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
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2
Q

What are the classes of lipids?

A
  • Fatty acids
  • Cholesterol
  • Triglycerides
  • Phospholipids
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3
Q

What are functions of cholesterol?

A
  • Cell membranes
  • Bile acid synthesis
  • Steroidogenesis: Adrenals & Gonads
  • Vitamin D precursor
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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
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5
Q

What are cholesterol esters?

A
  • Esters are derived from carboxylic acid groups
  • H is replaced by a hydrocarbon group
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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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