Atherosclerosis 2 Flashcards
How do the classes of LDL, VLDL, HDL and chylomicrons differ?
HDL have higher protein content, are smaller in diameter and contain ApoA1 and ApoA2.
LDL’s are larger, and contain ApoB100.
VLDL’s are even larger, with more Fatty acids (removed by LPL) contain apoB100 too.
Chylomicrons contain ApoB1-48, WITHOUT B100..!!!! and are huge!
What is the exogenous pathway of lipid transport?
Cholesterol, triglycerides + FAs from GI tract are transported as chylomicrons in lymph and then into the blood.
Endothelial bound lipoprotein lipase degrades chylomicrons into chylomicron remnants.
Chylomicron remnants are transported to liver and absorbed by endocytosis using LRP1.
What is the endogenous pathway of lipid transport?
De novo synthesis of cholesterol by mevallonate pathway, with rate limiting step being HMG-CoA reductase.
Cholesterol + Triglycerides are packaged into VLDL’s.
VLDLs are metabolised by lipoprotein lipase + hepatic lipase into LDLs.
LDL provides a source of cholesterol for cell membranes.
Peripheral cells can then use ABC transporters to produce HDL’s alongside ApoA1/ApoA2, which undergo reverse transport to the liver.
What are statins?
Statins inhibit HMG-CoA reductase to reduce levels of circulating LDL cholesterol and may have additional effects on inflammatory responses.
HMG-CoA reductase is the rate limiting step in the mevalonate pathway.
What are the effects of statins on cholesterol levels?
Decrease de novo synthesis of cholesterol - reducing LDL levels.
Reduced LDL causes hepatic cells to express more LDL receptors = resulting in increased clearance of LDL from the blood and triglcyerides.
HDL increases, TG’s + LDL decrease.
= LDL needed for PM and bile salts = liver attempts to scavenge cholesterol.
What is protein prenylation?
The covalent attachment of farnesyl and geranylgeranyl groups to cysteine residues in proteins.
Major regulation of small GTPase proteins like Rho, Rac, cdc42 = which have a range of important roles in inflammation.
How might statins also be anti-inflammatory?
Statins inhibit the formation of L-Mevalonate from HMG-CoA.
Therefore deplete the build up of downstream products of mevalonate pathway like Farnesyl PP.
Farnesyl PP plays an important role in protein prenylation….
= Reduced Farnesyl PP reduces protein prenylation of small GTPase proteins like Rho, Rac, cdc42 = which all play important roles in inflammation.
What are other desirable actions of statins?
Better endothelial function, reduced vascular inflammation + increased neovascularisation of ischeamic tissue.
Reduced platelet aggregation + stabilisation of atherosclerotic plauqe = anti-thrombotic actions.
What are fibrates?
Bezafibrate, ciprofibrate.
Agonists at PPARalpha nuclear receptors.
Increasing the transcription of LPL, ApoA1 + ApoA5.
= decreasing plasma VLDL, increasing plasma HDL!
Reduction in C-reactive protein and fibrinogen = anti-thrombotic too.
What are the effects of fibrates?
Agonism of PPARalpha nuclear receptor leads to increased transcription of ApoA1, ApoA5 and LPL.
LPL degrades chylomicrons to chylomicron remnants and VLDL into LDL!!!
ApoA1 in HDLs.
Also reduce C-reactive protein and fibrinogen = anti-inflammatory and anti-thrombotic!!!
Increased HDL and reduced plasma VLDL
What are bile acid resins?
Bile acid anion exchange resins sequester bile acids in the GI tract and prevent reabsorption.
= Decreased enterhepatic circulation of bile acids.
Bile acids are then eliminated in faeces.
What are the effects of bile acid resins?
Increased bile acid synthesis from endogenous cholesterol to replace excreted bile acids.
In order to increae endogenous cholesterol, more LDL receptors are expressed.
= increasing liver uptake of LDL + increaed clearance of LDL.
HDL levels remain unchanged.
Triglyceride levels increase!!!
What are the side effects of bile acid resins?
Bind to other lipid soluble factors = Warfarin, thyroxine!!!!!
= So be careful with anti-coagulants!!!
Unpalateble and lead to diarrhoea.
What is PCSK9?
PCSK9 post-translationally regulates hepatic LDL receptors.
PCSK9 binds to hepatic LDL receptors, leading to their degradation.
= reduce LDL receptor expression…
Blocking PCSK9 would increase LDL receptor expression and increase LDL clearance.
What do PCSK9 mutations show?
Gain of function PCSK9 mutations lead to reduced hepatic LDL receptor expression, familial hypercholesterolemia + increased CVD.
But loss of function = lower CVD and lower LDL cholesterol!!!
