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Lipoprotein metabolism - Coggle Diagram
Lipoprotein metabolism
Lipids
organic compounds poorly soluble in water
Important lipids in human physiology
Steroids
Steroid hormones e.g., testosterone
Cholesterol
Phospholipids
Sphingolipids
Triglycerides
In cardiovascular disease cholesterol and triglycerides are very important
Measurement
Enzymatic assays
measure total cholesterol, HDL cholesterol, Triglycerides
LDL cholesterol usually calculated
LDL-C = Total C - (HDL-C + Triglycerides/2.2)
Must be from a fasting sample
Lipoproteins
Main types
Chylomicron
VLDL
IDL
LDL
HLD
Transport cholesterol and triglycerides in the circulation via 2 pathways
Exogenous lipid pathway
Starts in the gut transports dietary lipids
Dietary lipids assembled in the small intestine into Chylomicrons
Chylomicrons = triglyceride rich lipoprotein
Chylomicrons begin with with only ApoB48 and ApoA1
HDL supplies Chylomicrons with ApoC2, C3 and ApoE
Chylomicrons supply HDL with ApoA1 later in the cycle
Lipoprotein lipase (LPL) acts on chylomicrons breaking the triglycerides down into glucose and NEFA (non esterified fatty acids)
Chylomicrons reduce in size from this action until they become chylomicron remnants
Remnants are then readily taken up by the liver
Endogenous lipid pathway
Delivers lipids from the liver
Liver can also excrete cholesterol with bile into the gut which helps with the uptake of dietary lipids
VLDL assembled in the liver, composed of mainly triglycerides
VLDL has 4 apolipoproteins - ApoB100, ApoC2, ApoC3 and ApoE
ApoB100 facilitates secretion of VLDL into the circulation
Secreted into circulation where it is progressively degraded by LPL to form glucose and NEFA
It becomes IDL which is taken up by the liver
ApoB100 and ApoE facilitate this uptake
Its further degraded by HPL to form LDL
LDL is primarily made up of cholesterol with only ApoB100 on its surface
LDL delivers its cholesterol to the peripheral tissues or can take it back to the liver
ApoB100 facilitates this
there is also reverse cholesterol transport from peripheral tissues
HDL is synthesised either in the gut or liver
Has ApoA1 in its shell
Function is to return cholesterol from the peripheral tissues to the liver
HDL picks up cholesterol as it moves through the body and takes it back to the liver
ApoA1 interacts with cell surface receptor on the liver to allow cholesterol deposition by HDL
Sometimes HDL can lose some of its cholesterol to VLDL due to the enzyme CETP
Cholesterol-ester transfer protein
Created within the small intestine and liver
Apolipoproteins
Sit in the shell of different lipoproteins and are key to their behaviour
Measurement
Ultracentrifugation
Measure lipoproteins
Slow and require specialist equipment
immunoassays
Measure apolipoproteins
Plasma lipoprotein/lipid levels
Determined by an interplay of supply, activity of key enzymes and cellular uptake
Lipid driven cardiovascular disease
Atherosclerosis
Chronic damage to the arterial wall, mediated by development of an atheroma
Atheroma = buildup of foam cells covered by fibrous cap
Foam cells = macrophages laden with cholesterol
Hardening / loss of elasticity in the in the artery
Partial blockage of the lumen
Arteries prone to rupture
Progression
Formation of fatty streaks
Atheromatous plaque formation
Plaque rupture
Fibrous cap ruptures causing total lumen obstruction
Results in tissue Ischaemia (myocardial infarction)
Smooth muscle cells stimulated by macrophages to migrate, proliferate and differentiate
The SMCs differentiate into fibroblasts which produce a fibrous collagen cap
Foam cells undergo necrosis and deposit LDL leaving a pool of extracellular cholesterol
This pool is covered with the fibrous cap from the SMCs which forms and atheroma
Begins with damage to arterial wall
LDLs are oxidised by o-free radicals and consumed by macrophages
Macrophages become laden with LDL
Foam cells
Foam cells collect within the arterial wall forming fatty streak
Epidemiological studies show that HDH-C reduced rates of CVD and LDL-C increased them
If any ApoB carrying lipoproteins are not up-taken by the liver, they can be taken into the arterial walls
LDLs are relatively long lived
Uptake of LDL in arterial walls is maximized by:
High concentrations of LDL
Damage to the arterial wall
That can be mechanical or chemical damage
Inherited disorders
Familial hypercholesterolaemia
An autosomal dominant condition
Mutation in the LDL receptor, ApoB or PCSK9
Common condition
Results in high LDL-C levels
Untreated it leads to premature CHD onset
Statin treatment is shown to reduce CVD risk