Pharmacology 5 - Lipid Metabolsim (science only) Flashcards
Are lipids soluble or insoluble in water?
Insoluble (or sparingly soluble)
Purpose of lipids?
Essential for membrane biogenesis and membrane integrityEnergy sources, precursors for hormones and signalling molecules
How are non-polar lipids (e.g. cholesterol esters and triglycerides) transported in blood?
Within lipoproteins e.g. high density lipoproteins, low density liporpteins
In terms of HDL and LDL, what is CV disease strongly associated with?
Elevated LDLDecreased HDL
What causes elevated LDL and decreased HDL?
Diet and lifestyle (particularly western)Genetic factors (e.g. familial hypercholestrerolaemia)
What are the 2 parts of a lipoprotein?
Hydrophobic coreHydrophilic coat
What is found within the hydrophobic core of a lipoprotein?
Esterified cholesterol and triglycerides
What is the hydrophilic coat of a lipoprotein composed of?
Monolayer of amphipathic cholesterol, phospholipids and one, or more, apoproteins (apo)
What are the major lipoproteins? (4)
HDL particlesLDL particlesVery-low density lipoprotein particlesChylomicrons
What apoproteins do HDL proteins contain? (2)
apoA1 and apoA2
What apoprotein does LDL particles contain?
apoB-100
What apoprotein does very-low density lipoprotein particles contain?
apB-100
What apoprotein does chylomicrons contain?
apoB-48
What is the purpose of apoB-containing lipoproteins?
Deliver triglycerides to muscle for ATP biogenesis and adipocytes for storage
Where are chylomicrons formed?What do they carry?What is this pathway called?
In intestinal cellsTransport dietary triglyceridesExogenous pathway
Where are VLDL formed?What do they carry?What is this pathway called?
Liver cellsTriglycerides synthesised in that organEndogenous pathway
What are the 3 stages of the life cycle of an ApoB-containing liposome?
AssemblyIntravascualr metabolismReceptor mediated clearance
Where does the majority of the bodies cholesterol come from?
75% = liver25% = diet
What happens to an chylomicron formed within the endoplasmic reticulum of an enterocyte?
It exits the enterocyte by exocytosis following the addition of a second apoprotein (apoA1), enters lymphatics and is carried in lymph to systemic circulation (subclavian vein) via the thoracic duct
What are VLDL particles containing triglycerides assembled in the liver hepatocytes from?
Free fatty acids derived from adipose tissue (particularly during fasting) and de novo synthesis
What must happen to activate chylomicrons and VLDL particles allowing them to target triclyceride delivery to adipose and muscle tissue?
They must be activated by by the transfer of apoCII from HDL particles
What is the name of the enzyme that is associated with the endothelium of capillaries in adipose and muscle tissue?
Lipoprotein lipase (lipolytic enzyme)
What facilitates the binding of chylomicrons and VLDL to LPL on the endothelium of capillaries in adipose and muscle tissue?
ApoCII
What does lipoprotein lipase do?
Hydrolyses core triglycerdies to free fatty acids and glycerol which enter tissues
What is name of particles depleted of triglycerides (But still containing cholesterol esters)?
Chylomicron and VLDL remnants
Why do chylomicrons and VLDL particles become relatively enriched in cholesterol?
Due to triglyceride metabolism due to LPL
What happens to ApoCII when the chylomicrons and VLDL dissociated from LPL?
It is transferred to HDL particles in exchange for apoE which is high affinity ligand for receptors mediated clearance - particles are now remnants
What happens to remnants?
They 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, come smaller and enriched in cholesterol ester and via intermediate density lipoproteins (IDL) become LDL particles asking ape and retaining solely apoB100
What is the most important place of LDL particle clearance?
the liver
Where is the most important site of LDL clearance?
Liver
What does cellular uptake of LDL occur by?
Receptor mediated endocytosis
How is cholesterol released once within the liver at the lysosome?
By hydrolysis
What does release of cholesterol within the liver cause?
Inhibition of HMG-CoA reductase (rate limiting enzyme in de novo cholesterol synthesis)Down regulation of LDL receptor expressionStorage of cholesterol as cholesterol ester
How does an atheromatous plaque form?
Uptake of LDL from the blood into the intima of the arteryLDL subsequently oxidised to atherogenic oxidised LDLMigration of monocytes across the endothelium into the intimate where they become macrophagesUptake of oxidised LDL by macrophages converts them to cholesterol laden foam cells that form a fatty streakRelease of inflammatory substances from various cell types causes division and proliferation of smooth muscle cells into the intimate and the deposition of collagenThe formation of an atheromatous plaque consisting of a lipid core (product of dead foam cells) and a fibrous cap (smooth muscle cells and connective tissue)
What is the only place in the body that has the capacity to eliminate cholesterol from the body?
Liver
Why are HDLs good?
They have a key role in removing excess cholesterol from cells by transporting it in plasma to the liver - only the liver has the ability to eliminate cholesterol
Where is HDL mainly formed?
In the liver
What is the name for the initial structure of HDL when formed in the liver?
pre-betaHDL
What is the structure of pre-BetaHDL?
ApoA1 in association with a small amount of surface phospholipid and unesterified choelsterol
What does pre-betaHDL mature to?
Alpha-HDL
Where does disc-like pre-beta-HDL mature to spherical alpha-HDL?
In the liver
What happens when pre-betaHDL matures to alpha-HDL?
Surface cholesterol is enzymatically converted to hydrophobic cholesterol ester that migrates to the core of the particle
What is reverse cholesterol transport?
Mature HDL accepts excess cholesterol from the plasma membrane of cells and delivers cholesterol to the liver
What receptor does HDL interact with at the liver?
Scavenger receptor-B1 (allows the transfer of cholesterol and cholesteryl esters into hepatocytes)
What mediates transfer of cholesterol esters from HDL to VLDL and LDL in the plasma?
Cholesterol ester transfer protein (indirectly return cholesterol to the liver)
What is primary dyslipidaemia?
That which occurs through a combination of diet and genetic factors
What is secondary dylipidaemia?
A consequence of another rids ease e.g. type II diabetes, hypothyroidism, alcoholism, liver disease
