Lipoprotein Metabolism Flashcards
1
Q
What are lipids?
A
- Virtually insoluble in water
- It includes oils and fats
- Circulating lipid is carried in lipoproteins
- Transport lipid to various tissues for energy, steroid hormone production and bile acid formation
2
Q
What are the classes of lipids?
A
- Fatty acids
- Cholesterol
- Triglycerides
- Phospholipids
3
Q
What are functions of cholesterol?
A
- Cell membranes
- Bile acid synthesis
- Steroidogenesis: Adrenals & Gonads
- Vitamin D precursor
4
Q
How is Cholesterol made?
A
- Most cholesterol is made from de novo synthesis from acetate in the liver
- Rate limiting step is controlled by HMG-CoA reductase
5
Q
What are cholesterol esters?
A
- Esters are derived from carboxylic acid groups
- H is replaced by a hydrocarbon group
6
Q
What are triglycerides?
A
- Triglycerides present in dietary fat and can be synthesised in liver and adipose tissue to provide a source of energy
- Formed by esterification of glycerol with 3 long chain fatty acids
- Need to be transported from sites of synthesis & absorption to sites of utilisation.
- Energy store – adipose tissue (15kg)-approx 3m survival
7
Q
What are Phospholipids?
A
- Fatty acyl group esterified to an alcohol
- Phosphate group linked to alcohol and another organic compound
- Essential component of cell membranes
- Glycerolipids e.g. lecithin
- Sphingolipids e.g. sphingomyelin
8
Q
What are lipoproteins?
A
- Lipids insoluble in water therefore transported associated with proteins
- Core contains fat and cholesterol. Lipid membrane that contains proteins called apolipoproteins
- Cholesterol ester is a protective form for storage in cells and transportation
- Unesterified (free) cholesterol is biologically active and has cytotoxic effects
9
Q
What is the principal carrier of free fatty acids?
A
- Albumin is the principal carrier of free fatty acids; other lipids circulate in complexes called cholesteryl esters
- Non polar core of trigs and Ces surrounded by a surface layer of phospholipids, cholesterol and apolipoproteins – involved both in structure and metabolism of lipoproteins
10
Q
What are apolipoproteins?
A
Amphipathic molecules capable of interacting with lipids of the lipoprotein core and the aqueous environment of the plasma
3 main functions:
- Structural
- Ligand for receptors
- Enzyme cofactors
11
Q
What are major classes of lipoproteins?
A
- Chylomicrons: Very large particles carrying dietary lipid
- Very low density lipoproteins (VLDL): Carry endogenous triglycerides and to a lesser degree cholesterol
- Intermediate density lipoproteins (IDL): Carry cholesterol esters and triglycerides
- Low density lipoproteins (LDL): Carry cholesterol esters
- High density lipoproteins (HDL): Carry cholesterol esters
12
Q
How are the Lipoproteins classified?
A
- Classified by their densities as demonstrated by ultrcentrifugation
- Metabolically distinct HDL2 and HDL3 based on density
- IDL only present in blood in very small amounts but can accumulate when pathological disturbance of liver metabolism
- Dynamic state of continuous exchange
13
Q
What is the process of the exogenous pathway?
A
- After meals enterocytes absorb free cholesterol, fatty acids and monoglycerides
- ApoB48 synthesised in enterocyte and following re-esterification, cholesteryl esters and triglycerides are incorporated into cores of chylomicron particles with ApoB48.
- ApoB48 is essential for chylomicron secretion, one molecule per chylomicron and remains with chylomicron for lifespan of particle. Multiple copies of other apolipoproteins (C-II, C-III and E) are obtained from HDL and undergo constant modification.
- Chylomicrons major transport form of exogenous (dietary) fat
- Enter lymphatics and reach the systemic circulation via the thoracic duct and into the subclavian
- Apo C-II allows interaction of chylomicron with Lipoprotein lipase (LPL) in the vascular endothelium which acts extracellularly to hydrolyse triglycerides in the chylomicron core which decreases in size
- Continuing loss of Apo C-II eventually prevents interaction with LPL and chylomicron remnant particles are created containing cholesteryl esters, Apo B48 and Apo E
- Remnant particles taken up by the liver
14
Q
How are Lipoproteins metabolised?
A
- Divided into endogenous and exogenous pathways
- Exogenous pathway starts with intestinal absorption of dietary cholesterol and fatty acids
- Mechanisms regulating the amount of dietary cholesterol absorbed are unknown
15
Q
How are Triglyceride removed from chylomicrons?
A
- Triglycerides are removed from chylomicrons by the action of lipoprotein lipase found on the luminal surface of the capillary endothleium of adipose tissue, skeletal and cardiac muscle.
- Result in FFAs being delivered to cells for energy substrate or storage.
- Activated by ApoCII.
- Removal of trigs makes Chylomicrons become smaller – cholesterol, phospholipids, apoA and ApoCII are released from surface of particles and taken up by HDL
- Esterified cholesterol is transferred to chylomicron remnants from HDL in exchange for trigs by cholesterylester transfer protein
16
Q
How are Chylomicrons cleared?
A
- Chylomicron remnants enter the space of Disse in the liver through fenestrated sinusoidal endothelium
- Rich in Heparan Sulphate proteoglycans (HSPGs), hepatic lipase (HL) and ApoE
- Proteoglycans and Apo E bind the remnant particles and more triglycerides are removed through the action of HL and LPL
- Remnants taken up in the process via HSPGs or via ApoEbinding to LDL receptor related protein (LRP)
- Cholesteryl esters from the chylomicron remnant particles may be used in the synthesis of bile acids or be secreted in VLDL
17
Q
What is the endogenous pathway?
A
- Liver secretes VLDL, a triglyceride rich particle containing Apo B100, with triglycerides either produced de novo by hepatocytes, or taken up from the plasma. Other apolipoproteins (C-I, C-II, C-III and E) are obtained from HDL in the circulation
- Apo C-II is required for interaction with LPL which causes hydrolysis of triglycerides
- Remnant particle produced which is enriched in Apo E are taken up by the liver by LRP which recognises Apo E
- Remnant particles not cleared by the liver undergo further hydrolysis by Hepatic Lipase to form LDL
- LDL is the main cholesterol carrying lipoprotein (accounts for >70% total plasma cholesterol). Contains single molecule of Apo B100 which is ligand for LDL receptor which are which are found in the liver and peripheral tissue
18
Q
What is the LDL receptor?
A
- LDL receptor recognises Apo B100 (LDL particles) and ApoE (chylomicron and VLDL remnants)
- Mediate endocytosis of cholesterol rich LDL in the liver and peripheral tissues
- Follwoing internalisation, the receptor dissociates from ligand and recycles back to cell surface receptor
- Rapid recycling provides an effiecient mechanism of cholesterol delivery to tissues
19
Q
How can macrophages take up LDL/
A
Scavenger receptors
- This occurs to some extent at normal LDL concentrations but enhanced when LDL concentrations are increased and by modification (e.g. oxidation) of LDL
- Important in the pathogenesis of atherosclerosis
20
Q
What is Lipoprotein Lipase?
A
- Extracellular enzyme bound to HSPG on the endothelium
- High concentration in capillaries of adipose tissue and muscle
- Catalyses partial hydrolysis of core TGs of chylomicrons and VLDL to monoglycerides and fatty acids
- Fatty acids are taken up by the tissue and either re-esterified and stored, or utilised as energy
- Regulates plasma concentration of TGs and HDL
21
Q
How is HDL formed?
A
- Nascent HDL (disc-shaped) synthesised in liver & intestine – bilayer of PLs, apoAI & apoAII
- It acquires free cholesterol from tissues – facilitated by ABC-A1
- It acquires free cholesterol from lipoprotein remnants
- It is then Converted to mature (spherical) HDL -esterification of cholesterol by lecithin-cholesterol acyl transferase (LCAT)
22
Q
What is Lipoprotein A?
A
- Has unknown function
- Larger and more dense than LDL but similar composition
- Like LDL contains Apo B100
- Contains apo (a) - contains part of plasminogen protein sequence (kringle 4 domain), repeated many times
- Retained in arterial wall longer than LDL and may interfere in thrombolysis
- Increased Lipoprotein (a) appears to be an independent risk factor for coronary heart disease
23
Q
What is SRB1?
A
- Scavenger Receptor B1 which functions as a receptor for HDL
- Highly expresssed in the liver and therefore facilitates the uptake of cholesterol esters from HDL into the Liver
24
Q
How is Cholesterol tested in the lab?
A
- Can measure Total cholesterol, HDL and TGs
- LDL is calculated using the formula (all in mmol/L):
LDL CHOL=TOTAL CHOL−(HDL CHOL+TRIG/2.2)
- Invalid if TG >4.5 mmol/L
- Ultracentrifugation or electrophoresis can be used to separate lipoprotein particles
- Apolipoproteins can be measured in the investigation of primary hyperlipidaemias
25
Q
What is Reverse Cholesterol Transport?
A
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