LRP1 (of LDL)
efflux: mature HDL
what makes a plaque inert/stable?
occludes blood vessels but is isolated by fibrous cap (smooth muscle and connective tissue)
what makes a plaque vulnerable?
thinning/rupture of fibrous cap exposes prothrombotic factors, causing thrombosis and total vessel occlusion
what are the effects of statins?
decr TC, LDL-C and incr in HDL-C (decr cardiovascular events and all-cause mortality)
where is VLDL and LDL formation primarily regulated?
liver
what does the liver package into VLDLs?
apolipoproteins (eg. B-100), cholesterol, triglycerides, etc.
where does cholesterol that liver uses to package in VLDLs come from? (2)
- dietary/extrinsic (taken up via LDL receptor)
2. synthesized in hepatocyte (HMG-CoA)
what pathway synthesizes cholesterol in the liver?
Mevalonate
what is the rate limiting enzyme in the Mevalonate pathway?
HMG-CoA reductase
what are statins? ex?
competitive inhibitors of HMG-CoA reductase; atorvastatin (Lipitor)
what does HMG-CoA catalyze?
conversion of HMG-CoA to mevalonic acid
where is HMG-CoA?
ER membrane (transmemb protein)
how do statins reduce circulating LDL-C?
decr production of cholesterol via mevalonate pathway by inhibiting HMG-CoA step
what is the compensatory response in the hepatocyte when HMG-CoA is inhibited?
low [chol] detected by sterol receptor in hepatocyte causes incr expression of LDL receptors to incr uptake of LDL from blood (decr circulating [chol])
why is having high extraction good for statins?
primary target is liver
are statins only administered as prodrugs?
no, can be given in active form (atorvastatin)
when are statins taken? why?
before bed; most cholesterol synthesis occurs during sleep
what are fibrates? ex?
agonists for intracellular receptor PPAR (act like steroids); fenofibrate
what does binding of fibrates to PPARa cause?
receptor acts as a TF and migrates to nucleus, heterodimerizes w/ RXR (retinoic acid receptors), binds to DNA and incr transcription of lipoprotein lipase
what is the main outcome of fibrates?
incr expression lipoprotein lipase leads to incr breakdown of triglycerides in VLDL and uptake of fa as E source in peripheral tissues
what are 2 other reported effects of fibrates?
incr uptake of LDLs (incr LDLR) and decr production of VLDLs in liver (not as effective as statins)
