Lipids Lecture 11 Flashcards
Describe lipid transport
Via lipoproteins
Non-polar core of cholesterol esters and/or triglycerides
Polar coat of apoproteins
Chylomicrons, VLDL, LDL, HDL
Can be transported endogenously or exogenously
Describe atherosclerosis and how does it form
Atheromas in large and medium arteries AND underlies the commonest cause of death
Evolves over decades in the walls of arteries:
- Endothelial dysfunction causes decrease NO
- Injury causes expression of adhesion molecules (monocytes)
- LDLs accumulate and are oxidised by monocytes/macrophages
- These are taken up by macrophages to become foam cells
- Foam cells and lymphocytes cause fatty streaks
- Macrophages release cytokines and GFs
- Proliferation of smooth muscle causes fibrous cap overlying lipid core
- Plaque can rupture leading to thrombosis
Describe the exogenous lipid pathway
Lipid emulsified by bile acids in the GIT
Absorbed in chylomicrons (more triglycerides than cholesterol esters)
-Upon reaching fat/muscle tissue chylomicrons attach to walls in blood vessel through apoproteins.
Triglycerides hydrolysed into free fatty acid stored in tissue by lipoprotein lipase associated with the endothelial cells in the liver
The chylomicron remnants (more cholesterol esters than triglycerides) go to liver and are recycled as bile acids
Describe the endogenous lipid pathway
1. Liver
- Synthesis of Cholesterol (C) + Triglyceride (TG) + Chorlestrol from exogenous pathway
- VLDLs are then secreted (C-ester and TG)
- TG is then removed leaving behind LDL (low density lipoproteins - only contain cholestrol)
2. Extrahepatic
Reverse cholesterol transport:
- Cholesterol from dying cells gets converted to HDL
- HDLs are good at taking away Cholestrol forming in plaques
- THe Cholestrol is then transferred to LDL from HDL by CETP which is taken to the liver
INcreased HDL promotes LDL removal
Describe LDLs
60-70% of circulating cholesterol- used in membranes, steroids and bile acids
Normal lipid- C= below 5mmol
Abnormal lipid levels (dyslipidaemia), increased LDL or decreased HDLs
Describe hyperlipidaemia
Primary (genetic)
- 6 phenotypes which differ in lipoprotein class affected (IIa is increased LDL and IIb is increased LDL and VLDL)
- Risk of atherosclerosis is increased
- LDL contains apoprotein similar to plasminogen, so competes for receptors -> decreased plasmin which can cause thrombosis - due to less able to break down fibrin and greater chance of clots to form
Secondary (Metabolic disorders)
- Diabetes
- Hypothyroidism
- Alcoholism
Describe the use of HMG CoA reductase inhibitors
Statins (atorvastatin, pravastatin)
- Potent competitive inhibitors (i.e. decreased cholesterol synthesis in liver)
- Decreased C -> increased transcription of gene for the enzyme and receptor
Leads to:
- Increased synthesis of cholesterol (partial)
- Increased LDL receptors
- Therefore decreased plasma cholesterol and decreased chance ofheart disease
Se- myositis, hepatitis, contraindicated in pregnancy (germ cell migration)
Describe the use of fibrates
Activate nuclear receptors to cause increased transcription
-Increased lipoprotein lipase and decreased VLDL production
=> Decreased TGs by 50%
-Increased liver uptake of LDL via increased receptors for apoproteins and increases HDL
Uses:
- Increased TGs - statin first choice
- Decreased heart disease
SE- myostitis
Describe the use of bile acid-binding resins
Bile acids:
- Essential for C absorption
- Reabsorbed
Normally the lipids are absorbed but resins bind and are not reabsorbed so:
- Lose C and bile acids
- Increased synthesis of bile acids
=> Increased LDL receptors
=> Decreased LDL levels and heart disease
Not first line - combined with a statin
Unpleasant GI side effects
Describe the use of ezetimibe
Inhibits intestinal absorption of cholesterol by blocking transport protein NPC1L1
But no evidence of decrease atherosclerosis
No effect on the absorption of fat soluble vitamins and have a much higher potentcy than resins
Describe PCSK9 inhibitors
eg Alirocumab
PCSK9 = proprotein convertase subtilisin kexin type 9
PCSK9 binds to LDL-receptors on hepatocytes - promotes their degredation and prevent their recylcing
Inhibitor increases LDL receptors and increased removal of LDLs - administered every 2 weeks
People with inactivated PCSK9 = low LDL and low cardiovascualr risk
Describe the use of nicotinic acid
Decreases TG synthesis, VLDL and LDL
Increases HDL
Combined with stations (+-resins)
SE- Common- flush and pruritis duer to prostaglandins and GI upset and jaundice in high doses
Describe the use of fish oil in hyperlipidaemia
Omega-3 triglycerides
Improve survival after myocardial infarction
Decreases TG(not relevant) and Increases Cholesrerol so not used in type 2a
Maybe decreases clotting by altering the structure of eicosanoids - control cardiovascular properties such as clotting
(thromboxane, leukotrienes- less active forms, prostaglandins- more active)
Outline the prescribing guidelines for hyperlipidaemia
Primary prevention- to stop heart attack/stroke
Statins in diabetics >40yr old, can combine with ezetimibe or PCSK9 inhibitors
Secondary prevention- stations or fibrates/resins, Nicotinic acid
