26 - Atherosclerosis Flashcards
Are lipids such as cholesterol and triglycerides soluble in plasma?
No, these lipids must be transported in association with proteins (lipoproteins) in the circulation
What are the 5 main types of lipoproteins?
Chylomicrons
VLDL
IDL
LDL
HDL
Describe chylomicrons
produced by intestine from dietary lipids. Involved in transport of dietary triglycerides (TG) and cholesterol to peripheral tissues and liver
Describe VLDL
produced by liver. Carry lipids (TG) from liver to tissues
Describe IDL
VLDL remnant. The removal of TG from VLDL by muscle and adipose tissue results in formation of IDL particle
Describe LDL
particles are derived from VLDL and IDL particle. LDL carries the majority of the cholesterol that is in the circulation
Describe HDL
important role in reverse cholesterol transport from peripheral tissues to the liver. remove excess cholesterol from the cells and tissues*
What are lipoproteins? How are they categorized?
packages of lipids (TG, cholesterol) surrounded by apolipoproteins and phospholipids
categorized according to size and presence of specific apolipoproteins
What determines a lipid’s density
The amount of lipid present with a lipoprotein
If lipoprotein density is low, it comprises of more degree of lipid than protein
High levels of total cholesterol (especially LDL-C) are linked to adverse cardiovascular events. What does cholesterol cause that leads to these events?
Formation of atherosclerotic plaques.
Rupture of atherosclerotic plaques followed by occlusion of vessels in the heart or brain
Elevated HDL is linked with reduced chances of atherosclerosis. What is the major anti-atherosclerotic effect of HDL?
The major anti-a
What is atherosclerosis?
Disease that is characterized by the accumulation of lipids in the blood. Plaques in the walls of large and medium sized arteries form. This reduces the supply of oxygen rich blood to tissues and organs in the body, leading to tissue ischemia
List the steps in the development of Atherosclerosis
1) dysfunction of endothelial cells (EC) leads to migration LDL, resulting in expression of monocyte on the ECs and inflammation
2) monocytes transmigrate intima (penetrating capillaries) and differentiate to macrophages binding to oxidized LDL, which causes the formation of foam cells and cell death
3) inflammation drives smooth muscle cell migration with collagen, forming a fibrous cap
4) plaque accumulation and inflammation thin the fibrous cap, leading to rupture and thrombus formation
Consequences of atherosclerotic plaques
reduced blood flow
blood clot (thrombus) formation
plaque rupture due to instability
plaque may occlude blood flow
ruptured plaque or clot may dislodge and enter circulation (embolism)
What are statins
Most commonly prescribed drugs, being first-line therapy for atherosclerosis and clinical management of the cardiovascular risk
They inhibit HMG-CoA reductase, causing less cholesterol to be available for packaging in the hepatocyte
convert HMG-COA to mevalonate in cholesterol synthesis with HMG-COA reductase
The cellular response is to generate more LDL receptors to scavenge LDL/cholesterol from the bloodstream
end: decreases serum LDL
What type of metabolism do statins undergo in the liver?
First pass. Some are administered as prodrugs, some are administered in their active form
When are short-acting statins taken?
Night, because cholesterol synthesis is highest during sleep
When are long-acting statins taken?
Any time
Simvastatin and lovastatin are examples of what type of statin?
Short acting
Atorvastatin and rosuvastatin are what type of statins?
Long acting
What are the common adverse effects of statins?
GI problems
What are fibrates?
class of drugs that treat high cholesterol
They activate a nuclear receptor called PPAR-alpha, affecting gene expression in lipid metabolism and leading to decreased TG levels, increased HDL cholesterol, and slight decrease in LDL cholesterol
How do fibrates (fenofibrates) work?
Upon activation by ligand binding in the cytoplasm, PPARs migrate to the nucleus where they heterodimerize with the retinoic acid X receptor (RXR)
PPAR-RXR dimers bind to DNA specific sequences called peroxisome proliferator response element (PPRE) of target genes
Once bound to its PPRE, the receptor complex can stimulate or dampen the transcription of key genes of the lipid metabolism
Increased PPAR alpha activity also mitigates atherosclerosis by blocking macrophage foam cell formation
What is the main cholesterol absorption inhibitor?
Ezetimibe. Inhibits intestinal brush border absorption of dietary and biliary cholesterol
Primary target of action is the cholesterol transport system Nieman Pick C1 like protein
Cholesterol pathways
1) excreted by GI tract and skin
2) converted into bile acids and steroid hormones
