Lipid Drugs Flashcards
What are transported in blood within lipoproteins?
Non polar lipids
Give some examples of non polar lipids?
cholesterol esters and triglycerides
What do lipoproteins consist of?
hydrophobic core - containing esterified cholesterol and triglycerides
hydrophilic coat - comprising a monolayer of amphipathic cholesterol, phospholipids and one, or more, apoproteins (apo)
What do HDL particles contain?
apoA1 and apoA2
What do LDL particles contain?
apoB-100
What do Very-low density lipoprotein (VLDL) particles contain?
apoB-100
What do Chylomicrons contain?
apoB-48
What do apoB containing lipoproteins deliver and to where?
triglycerides
- to muscle for ATP biogenesis and adipocytes for storage
Where are Chylomicrons formed and what do they transport?
formed in intestinal cells
transport dietary triglycerides (exogenous pathway)
Where are VLDL particels formed and what do they transport?
formed in liver cells
transport triglycerides synthesised in that organ (endogenous pathway)
Name the 3 main steps of the ApoB-containing liposomes life cycle.
- Assembly
- Intravascular metabolism
- Receptor Mediated clearance
Describe the assembly step of VLDL particles.
VLDL particles containing triglycerides are assembled in liver hepatocytes from free fatty acids derived from
- adipose tissue (particularly during fasting)
- de novo synthesis
Describe the assembly step of Chylomicrons.
In the endoplasmic reticulum in the Enterocyte, triglycerides bind with apoB-48 and undergo lipidation, by the Microsomal triglyceride transfer protein. This then happens again and then the chylomicron leaves, following the addition of a second apoprotein apoA1 and enters lymphatics.
How are Chylomicrons and VLDLs activated?
- transfer of apoCII from HDL proteins
What are Lipoprotein lipase (LPL)?
lipolytic enzyme associated with the endothelium of capillaries in adipose and muscle tissue
What is the intravascular metabolism of ApoB-containing lipoprotiens?
- ApoCII facilitates binding of chylomicrons and VLDL particles to LPL
- LPL hydrolyses core triglycerides to free fatty acids and glycerol which enter tissues
- Particles depleted of triglycerides are now called chylomicron and VLDL remnants
What is the mechanisms of clearance for ApoB-containing lipoproteins?
LPL causes chylomicrons and VLDL particles to become relatively enriched in cholesterol due to triglyceride metabolism
Chylomicrons and VLDL dissociate from LPL
ApoCII is transferred to HDL particles in exchange for apoE which is a high affinity ligand for receptor mediated clearance. Particles are now remnants
Remnants return to the liver and are further metabolised by hepatic lipase
All apoB48-containing remnants and 50% of apo100 containing-remnants are cleared by receptor-mediated endocytosis into hepatocytes
Remaining apoB100-containing remnants loose further triglyceride through hepatic lipase, become smaller and enriched in cholesteryl ester and via intermediate density lipoproteins (IDL) become LDL particles lacking apoE and retaining solely apoB100
What does the clearance of LDL particas depend on?
LDL receptor expressed by the liver and other tissues. Clearance by liver is most important
What does cellular uptake of LDL particles occur by?
via receptor-mediated endocytosis
What does cholesteryl ester release by hydrolysis?
cholesterol
What does released cholesterol cause?
- inhibition of HMG-CoA reductase which is the rate limiting enzyme in de novo cholesterol synthesis
- down regulation of LDL receptor expression
- storage of cholesterol as cholesterol ester
What does an atheromatous plaque consist of?
lipid core - product from dead foam cells
firbous cap - smooth muscle cells and connective tissue
What is the role of HDL cholesterol?
removing excess cholesterol from cells by transporting it in plasma to the liver (reverse cholesterol transport)
Where is HDL formed and as what?
liver
initially as ApoA1 in association with a small amount of surface phospholipid and unesterified cholesterol (pre–HDL)
