Lecture 3: lipoprotein metabolism Flashcards
Why does cholesterol have to be esterfied?
Cholesterol is only minimally soluble in water. In order to be transported in the blood plasma via carriers, a portion must be esterified
What is cholesterol used for?
the cell wall
synthesis of bile acids (for digesting fat)
hormones
metabolism of fat soluble vitamins
Where is the majority of our cholesterol obtained?
Not from the diet, but synthesised from Acetyl CoA through the HMG CoA reductase pathway
What is atheromatus disease?
This underlies the commonest causes of death which are myocardial infarction and disability (stroke) in industrial societies.
It is a focal disease of the large and medium sized arteries and progresses over many decades.
Results in plague build up in the lining of the arteries causing near blockage as the plaque enlarges
What is a healthy artery made up of?
tunica intima (inner endothelial layer) tunica media (smooth muscle and elastic fiber) tunica externa or tunica adventitial (connective tissue and fibroblasts)
what makes up a diseased artery?
an accumulation of white blood cells and cholesterol within the intima and media layers (atheroma or plague)
what are the risk factors of atheromatus disease?
raised LDL reduced HDL hypertension diseases e.g. diabetes cigarette smoking obesity physical inactivity genetics age raised coagulation factors
What are the key events and consequences of atherogenesis?
- compromised endothelial layer
- attraction and filtration of monocytes and LDL
- LDL oxidised
- ox-LDL ingested by monocytes to form macrophage foam cells
- Foam cells release more free radicals and growth factors
- LDL receptors damaged and accumulation of lipids
- Migration of smooth muscle cells
- Formation of extracellular matrix (elastic and collagen)
- occlusion of artery or rupture of plague
- oxygen deficiency or thrombis leading to stroke/MI
What are lipoprotiens?
These are the form of lipids like cholesterol and triglyceride when they are transported in the plasma
What are the 4 classes of lipoproteins?
chylomicrons
very low density lipoproteins
low density lipoproteins
high density lipoproteins
What are chylomicrons?
e.g. ApoB48,E and C2.
These carry cholesterol to the liver
What are VLDLs?
very low density lipoproteins
e.g. ApoB100, E and C2
These carry C from the liver
What are LDLs?
low density lipoproteins
e.g. ApoB100
These carry cholesterol to the tissue and back to the liver
What are HDLs?
high density lipoproteins
e.g. ApoA1
These carry cholesterol from the blood and tissue to the liver
What does an LDL molecule consist of?
Cholesterol ester in the core, surrounded by phospholipids and unesterified cholesterol.
ApolipoproteinB100 (LDL or VLDL) surrounds the outside for easy transport through the plasma
What is the exogenous pathway of cholesterol?
Cholesterol and triglyceride are absorbed from the GIT, transported in the lymph and plasma as chylomicrons to the capillaries in muscle and adipose tissue.
TG is hydrolysed by lipoprotein lipase, and the free fatty acids are taken up by tissues.
The chylomicron remnant containing the CE pass to the liver, bind to receptors on hepatocytes and undergo endocytosis.
CE is liberated in liver cells
What is the endogenous pathway of cholesterol?
CE and TG are transported from the liver as VLDL to the muscle and adipose tissues
TG is hydrolysed by LPL.
the VLDL particles become VLDL remnants, then becoming LDL.
Cells take up LDL by endocytosis via LDL receptors
Cholesterol can also return to the plasma from the tisses in HDL
What is dyslipidemia?
An abnormal ratio of lipoprotein particles.
These can be primary or secondary to some generalised diseases
How is dyslipidemia classified?
according to which lipoprotein is raised
The higher the plasma concentration of LDL, the lower the concentration of HDL cholesterol and therefore the higher the risk of ischaemic heart disease
What are the ideal cholesterol levels as quoted by the NZ heart foundation?
Total cholesterol < 4mmol/L LDL cholesterl < 2.0mmol/L HDL cholesterol > 1mmol/L TC/HDL ratio < 4.0 triglycerides < 1.7mmol/L
What are the main drug classes to prevent atheromatous disease?
statis
fibrates
bile acid binding resins
Who are statins recommended for?
Patients with high LDL and multiple risk factors (5-40mg/day)
What type of drugs are statins?
specific, competitive reversible HMG CoA reductase inhibitors
What are examples of statins?
Lovostatin (naturally occuring) Simvastatin (lipex, double the potency of lovostatin) pravastatin rosuvastatin atorvastatin