Pharmacology 4 - Lipid Metabolism and Cardiovascular Disease Flashcards
How are non-polar lipids transported in the blood?
As cholesterol esters or triglycerides within lipoproteins
These lipoproteins can be:
- High density lipoprotein (HDL)
- Low density lipoprotein (LDL)
In regards to both HDL and LDL, what is cardiovascular disease (atherosclerosis) associated with?
Elevated LDL
Decreased HDL
In general terms, what does the statin class of drugs do?
Increases the ration of HDL to LDL
What are the two main causes of a low HDL to LDL ratio?
- Diet and lifestyle
- Genetic factors
What are lipoproteins?
Spherical particles with a hydrophobic core and hydrophilic coat formed by a monolayer of amphipathic molecules such as cholesterol, phospholipids and apolipoprotein
What is the role of apolipoprotein in a lipoprotein?
To stabilise the outer shell and act as a molecular address by mapping certain lipoproteins to certain body regions
What are the major lipoproteins? (4)
- HDL - contains apoA1 and apoA2
- LDL - contains apoB-100
- Very low density lipoprotein (VLDL) - contains apoB-100
- Chylomicrons - contains apoB-48
What is the purpose of apo-B containing lipoproteins?
Deliver triglycerides to muscle or fat tissue to be broken down for energy (muscle) or storage by forming adipose tissue from triglycerides (adipocytes)
Which cells produce chylomicrons?
Enterocytes (intestinal cells)
Chylomicrons are important for what, and since their triglyceride originates from outside the body this is what type of pathway?
Important for transporting dietary triglycerides to muscle
This is an exogenous pathway
Where are VLDLs produced?
Liver
What is the purpose of VLDL, and which type of pathway does it involve regarding triglycerides?
They are formed in liver cells and transport triglycerides synthesised there around the body
This is the endogenous pathway (triglycerides originate from within the body)
Describe the three steps of apoB containing liposomes
- Assembly - incorporation with apoB100 (liver) or apoB48 (intestine)
- Intravascular metabolism - lipoprotein lipase attacks the triglyceride component generating 3 fatty acids which can be taken up into fat or muscle cells
- Receptor mediated clearance
What are triglycerides broken down into when they pass through the enterocyte wall of the intestine?
Broken down to monoglyceride and 3 fatty acids
This is because trigllycerides cannot pass through the epithelium otherwise
What happens after the components of a triglyceride has passed across the membrane of the enterocyte?
The triglyceride is resynthesised
How does cholesterol pass across the enterocyte membrane?
Specific transport protein
Nienmann-Pick-C1-like 1 protein (NPC1L1)
Where does cholesterol mostly come from?
Liver (75%)
Diet (25%)
What happens to the cholesterol when it enters enterocytes?
It is esterified
When many triglycerides enter the cytoplasm of the enterocte, what happens next?
The triglyceride core is coated with apoB48 by ribosomes
Microsomal triglyceride transfer protein aids the addition of more triglycerides which form droplets called chylomicrons
At which point is a mature chylomicron formed in the enterocyte?
When both triglyceride and cholesterol ester have been added
What happens to a mature chylomicron when apoA1 is added in the enterocyte?
Exocytosis occurs and the chylomicrons exit the cell via the lymphatic system
They enter the central lacteal in the intestinal villus which allows them to be carried to the subclavian veins where they can enter the systemic circulation
What are VLDL particles formed and what from?
Liver from triglycerides
From which two sources can triglycerides come from?
- Breakdown of adipose tissue
- De nove synthesis in the liver
Before chylomicrons and VLDL particles can offload triglyceride and cholesterol, what must happen?
They must become activated
This involves apoCII, from HDL, being incorporated into the shell of LDL and chylomicrons
ApoCII facilitates binding between chylomicrons and VLDL to lipoprotein lipase which allows hydrolysis to occur
What happens to the ratio of cholesterol to triglyceride content as hydrolysis of the lipoprotein occurs?
It increases
Triglyceride is hydrolysed, by cholesterol concentration stays the same
After the triglycerides are all “used up” after hydrolysis, what are the remaining structures of chylomicrons and VLDLs called?
Chylomicron and VLDL remnants
At which point does lipoprotein lipase dissociate from either VLDL or chylomicrons?
When the cholesterol concentration becomes very high in comparison to the triglceride content
When lipoprotein lipase dissociates from VLDL or chylomicrons, what happens to apoCII?
It returns to HDL
After apoCII returns to HDL from chylomicrons and VLDLs what is it replaced with and why?
ApoE
This acts as a high affinity ligand for receptos in the liver which faciliates clearance of the remnants
What happens to chylomicrons and VLDL remnants in the liver?
They are further metabolised in the liver by hepatic lipase to remove any additional triglycerides
All apoB48 containing remnants and half of apoB100 remnants are cleared by receptor-mediated endocytosis in the liver
What is the ultimate fate of the remaining apoB100 containing remnants that lose more triglyceride by hepatic lipase?
Their size decreases until they are more enriched in cholesteryl ester
Via intermediate density lipoprotein they become LDL lacking apoE and retaining only apoB100
The LDL receptor on liver cells receognised apoB100 and this allows for LDL engulfment
Inside the cell, at the lysosome, cholesterol is released from the pore generating 3 cholesterol and triggering the LDL receptor to re-enter the membrane
When cholesterol is produced inside the cell after the breakdown of LDL, what will the release of this cholesterol do? (3)
- Inhibition of HMG-CoA reductase
- Down regulation of LDL receptor expression - increases cytoplasmic LDL concentration
- Storage of cholesterol as cholesterol ester
Which enzyme is the target for the statin group of drugs?
HMG-CoA reductase
(statins can treat dyslipidaemia)
Which is the “good” and which is the “bad” cholesterol?
Good - HDL
Bad - LDL
What causes atherosclerosis in arteries?
Damage to the endothelial wall by high blood pressure, diabetes, smoking etc.
Describe the process of atherosclerosis and the role of LDL
- Endothelial wall damaged
- LDL is taken up into injury site
- LDL is oxidised to form OXLDL
- Monocytes migrate to injury site and becom macrophages
- Macrophages absorb OXLDL and convert to foam cells filled with cholesterol
- Foam cells form the fatty streak on arteries which is the first step in atheromatous deposits
- Inflammatory substances from various cell types causes division of smooth muscle cells and deposition of collagen
- An atheromatous plaque has been formed (lipid core - dead foam cells, fibrous cap - smooth muscle cells and connective tissues)
What is the main role of HDL?
It can transport excess cholesterol back to the liver
What does the liver do with excess cholesterol?
Uses it to synthesise bile acid and bile salts
Where is HDL mainly synthesised?
Liver
Initially as apoA1 in association with a small amount of surface phospholipid and unesterified cholesterol
These are early HDL structures known as pre-beta-HDL
Where are pre-beta-HDL allowed to mature into HDL?
Plasma
Surface cholesterol is enzymatically converted to hydrophobic cholesterol ester which migrates to the centre of particles allowing more cholesterol to bind
This process continues and acts like a cholesterol magnet
From which cells does HDL accept cholesterol from?
Macrophages
(and other cell types)
How is cholesterol and cholesterol ester delivered into the liver?
HDL particles react with scavenger receptors (SR-B1) which allows cholesterol and cholestrol ester transplant to hepatocytes
In the plasma, what is the what is the role of cholesterol ester transfer protein (CETP)?
To mediate transfer of cholesterol esters from HDL to VLDL and LDL which indirectly returns cholesterol to the liver
What causes primary dyslipidaemia?
A combination of diet and genetic factors
What is secondary dyslipidaemia a consequence of?
Other diseases such as type II diabetes, hypothyroidism, alcoholism and liver disease
If LDL is elevated, what is the treatment?
Statin and ezetimibe (blocks NPC1L1 receptor)
If both LDL and VLDL are elevated, what is the treatment?
Fibrate, statin and nicotinic acid
What is the treatent when any type of VLDL is elevated?
Fibrates
What is the treatment when chylomicrons are elevated?
No treatment
What is the treatment when both chylomicrons and VLDL are elevated?
Fibrate, niacin, fish oil and statin
What can statins achieve as a treatment? (3)
- Reduce cholesterol and LDL
- Decrease triglycerides
- Increase HDL
Give two example of statins
- Simvastatin
- Atorvastatin
How do statins function?
They are competitive inhibitors of HMG-CoA reductase preventing conversion of HMG-CoA to mevalonate
This means that there is a decrease in hepatocyte cholesterol synthesis
This leads to a compensatory incraese in LDL receptor expression of hepatocyte surfaces aiding LDL clearance
Which condition proves the proposed method that statins work by?
Homozygous familial hyperholesterolaemia
This is a disease where LDL receptors are lacking meaning LDL receptor expression cannot be increased and hence LDL levels cannot be lowered
When are statin administered and why?
Orally at night
To ensure they are working by morning when cholesterol synthesis is at its highest
What are the two main downsides to statins?
- Myositis - inflammation of skeletal muscle
- Rhabdomyolysis - breakdown of skeletal muscle
When may the incidence of the side effects of statins be increased?
When the statin is prescribed with a fibrate
What 3 main things can fibrates achieve?
- Decrease triglycerides
- Decrease LDL
- Increase HDL
Give two examples of fibrates
- Bezafibrate
- Gemfibrozil
What are the first line drugs for patients with high triglycerides?
Fibrates
What are the first line drugs for patients with low HDL to LDL ratios?
Statins
How do fibrates function?
- Act as agonists of PPARα found in a cell nucleus
- This increases gene transcription of genes including one that increases lipoprotein lipase activity
- By enhancing the activity, triglycerides are broken down more into glyceral and 3 fatty acids reducing plasma triglyceride levels
What are the side effects of fibrates?
- Myositis - avoid with statins or both have combined effect
- GI symptoms
- Pruritis - itching
- Rash
- Avoid for alcoholics who are predisposed to hypertriglyceridaemias and also rhabdomyolosis
Why will drugs that inhibit cholesterol absorption almost certain have reduced effect compared with other drugs?
Only 25% of cholesterol is taken in through diet
Which drug class can prevent cholesterol absorption and give examples?
Bile acid resins
- Colestyramine
- Colestipol
- Colsevelam
Where are bile acids stored and when do they emerge?
Gallbladder
Emerge into duodenum (via major duodenal papillar (ampulla of Vater)) during a meal and assist fat digestion
What is a good way to reduce intrahepatic concentration of cholesterol?
Bile salt synthesis
Where are bile salts reabsorbed and where are they returned to?
Terminal part of the ileum
Redirected to liver
What can any of the aforementioned drugs do to the bile salt and prevent it from doing?
The drugs can prevent the reabsorption of the bile salt and ansure active bile salt excretion occurs
To compensate for active bile salt excretion from drug action, what will the body do?
The liver synthesises replacemnet bile salts using up cholesterol
How does reducing cholesterol via active bile salt excretion affect triglyceride levels?
Absorption of triglycerides decreases
What happens when hepatocyte cholesterol levels decrease?
There is increased expression of HDL receptors on the plasma membrane of the hepatocytes facilitating clearnace of remnants from the plasma
How does ezetimide function?
A competitive inhibitor of Niemann-Pick C1 like-1 (NPC1L1) transport proteins in enterocytes of the duodenum
This normally absorbs cholesterol, but now no longer can
This decreases LDL
Usually it is used as a second line treatment with stains when statins alone do not achieve the desired response
What are the adverse effects of ezetimide?
- Diarrhoea
- Abdominal pain
- Headache
Why is ezetimide contraindicated in breastfeeding females?
As well as statins, ezetimide is contraindicated in breastfeeding females as neonates require cholesterol for normal development
