Artherosclerosis, Lipoprotein Flashcards
How are lipids made water soluble in blood?
Covered by proteins-different ones for different lipid balls
LDL-ApoB
HDL-ApoA1
Can be measured and used as markers of risks
How are fats carried from the intestine to the body?
From the intestine-endogenous-mainly TG and a bit of Chol
Carried in Chylomicrons to skeletal muscle, adipose and Liver (main)
But main cholesterol comes in endogenous form
Recap the endogenous pathway of lipoprotiens? And reverse chol transport
Liver produces VLDL-and as it passes by the cells-reduces in size and become LDL, IDL, etc and is taken in back in . by the liver at the end
Reverse transport is mainly via HDL-and takes cholesterol back from cells and towards the liver-but there is a part where it exchanged with VLDL -making probably bad mixed
what is thought to be the inital part of artherosclerosis and how does it develop?
well first point-not all plaques go through this-
usually thought to start with damaged endothelium- -increases permeability->adhesion-> infiltration of neutrophils (that forms fatty streaks-happens early in life)
As go on-foam cells, pro-inflammation-fibrious cap formation-foam cells go take in too much of extracellular lipid-start forming a necrotic core-even more proinflammation-bring more immune cells in-grows as fat deposits easier in v damaged endothelium + more cells come in
=> as long as fibrious cap is intact can be okay-when rupture-thrombosis
What are remnant lipoproteins?
Remnants seem to be leftover chylomycrons after most has been taken out- thought to be very artherogenic (pro artherosclerosis) (remnant cholesterol)
but maybe LDL causes fatty streaks without inflammation and remnant cholesterol is more pro-inflammation
What is the difference between a stable and vulnerable plaque?
Usually, stable plaques tend to have much larger wall seperating the lipid and the lumen-worse symptoms but better prognosis
Unstable plaques tend to have a thinner division-if BP goes up sharply-can break down, or as plaque progresses/inflammatory processes (from immune cells) -> thrombus -> bloquing and death
WHat is the relation between HDL and LDL?
LDL-higher means more CHD chance-increased by smoking, diabetes, hypertension
HDL-lower means more chance of CHD-reduced in smoking, obesity, inactivity
also many things interact but cant over estimate it-but need to treat more than one thing
How do statins function?
Inhbit the rate limiting step of cholesterol synthesis-stops HMG-COA reductase
Stops production of several biproduct of chol synthesis that cannot be obtained from circulation ->these are usefull in producing growth signals –reduced
Also lowers Cholesterol in liver cells-so they produce more LDLR-absorb more LDL from circulation-reduce LDL
What are the problems with statins?
“rule of 6”-if you double the dose, only lose about 6% total LDL (not much)-
also some people just cannot tolerate them
have a risk of giving diabetes
but they do reduce CHD well
How do fibrates work to reduce LDL?
Activation of PPAR alpha receptor on cell receptors-
they have a lot of actions-but bottom lines is reduces plasma TA and TG
One study showed really good TG reduction, higher HDL, lower IHD and stuff
How does nicotinic acid reduce LDL?
Niacin-vitamin in low dose
Should lower VLDL, reduce inflammation, increase HDL
but it doesnt -studies have shown even bad results
how does ezetimibe help reduce LDL?
Inhbits cholesterol absorption
absorbed and transformed to glucosimide-
Works but not as well as statins-so best use is to combine with statins- (bypass the rule of 6)
What is the role of choline ester transferase? Did it make a good drug target?
Exchanges some chol ester from HDL and LDL-causing reduction of HDL levels - so inhbiting it should help increase HDL
Inhbitors were easy to make, but really didnt help the patients-even made it worse
Possibly because it was having negative secondary effects
Other similar drugs have seemed to not have these effects
What is PCSK9? Is it a good target to reduce LDL? How?
PSCK9 is secreted by cells and inhbits LDLR-causing endocytosis of the receptor
As a result, inhbiting PCSK9 should provide more LDLR activity and intake more LDL (especially as statin increase PSCK9)-
Create monoclonal AB-2 have been patented (but very expensive)-but work well with statin
-so maybe only for FH patients/statin intolerant
Been ideas of RNAi (inclisiran) against PCSK9-2 times a year-more convenient and maybe cheaper?
